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Bertulfo K, Perez-Duran P, Miller H, Ma C, Ambesi-Impiombato A, Samon J, Mackey A, Lin WHW, Ferrando AA, Palomero T. Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2025; 122:e2426742122. [PMID: 40163723 PMCID: PMC12002235 DOI: 10.1073/pnas.2426742122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 01/30/2025] [Indexed: 04/02/2025] Open
Abstract
Gamma Secretase Inhibitors (GSIs) effectively block oncogenic Notch homolog-1 (NOTCH1), a characteristic feature of T cell acute lymphoblastic leukemias (T-ALL). However, their clinical application has been stalled by the induction of severe gastrointestinal toxicity resulting from the inhibition of NOTCH signaling in the gut, which translates into increased goblet cell differentiation. Genome-wide CRISPR loss-of-function screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924, rescued GSI-induced differentiation in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1, a direct NOTCH1 transcriptional target and key regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in a murine Notch1-dependent model of T-ALL led to leukemia regression and improved overall survival in the absence of gut toxicity. Overall, these results support the combined targeting of the NOTCH1 and neddylation pathways for the treatment of NOTCH1-induced T-ALL.
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Affiliation(s)
- Kalay Bertulfo
- Institute for Cancer Genetics, Columbia University, New York, NY10032
- Department of Biological Sciences, Columbia University, New York, NY10027
| | - Pablo Perez-Duran
- Institute for Cancer Genetics, Columbia University, New York, NY10032
| | - Hannah Miller
- Institute for Cancer Genetics, Columbia University, New York, NY10032
| | - Cindy Ma
- Institute for Cancer Genetics, Columbia University, New York, NY10032
| | | | - Jeremy Samon
- Institute for Cancer Genetics, Columbia University, New York, NY10032
| | - Adam Mackey
- Institute for Cancer Genetics, Columbia University, New York, NY10032
| | - Wen-Hsuan Wendy Lin
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032
| | - Adolfo A. Ferrando
- Institute for Cancer Genetics, Columbia University, New York, NY10032
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032
- Department of Pediatrics, Columbia University Medical Center, New York, NY10032
| | - Teresa Palomero
- Institute for Cancer Genetics, Columbia University, New York, NY10032
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032
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Nakamura K, Baba R, Kokubu K, Harada M, Morimoto H. Alterations in Ileal Secretory Cells of The DSS-Induced Colitis Model Mice. Acta Histochem Cytochem 2024; 57:199-209. [PMID: 39776935 PMCID: PMC11703563 DOI: 10.1267/ahc.24-00049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/18/2024] [Indexed: 01/11/2025] Open
Abstract
Inflammatory bowel disease is triggered by abnormalities in epithelial barrier function and immunological responses, although its pathogenesis is poorly understood. The dextran sodium sulphate (DSS)-induced colitis model has been used to examine inflammation in the colon. Damage to mucosa primality occurs in the large intestine and scarcely in the small intestine. To evaluate the effect on the ileum, we histologically analyzed the inflammatory and recovery phases in DSS model mice, and 40 kDa FITC-dextran was used to investigate barrier function. In the inflammatory phase, histological damage was insignificant. However, expanded crypts, hypertrophic goblet and Paneth cells, increased mucus production and secretion were observed. The cellular morphology was restored to that of the control in the recovery phase. According to in situ hybridization and lectin histochemistry, the expression of intestinal stem cell markers, secretory cell differentiation factors, and glycosylation of secretory granules in Paneth cells differed in the DSS model. DSS-treatment did not influence the barrier function in the ileum, and FITC-dextran did not diffuse via the paracellular pathway into the mucosa. However, cells incorporating FITC appeared even under normal conditions. The number of FITC-positive Paneth cells was lower in the DSS group than the control group. Our results showed morphological and functional alterations in ileal epithelial cells, especially secretory cells, in the DSS colitis model.
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Affiliation(s)
- Kenta Nakamura
- Third Department of Internal Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
| | - Ryoko Baba
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
| | - Keiji Kokubu
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
| | - Hiroyuki Morimoto
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1–1, Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka 807–8555, Japan
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3
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Liu X, Li D, Gao W, Liu H, Chen P, Zhao Y, Zhao W, Dong G. Shared genetic architecture between COVID-19 and irritable bowel syndrome: a large-scale genome-wide cross-trait analysis. Front Immunol 2024; 15:1442693. [PMID: 39620219 PMCID: PMC11604633 DOI: 10.3389/fimmu.2024.1442693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 10/30/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND It has been reported that COVID-19 patients have an increased risk of developing IBS; however, the underlying genetic mechanisms of these associations remain largely unknown. The aim of this study was to investigate potential shared SNPs, genes, proteins, and biological pathways between COVID-19 and IBS by assessing pairwise genetic correlations and cross-trait genetic analysis. MATERIALS AND METHODS We assessed the genetic correlation between three COVID-19 phenotypes and IBS using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Two different sources of IBS data were combined using METAL, and the Multi-trait analysis of GWAS (MTAG) method was applied for multi-trait analysis to enhance statistical robustness and discover new genetic associations. Independent risk loci were examined using genome-wide complex trait analysis (GCTA)-conditional and joint analysis (COJO), multi-marker analysis of genomic annotation (MAGMA), and functional mapping and annotation (FUMA), integrating various QTL information and methods to further identify risk genes and proteins. Gene set variation analysis (GSVA) was employed to compute pleiotropic gene scores, and combined with immune infiltration algorithms, IBS patients were categorized into high and low immune infiltration groups. RESULTS We found a positive genetic correlation between COVID-19 infection, COVID-19 hospitalization, and IBS. Subsequent multi-trait analysis identified nine significantly associated genomic loci. Among these, eight genetic variants were closely related to the comorbidity of IBS and COVID-19. The study also highlighted four genes and 231 proteins associated with the susceptibility to IBS identified through various analytical strategies and a stratification approach for IBS risk populations. CONCLUSIONS Our study reveals a shared genetic architecture between these two diseases, providing new insights into potential biological mechanisms and laying the groundwork for more effective interventions.
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Affiliation(s)
- Xianqiang Liu
- Medical School of Chinese PLA, Beijing, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Dingchang Li
- Medical School of Chinese PLA, Beijing, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wenxing Gao
- Medical School of Chinese PLA, Beijing, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hao Liu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Peng Chen
- Medical School of Chinese PLA, Beijing, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yingjie Zhao
- Medical School of Chinese PLA, Beijing, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wen Zhao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Guanglong Dong
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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4
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Erkert L, Gamez-Belmonte R, Kabisch M, Schödel L, Patankar JV, Gonzalez-Acera M, Mahapatro M, Bao LL, Plattner C, Kühl AA, Shen J, Serneels L, De Strooper B, Neurath MF, Wirtz S, Becker C. Alzheimer's disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis. Gut 2024; 73:1618-1631. [PMID: 38684238 DOI: 10.1136/gutjnl-2023-331622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 04/16/2024] [Indexed: 05/02/2024]
Abstract
OBJECTIVE Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis. DESIGN Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis. RESULTS Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation. CONCLUSION Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.
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Affiliation(s)
- Lena Erkert
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Reyes Gamez-Belmonte
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Melanie Kabisch
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Lena Schödel
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Jay V Patankar
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Miguel Gonzalez-Acera
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Mousumi Mahapatro
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Li-Li Bao
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
| | - Christina Plattner
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Anja A Kühl
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jie Shen
- Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lutgarde Serneels
- VIB Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
| | - Bart De Strooper
- VIB Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
- UK Dementia Research Institute@UCL, University College London, London, UK
| | - Markus F Neurath
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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Cui C, Wang X, Zheng Y, Wu L, Li L, Wei H, Peng J. Nur77 as a novel regulator of Paneth cell differentiation and function. Mucosal Immunol 2024; 17:752-767. [PMID: 37683828 DOI: 10.1016/j.mucimm.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/11/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023]
Abstract
Serving as a part of intestinal innate immunity, Paneth cells play an important role in intestinal homeostasis maintenance via their multiple functions. However, the regulation of Paneth cells has been proven to be complex and diverse. Here, we identified nuclear receptor Nur77 as a novel regulator of Paneth cell differentiation and function. Nur77 deficiency led to the loss of Paneth cells in murine ileal crypts. Intestinal tissues or organoids with Nur77 deficiency exhibited the impaired intestinal stem cell niche and failed to enhance antimicrobial peptide expression after Paneth cell degranulation. The defects in Paneth cells and antimicrobial peptides in Nur7-/- mice led to intestinal microbiota disorders. Nur77 deficiency rendered postnatal mice susceptible to necrotizing enterocolitis. Mechanistically, Nur77 transcriptionally inhibited Dact1 expression to activate Wnt signaling activity, thus promoting Paneth cell differentiation and function. Taken together, our data suggest the regulatory role of Nur77 in Paneth cell differentiation and function and reveal a novel Dact1-mediated Wnt inhibition mechanism in Paneth cell development.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Yao Zheng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Lin Wu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
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6
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Cui H, Li X, Que J, Li S, Shi X, Yuan T. A water-soluble arabinoxylan from Chinese liquor distillers' grains: Structural characterization and anti-colitic properties. Int J Biol Macromol 2024; 266:131186. [PMID: 38554909 DOI: 10.1016/j.ijbiomac.2024.131186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 04/02/2024]
Abstract
Chinese liquor distillers' grain (CLDG) is a valuable and abundant by-product from traditional Chinese baijiu production, containing a diverse array of bioactive components that have attracted significant interest. Herein, a water-soluble polysaccharide, DGPS-2B, with a weight-average molecular weight of 37.3 kDa, was isolated from the alkali-extract fraction of CLDG. Methylation and NMR analysis identified that the primary constituents of DGPS-2B are arabinoxylans, with an arabinose-to-xylose ratio of 0.66. In an animal model of colitis, DGPS-2B treatment significantly altered the gut microbiota composition by increasing the SCFA-producing bacteria (e.g., Butyricicoccus) and reducing the mucin-degrading bacteria such as Muribaculaceae. This microbial shift resulted in elevated production of butyrate, acetate, and propionate, which subsequently suppressed NF-κB signaling, decreased the levels of IL-1β, IL-6, and TNFα, and potentially inactivated Notch signaling. These multifaceted effects stimulated mucin 2 production, reduced inflammation and apoptosis in the gut epithelium, and ultimately alleviated colitis symptoms. Collectively, this study not only elucidates the purification and characterization of DGPS-2B from CLDG but also illuminates its anti-colitic properties and the underlying molecular mechanisms. These findings underscore the potential of DGPS-2B as a therapeutic intervention for managing inflammatory bowel disease and emphasize CLDG as a promising source for developing value-added products.
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Affiliation(s)
- Hao Cui
- National Research Center for Carbohydrate Synthesis, College of Life Science, Jiangxi Normal University, Nanchang 330022, China
| | - Xia Li
- National Research Center for Carbohydrate Synthesis, College of Life Science, Jiangxi Normal University, Nanchang 330022, China
| | - Jiayi Que
- National Research Center for Carbohydrate Synthesis, College of Life Science, Jiangxi Normal University, Nanchang 330022, China
| | - Shuyue Li
- National Research Center for Carbohydrate Synthesis, College of Life Science, Jiangxi Normal University, Nanchang 330022, China
| | - Xiaodan Shi
- School of Health, Jiangxi Normal University, Nanchang 330022, China.
| | - Tao Yuan
- National Research Center for Carbohydrate Synthesis, College of Life Science, Jiangxi Normal University, Nanchang 330022, China; School of Health, Jiangxi Normal University, Nanchang 330022, China.
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7
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Akinsuyi OS, Xhumari J, Ojeda A, Roesch LFW. Gut permeability among Astronauts during Space missions. LIFE SCIENCES IN SPACE RESEARCH 2024; 41:171-180. [PMID: 38670644 DOI: 10.1016/j.lssr.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/02/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024]
Abstract
The space environment poses substantial challenges to human physiology, including potential disruptions in gastrointestinal health. Gut permeability has only recently become widely acknowledged for its potential to cause adverse effects on a systemic level, rendering it a critical factor to investigate in the context of spaceflight. Here, we propose that astronauts experience the onset of leaky gut during space missions supported by transcriptomic and metagenomic analysis of human and murine samples. A genetic map contributing to intestinal permeability was constructed from a systematic review of current literature. This was referenced against our re-analysis of three independent transcriptomic datasets which revealed significant changes in gene expression patterns associated with the gut barrier. Specifically, in astronauts during flight, we observed a substantial reduction in the expression genes that are crucial for intestinal barrier function, goblet cell development, gut microbiota modulation, and immune responses. Among rodent spaceflight studies, differential expression of cytokines, chemokines, and genes which regulate mucin production and post-translational modifications suggest a similar dysfunction of intestinal permeability. Metagenomic analysis of feces from two murine studies revealed a notable reduction probiotic, short chain fatty acid-producing bacteria and an increase in the Gram-negative pathogens, including Citrobacter rodentium, Enterobacter cloacea, Klebsiella aerogenes, and Proteus hauseri which promote LPS circulation, a recipe for barrier disruption and systemic inflammatory activation. These findings emphasize the critical need to understand the underlying mechanisms and develop interventions to maintain gastrointestinal health in space.
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Affiliation(s)
- Oluwamayowa S Akinsuyi
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Jessica Xhumari
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Amanda Ojeda
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Luiz F W Roesch
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA.
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8
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Metwaly A, Haller D. The TNF∆ARE Model of Crohn's Disease-like Ileitis. Inflamm Bowel Dis 2024; 30:132-145. [PMID: 37756666 DOI: 10.1093/ibd/izad205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Indexed: 09/29/2023]
Abstract
Crohn's disease (CD) is one of the 2 main phenotypes of inflammatory bowel diseases (IBDs); CD ischaracterized by a discontinuous, spontaneously recurring, transmural immunopathology that largely affects the terminal ileum. Crohn's disease exhibits both a relapsing and progressive course, and its prevalence is on the rise globally, mirroring the trends of industrialization. While the precise pathogenesis of CD remains unknown, various factors including immune cell dysregulation, microbial dysbiosis, genetic susceptibility, and environmental factors have been implicated in disease etiology. Animal models, particularly ileitis mouse models, have provided valuable tools for studying the specific mechanisms underlying CD, allowing longitudinal assessment and sampling in interventional preclinical studies. Furthermore, animal models assess to evaluate the distinct role that bacterial and dietary antigens play in causing inflammation, using germ-free animals, involving the introduction of individual bacteria (monoassociation studies), and experimenting with well-defined dietary components. An ideal animal model for studying IBD, specifically CD, should exhibit an inherent intestinal condition that arises spontaneously and closely mimics the distinct transmural inflammation observed in the human disease, particularly in the terminal ileum. We have recently characterized the impact of disease-relevant, noninfectious microbiota and specific bacteria in a mouse model that replicates CD-like ileitis, capturing the intricate nature of human CD, namely the TNF∆ARE mouse model. Using germ-free mice, we studied the impact of different diets on the expansion of disease-relevant pathobionts and on the severity of inflammation. In this review article, we review some of the currently available ileitis mouse models and discuss in detail the TNF∆ARE model of CD-like Ileitis.
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Affiliation(s)
- Amira Metwaly
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany
- ZIEL Institute for Food and Health, Technical University of Munich, Freising, Germany
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9
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Ning H, Liu J, Tan J, Yi M, Lin X. The role of the Notch signalling pathway in the pathogenesis of ulcerative colitis: from the perspective of intestinal mucosal barrier. Front Med (Lausanne) 2024; 10:1333531. [PMID: 38249980 PMCID: PMC10796567 DOI: 10.3389/fmed.2023.1333531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/12/2023] [Indexed: 01/23/2024] Open
Abstract
Ulcerative colitis is a common digestive disorder worldwide, with increasing incidence in recent years. It is an urgent problem to be solved, as it seriously affects and threatens the health and life of the global population. Studies have shown that dysfunction of the intestinal mucosal barrier is a critical pathogenic factor and molecular basis of ulcerative colitis, and some scholars have described it as a "barrier organ disease." While the Notch signalling pathway affects a series of cellular processes, including proliferation, differentiation, development, migration, and apoptosis. Therefore, it can regulate intestinal stem cells, CD4+ T cells, innate lymphoid cells, macrophages, and intestinal microbiota and intervene in the chemical, physical, immune, and biological mucosal barriers in cases of ulcerative colitis. The Notch signalling pathway associated with the pathogenesis of ulcerative colitis has distinct characteristics, with good regulatory effects on the mucosal barrier. However, research on ulcerative colitis has mainly focused on immune regulation, anti-inflammatory activity, and antioxidant stress; therefore, the study of the Notch signalling pathway suggests the possibility of understanding the pathogenesis of ulcerative colitis from another perspective. In this article we explore the role and mechanism of the Notch signalling pathway in the pathogenesis of ulcerative colitis from the perspective of the intestinal mucosal barrier to provide new targets and theoretical support for further research on the pathogenesis and clinical treatment of ulcerative colitis.
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Affiliation(s)
- Hang Ning
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jiemin Liu
- Guizhou Provincial People’s Hospital, Guiyang, China
| | - Jiaqian Tan
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Mengni Yi
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Xiaoyuan Lin
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
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Hibdon ES, Keeley TM, Merchant JL, Samuelson LC. The bHLH transcription factor ASCL1 promotes differentiation of endocrine cells in the stomach and is regulated by Notch signaling. Am J Physiol Gastrointest Liver Physiol 2023; 325:G458-G470. [PMID: 37698169 PMCID: PMC10887855 DOI: 10.1152/ajpgi.00043.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/13/2023]
Abstract
Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell differentiation are poorly understood. Here we tested the role of the bHLH transcription factor Achaete-Scute homolog 1 (ASCL1) in gastric epithelial cell differentiation, and its regulation by Notch. Newborn Ascl1 null mice showed a loss of expression of markers of neurogenin-3-dependent enteroendocrine cells, with normal expression of enterochromaffin-like cells, mucous cells, chief cells, and parietal cells. In adult mice, Ascl1 gene expression was observed in the stomach, but not the intestine, with higher expression in antral than corpus epithelium. Lineage tracing in Ascl1-CreERT2; Rosa26-LSL-tdTomato mice revealed single, scattered ASCL1+ cells in the gastric epithelium, demonstrating expression in antral gastrin- and serotonin-producing endocrine cells. ASCL1-expressing endocrine cells persisted for several weeks posttamoxifen labeling with a half-life of approximately 2 months. Lineage tracing in Gastrin-CreERT2 mice demonstrated a similar lifespan for gastrin-producing cells, confirming that gastric endocrine cells are long-lived. Finally, treatment of Ascl1-CreERT2; Rosa26-LSL-tdTomato mice with the pan-Notch inhibitor dibenzazepine increased the number of lineage-labeled cells in the gastric antrum, suggesting that Notch signaling normally inhibits Ascl1 expression. Notch regulation of Ascl1 was also demonstrated in a genetic mouse model of Notch activation, as well as Notch-manipulated antral organoid cultures, thus suggesting that ASCL1 is a key downstream Notch pathway effector promoting endocrine cell differentiation in the gastric epithelium.NEW & NOTEWORTHY Although Notch signaling is known to regulate cellular differentiation in the stomach, downstream effectors are poorly described. Here we demonstrate that the bHLH transcription factor ASCL1 is expressed in endocrine cells in the stomach and is required for formation of neurogenin-3-dependent enteroendocrine cells but not enterochromaffin-like cells. We also demonstrate that Ascl1 expression is inhibited by Notch signaling, suggesting that ASCL1 is a Notch-regulated transcriptional effector directing enteroendocrine cell fate in the mouse stomach.
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Affiliation(s)
- Elise S Hibdon
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
| | - Theresa M Keeley
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
| | - Juanita L Merchant
- Department of Medicine, University of Arizona, Tucson, Arizona, United States
| | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
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11
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Kollmann C, Buerkert H, Meir M, Richter K, Kretzschmar K, Flemming S, Kelm M, Germer CT, Otto C, Burkard N, Schlegel N. Human organoids are superior to cell culture models for intestinal barrier research. Front Cell Dev Biol 2023; 11:1223032. [PMID: 37849736 PMCID: PMC10577213 DOI: 10.3389/fcell.2023.1223032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/19/2023] [Indexed: 10/19/2023] Open
Abstract
Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death.
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Affiliation(s)
- Catherine Kollmann
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Hannah Buerkert
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Michael Meir
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Konstantin Richter
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Kai Kretzschmar
- Mildred-Scheel Early Career Centre (MSNZ) for Cancer Research, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Sven Flemming
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Matthias Kelm
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Christoph Otto
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Natalie Burkard
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
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12
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Atanga R, Romero AS, Hernandez AJ, Peralta-Herrera E, Merkley SD, In JG, Castillo EF. Inflammatory macrophages prevent colonic goblet and enteroendocrine cell differentiation through Notch signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.29.547119. [PMID: 37425818 PMCID: PMC10327198 DOI: 10.1101/2023.06.29.547119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. Utilizing IL-10-deficient (Il10-/-) mice, a model of spontaneous colitis, we found an increase in Notch activity in the colonic epithelium as well as an increase in intestinal macrophages expressing Notch ligands, which are increased in macrophages upon inflammatory stimuli. Furthermore, a co-culture system of inflammatory macrophages and intestinal stem and proliferative cells during differentiation reduced goblet and enteroendocrine cells. This was recapitulated when utilizing a Notch agonist on human colonic organoids (colonoids). In summary, our findings indicate that inflammatory macrophages upregulate notch ligands that activate notch signaling in ISC via cell-cell interactions, which in turn inhibits secretory lineage differentiation in the gastrointestinal (GI) tract.
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Affiliation(s)
- Roger Atanga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Aaron S. Romero
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Anthony Jimenez Hernandez
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | | | - Seth D. Merkley
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Julie G. In
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
- Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM
| | - Eliseo F. Castillo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
- Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM
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13
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Liu L, Li F, Shao T, Zhang L, Lee J, Dryden G, McClain CJ, Zhao C, Feng W. FGF21 Depletion Attenuates Colitis through Intestinal Epithelial IL-22-STAT3 Activation in Mice. Nutrients 2023; 15:2086. [PMID: 37432218 PMCID: PMC10181108 DOI: 10.3390/nu15092086] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 07/12/2023] Open
Abstract
Fibroblast growth factor 21 (FGF21) is a glucose and lipid metabolic regulator. Recent research revealed that FGF21 was also induced by inflammatory stimuli. Its role in inflammatory bowel disease (IBD) has not been investigated. In this study, an experimental IBD model was established in FGF21 knockout (KO) and wild-type (WT) mice by adding 2.5% (wt/vol) dextran sodium sulfate (DSS) to their drinking water for 7 days. The severity of the colitis and the inflammation of the mouse colon tissues were analyzed. In WT mice, acute DSS treatment induced an elevation in plasma FGF21 and a significant loss of body weight in a time-dependent manner. Surprisingly, the loss of body weight and the severity of the colitis induced by DSS treatment in WT mice were significantly attenuated in FGF21 KO mice. Colon and circulating pro-inflammatory factors were significantly lower in the FGF21 KO mice compared to the WT mice. As shown by BrdU staining, the FGF21 KO mice demonstrated increased colonic epithelial cell proliferation. DSS treatment reduced intestinal Paneth cell and goblet cell numbers in the WT mice, and this effect was attenuated in the FGF21 KO mice. Mechanistically, FGF21 deficiency significantly increased the signal transducer and activator of transcription (STAT)-3 activation in intestinal epithelial cells and increased the expression of IL-22. Further study showed that the expression of suppressor of cytokine signaling-2/3 (SOCS 2/3), a known feedback inhibitor of STAT3, was significantly inhibited in the DSS-treated FGF2 KO mice compared to the WT mice. We conclude that FGF21 deficiency attenuated the severity of DSS-induced acute colitis, which is likely mediated by enhancing the activation of the IL-22-STAT3 signaling pathway in intestinal epithelial cells.
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Affiliation(s)
- Liming Liu
- College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin 132101, China
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Fengyuan Li
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Tuo Shao
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Lihua Zhang
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Jiyeon Lee
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Gerald Dryden
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA
- Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40206, USA
| | - Cuiqing Zhao
- College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin 132101, China
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA
- Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
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14
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Kamitani Y, Kurumi H, Kanda T, Ikebuchi Y, Yoshida A, Kawaguchi K, Yashima K, Umekita Y, Isomoto H. Comparative study between histochemical mucus volume, histopathological findings, and endocytoscopic scores in patients with ulcerative colitis. Medicine (Baltimore) 2023; 102:e33033. [PMID: 36862904 PMCID: PMC9981389 DOI: 10.1097/md.0000000000033033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Ulcerative colitis (UC) causes a reduction in goblet cells. However, there have been few reports on the relationship between endoscopic and pathological findings and mucus volume. In this study, we quantitatively evaluated histochemical colonic mucus volume by fixing biopsied tissue sections taken from patients with UC in Carnoy's solution and compared it with endoscopic and pathological findings to determine whether there is a correlation between them. Observational study. A single-center, university hospital in Japan. Twenty-seven patients with UC (male/female, 16/11; mean age, 48.4 years; disease median duration, 9 years) were included in the study. The colonic mucosa of the most inflamed area and the surrounding less inflamed area were evaluated separately by local MES and endocytoscopic (EC) classification. Two biopsies were taken from each area; one was fixed with formalin for histopathological evaluation, and the other was fixed with Carnoy's solution for the quantitative evaluation of mucus via histochemical Periodic Acid Schiff and Alcian Blue staining. The relative mucus volume was significantly reduced in the local MES 1-3 groups, with worsening findings in EC-A/B/C and in groups with severe mucosal inflammation, crypt abscess, and severe reduction in goblet cells. The severity of inflammatory findings in UC by EC classification correlated with the relative mucus volume suggesting functional mucosal healing. We found a correlation between the colonic mucus volume and endoscopic and histopathological findings in patients with UC, and a stepwise correlation with disease severity, particularly in EC classification.
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Affiliation(s)
- Yu Kamitani
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Hiroki Kurumi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
- * Correspondence: Hiroki Kurumi, Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan (e-mail: )
| | - Tsutomu Kanda
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Yuichiro Ikebuchi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Akira Yoshida
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Koichiro Kawaguchi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Kazuo Yashima
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Yoshihisa Umekita
- Department of Pathology, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
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15
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Arai J, Otoyama Y, Nozawa H, Kato N, Yoshida H. The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review. Oncogene 2023; 42:549-558. [PMID: 36572816 PMCID: PMC9937921 DOI: 10.1038/s41388-022-02583-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/27/2022]
Abstract
Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.
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Affiliation(s)
- Jun Arai
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
| | - Yumi Otoyama
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hisako Nozawa
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- grid.136304.30000 0004 0370 1101Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Yoshida
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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16
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Yagishita Y, Joshi T, Kensler TW, Wakabayashi N. Transcriptional Regulation of Math1 by Aryl Hydrocarbon Receptor: Effect on Math1 + Progenitor Cells in Mouse Small Intestine. Mol Cell Biol 2023; 43:43-63. [PMID: 36720468 PMCID: PMC9937019 DOI: 10.1080/10985549.2022.2160610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/29/2022] [Indexed: 01/28/2023] Open
Abstract
The physiological roles of aryl hydrocarbon receptor (AhR) in the small intestine have been revealed as immunomodulatory and barrier functions. However, its contributions to cell fate regulation are incompletely understood. The Notch-activated signaling cascade is a central component of intestinal cell fate determinations. The lateral inhibitory mechanism governed by Notch directs cell fates toward distinct cell lineages (i.e., absorptive and secretory cell lineages) through its downstream effector, mouse atonal homolog 1 (MATH1). An investigation employing cell lines and intestinal crypt cells revealed that AhR regulates Math1 expression in a xenobiotic response element (XRE)-dependent manner. The AhR-Math1 axis was further addressed using intestinal organoids, where AhR-Math1 and HES1-Math1 axes appeared to coexist within the underlying Math1 transcriptional machinery. When the HES1-Math1 axis was pharmacologically suppressed, β-naphthoflavone-mediated AhR activation increased the number of goblet and Math1+ progenitor cells in the organoids. The same pharmacological dissection of the AhR-Math1 axis was applied in vivo, demonstrating an enhanced number of Math1+ progenitor cells in the small intestine following AhR activation. We report here that AhR-Math1 is a direct transcriptional axis with effects on Math1+ progenitor cells in the small intestine, highlighting a novel molecular basis for fine-tuning Notch-mediated cell fate regulation.
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Affiliation(s)
- Yoko Yagishita
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Tanvi Joshi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Thomas W. Kensler
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Nobunao Wakabayashi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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17
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Vital KD, Cardoso BG, Lima IP, Campos AB, Teixeira BF, Pires LO, Dias BC, de Alcantara Candido P, Cardoso VN, Fernandes SOA. Therapeutic effects and the impact of statins in the prevention of ulcerative colitis in preclinical models: A systematic review. Fundam Clin Pharmacol 2022; 37:493-507. [PMID: 36514874 DOI: 10.1111/fcp.12859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 11/25/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Ulcerative Colitis (UC) is a chronic inflammatory condition of the large intestines. Although great advances have been made in the management of the disease with the introduction of immunomodulators and biological agents, the treatment of UC is still a challenge. So far, there are no definitive therapies for this condition. Statins are potent inhibitors of cholesterol biosynthesis, possess beneficial effects on primary and secondary prevention of coronary heart disease, and have high tolerability and safety. Furthermore, they may have potential roles in UC management due to their possible anti-inflammatory, immunomodulatory, and antioxidant activities. This systematic review aimed to gather information about the potential benefits of statins for managing UC, reducing inflammation and disease remission in animal models. A systematic search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Virtual Health Library. The data were summarized in tables and critically analyzed. After the database search, 21 relevant studies were identified as eligible for this review. Preclinical studies using several colitis-induction protocols and various statins have shown numerous beneficial effects of these drugs on reducing disease activity, inflammatory profile, oxidative stress, and general clinical parameters of animals with UC. These studies revealed the potential of statins against the pathogenesis of UC. However, there are still important gaps regarding the molecular mechanisms of action of statins, leading to some contradictory results. Thus, more research on the molecular level to determine the roles of statins in colitis should be carried out to elucidate their mechanisms of action.
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Affiliation(s)
- Kátia Duarte Vital
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Barbara Gatti Cardoso
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Iasmin Pinheiro Lima
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Aline Beatriz Campos
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Bruno Faria Teixeira
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luiz Octávio Pires
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Beatriz Coutinho Dias
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Patrícia de Alcantara Candido
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Valbert Nascimento Cardoso
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Simone Odília Antunes Fernandes
- Laboratório de Radioisótopos. Departamento de Ciências Farmacêuticas e Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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18
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Xiu M, Wang Y, Yang D, Zhang X, Dai Y, Liu Y, Lin X, Li B, He J. Using Drosophila melanogaster as a suitable platform for drug discovery from natural products in inflammatory bowel disease. Front Pharmacol 2022; 13:1072715. [PMID: 36545307 PMCID: PMC9760693 DOI: 10.3389/fphar.2022.1072715] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/24/2022] [Indexed: 12/07/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and life-treating inflammatory disease that can occur in multiple parts of the human intestine and has become a worldwide problem with a continually increasing incidence. Because of its mild early symptoms, most of them will not attract people's attention and may cause more serious consequences. There is an urgent need for new therapeutics to prevent disease progression. Natural products have a variety of active ingredients, diverse biological activities, and low toxicity or side effects, which are the new options for preventing and treating the intestinal inflammatory diseases. Because of multiple genetic models, less ethical concerns, conserved signaling pathways with mammals, and low maintenance costs, the fruit fly Drosophila melanogaster has become a suitable model for studying mechanism and treatment strategy of IBD. Here, we review the advantages of fly model as screening platform in drug discovery, describe the conserved molecular pathways as therapetic targets for IBD between mammals and flies, dissect the feasibility of Drosophila model in IBD research, and summarize the natural products for IBD treatment using flies. This review comprehensively elaborates that the benefit of flies as a perfact model to evaluate the therapeutic potential of phytochemicals against IBD.
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Affiliation(s)
- Minghui Xiu
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou, China,Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, China
| | - Yixuan Wang
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Dan Yang
- College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xueyan Zhang
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yuting Dai
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yongqi Liu
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, China
| | - Xingyao Lin
- Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, China
| | - Botong Li
- College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jianzheng He
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, China,College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China,*Correspondence: Jianzheng He,
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19
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Jiang H, Shi GF, Fang YX, Liu YQ, Wang Q, Zheng X, Zhang DJ, Zhang J, Yin ZQ. Aloin A prevents ulcerative colitis in mice by enhancing the intestinal barrier function via suppressing the Notch signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 106:154403. [PMID: 36075180 DOI: 10.1016/j.phymed.2022.154403] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/24/2022] [Accepted: 08/17/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Previous studies reported that Aloe vera ameliorated DSS-induced colitis and promoted mucus secretion. However, the effect of Aloin A (AA), a major compound of Aloe vera, on colitis and its exact mechanism remains uncovered. METHODS C57BL/6 mice were successively subjected to 3% DSS solution for 5 days and distilled water for 2 days. Concurrently, AA (25, 50 mg/kg) and 5-aminosalicylic (500 mg/kg) were administrated intragastrically from day 1 to day 7. Colitis was evaluated by disease active index (DAI), colon length, inflammation response, and intestinal barrier function. In vitro LS174T cells challenged with 50 ng/ml of lipopolysaccharides (LPS) were used to validate the modulatory action of AA on the Notch signaling pathway. RESULTS Our results showed that oral administration with AA prominently prevented DSS-induced colitis symptoms in terms of decreased DAI, prevention of colon shortening, and reduced pathological damage. AA mitigated the inflammatory response evidenced by the decreased proinflammatory cytokines (TNF-α, IL-1β, IL-6) and increased anti-inflammatory cytokine (IL-10). Besides, AA inhibited apoptosis and facilitated proliferation in colons. Moreover, AA treatment up-regulated the expression of tight junction (TJ) proteins (ZO-1, Occludin) and promoted the secretion of MUC2 to decrease colon permeability. Mechanistically, AA inhibited the Notch pathway to promote the secretion of MUC2, which was consistent with LPS-challenged LS174 cells. CONCLUSION These results suggested that AA could prevent colitis by enhancing the intestinal barrier function via suppressing the Notch signaling pathway. Thus, AA might be a prospective remedy for ulcerative colitis.
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Affiliation(s)
- Hui Jiang
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - Gao-Feng Shi
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China
| | - Yu-Xi Fang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - You-Qian Liu
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China
| | - Qi Wang
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China
| | - Xian Zheng
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - Dong-Jian Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China
| | - Jian Zhang
- Department of Gastroenterology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, PR China.
| | - Zhi-Qi Yin
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
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20
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Nasser S, Abdallah DM, Ahmed KA, Abdel-Mottaleb Y, El-Abhar HS. The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model. Front Pharmacol 2022; 13:1008085. [PMID: 36386153 PMCID: PMC9641009 DOI: 10.3389/fphar.2022.1008085] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/12/2022] [Indexed: 11/30/2023] Open
Abstract
Although dysautonomia was documented in inflammatory bowel disease, with activation of the stress-related sympathetic system, the role of agonists/antagonists of the adrenergic receptors is not conclusive. Moreover, ulcerative colitis was recently linked to dementia, but the potential role of the presenilin 1(PS1)/BACE-1/beta-amyloid (Aβ) axis has not been evaluated. Hence, we investigated the impact of mirabegron (β3-agonist) and/or carvedilol (β1/β2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/Aβ axis in ulcerative colitis, and its relation to the inflammatory cascade, fibrotic processes, and the gut barrier dysfunction. Ulcerated rats were either left untreated or treated for 8 days with mirabegron and/or carvedilol. Besides minimizing colon edema and weight loss, and improving colon structure, mirabegron and/or carvedilol abated colonic PS1/BACE-1/Aβ axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-β/NF-κΒ/TNF-α, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-β1, α-SMA immunoexpression, and MTC staining. Moreover, the drugs improved the gut barrier function, attested by the increased goblet cells and expression of E-cadherin, and the inhibited expression of p (Y654)-β-catenin to preserve the E-cadherin/β-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-γ, a transcription factor known for its anti-colitic effect. Conclusion: Besides maintaining the gut barrier, mirabegron and/or carvedilol mediated their anti-colitic effect by their anti-oxidant, anti-inflammatory, and anti-fibrotic capacities. The therapeutic effect of these drugs depends partly on suppressing the harmful signaling pathways PS1/BACE-1/Aβ, NOTCH1/NICD/HES1, GSK3-β/NF-κΒ/TNF-α, and TGF-1β/α-SMA while enhancing PPAR-γ, SMAD-7, mucus, and AJ.
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Affiliation(s)
- Salma Nasser
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), New Cairo, Egypt
| | - Dalaal M. Abdallah
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Kawkab A. Ahmed
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Yousra Abdel-Mottaleb
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), New Cairo, Egypt
| | - Hanan S. El-Abhar
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), New Cairo, Egypt
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21
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Zheng L, Duan SL, Wen XL, Dai YC. Molecular regulation after mucosal injury and regeneration in ulcerative colitis. Front Mol Biosci 2022; 9:996057. [PMID: 36310594 PMCID: PMC9606627 DOI: 10.3389/fmolb.2022.996057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/26/2022] [Indexed: 12/02/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease with a complex etiology. Intestinal mucosal injury is an important pathological change in individuals with UC. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5+) intestinal stem cells (ISCs) exhibit self-renewal and high differentiation potential and play important roles in the repair of intestinal mucosal injury. Moreover, LGR5+ ISCs are intricately regulated by both the Wnt/β-catenin and Notch signaling pathways, which jointly maintain the function of LGR5+ ISCs. Combination therapy targeting multiple signaling pathways and transplantation of LGR5+ ISCs may lead to the development of new clinical therapies for UC.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi Province, China
| | - Yan-Cheng Dai
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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22
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Hu S, Wei P, Li W, Liu Q, Chen S, Hu C, Guo X, Ma X, Zeng J, Zhang Y. Pharmacological effects of berberine on models of ulcerative colitis: A meta-analysis and systematic review of animal studies. Front Pharmacol 2022; 13:937029. [PMID: 36147325 PMCID: PMC9486070 DOI: 10.3389/fphar.2022.937029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/08/2022] [Indexed: 12/09/2022] Open
Abstract
Berberine (BBR) is the main active constituent of the Rhizoma coptidis (Huanglian) and has multiple biological activities. Although current evidence suggests that the BBR has a multi-target effect in ulcerative colitis (UC), its action and mechanism are unclear. The purpose of this meta-analysis was to assess the pharmacological effects and potential mechanisms of BBR in UC models. Studies were searched from four databases (PubMed, Embase, Web of Science, and Cochrane Library) until March 2022. Standardized mean difference (SMD) and 95% confidence intervals (CI) were used for the adjudication of outcomes. Stata 15.0 software was used for statistical analysis. Twenty-eight publications and 29 studies involving 508 animals were included in the meta-analysis. The results showed that BBR reduced disease activity index (DAI) scores, alleviated UC-induced colon length (CL) loss, prevented weight loss, and reduced histological colitis score (HCS). Mechanistically, BBR was found to reduce myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, reduce levels of pro-inflammatory factors interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and mRNA expression of interleukin 17, increase levels of anti-inflammatory factor interleukin 10 (IL-10), and to increase levels of tight junction protein zonula occludens-1 (ZO-1) and occludin, which may involve antioxidant, anti-apoptotic, neuromodulation, anti-fibrotic, anti-inflammatory, barrier protection, and flora regulation aspects. However, additional attention should be paid to these outcomes due to the heterogeneity and methodological quality of the studies.
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Affiliation(s)
- Shuangyuan Hu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Pengfei Wei
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Li
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qingsong Liu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuanglan Chen
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Caiyu Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaochuan Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiao Ma, ; Jinhao Zeng, ; Yi Zhang,
| | - Jinhao Zeng
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiao Ma, ; Jinhao Zeng, ; Yi Zhang,
| | - Yi Zhang
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiao Ma, ; Jinhao Zeng, ; Yi Zhang,
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23
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Grey MJ, De Luca H, Ward DV, Kreulen IA, Bugda Gwilt K, Foley SE, Thiagarajah JR, McCormick BA, Turner JR, Lencer WI. The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development. J Clin Invest 2022; 132:e153519. [PMID: 35727638 PMCID: PMC9435652 DOI: 10.1172/jci153519] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free WT mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.
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Affiliation(s)
- Michael J. Grey
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Digestive Disease Center, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Heidi De Luca
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Doyle V. Ward
- Department of Microbiology and Physiological Systems, and
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Irini A.M. Kreulen
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Katlynn Bugda Gwilt
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Sage E. Foley
- Department of Microbiology and Physiological Systems, and
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Jay R. Thiagarajah
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Digestive Disease Center, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Beth A. McCormick
- Department of Microbiology and Physiological Systems, and
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Jerrold R. Turner
- Harvard Digestive Disease Center, Boston Children’s Hospital, Boston, Massachusetts, USA
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Departments of Pathology and Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Wayne I. Lencer
- Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Digestive Disease Center, Boston Children’s Hospital, Boston, Massachusetts, USA
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24
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Wu J, Wu Y, Feng W, Chen Q, Wang D, Liu M, Yu H, Zhang Y, Wang T. Role of Microbial Metabolites of Histidine in the Development of Colitis. Mol Nutr Food Res 2022; 66:e2101175. [PMID: 35585003 DOI: 10.1002/mnfr.202101175] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/17/2022] [Indexed: 12/31/2022]
Abstract
SCOPE Colitis is a chronic relapsing inflammatory disease of colon. Clinical studies show that meat-rich diet plays a critical role in the relapse of colitis. However, it is unclear whether the microbial metabolites of histidine, which is an amino acid widely found in meat, have an impact on the health of the intestine. METHODS AND RESULTS Six metabolites of histidine are given to IEC-6 cells. The cell activity measurement shows that imidazole propionate (IMP) is the most detrimental metabolite. Then, IMP is injected to mice by rectal administration, with blood and colon tissues collected for the measurement of colitis related parameters. The results show that treatment with IMP significantly increased NF-κB, iNOS, and IL-6, decreased number of goblet cell, and inhibited expressions of miR-146b. However, overexpression of miR-146b in mice rescues the decline of the physical condition. Additionally, Notch receptor 1 (Notch1) is identified as a target gene of miR-146b. Further analysis shows that miR-146b restored the abundance of goblet cells by regulating Notch1 signaling pathway. CONCLUSION IMP is able to induce intestinal inflammation, impairs the intestinal barrier, and affects the proliferation of goblet cells. The underlined mechanism may partially contribute to the dysregulation of miR-146b/Notch1 axis.
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Affiliation(s)
- Jiaqi Wu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China
| | - Yuzheng Wu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China
| | - Wen Feng
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China
| | - Qian Chen
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China
| | - Dan Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China
| | - Mengyang Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China
| | - Yi Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China
| | - Tao Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine. 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae (Tianjin University of Traditional Chinese Medicine), Ministry of Education, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China
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25
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Khoramjoo SM, Kazemifard N, Baradaran Ghavami S, Farmani M, Shahrokh S, Asadzadeh Aghdaei H, Sherkat G, Zali MR. Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs). Front Med (Lausanne) 2022; 9:865131. [PMID: 35677821 PMCID: PMC9170180 DOI: 10.3389/fmed.2022.865131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.
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Affiliation(s)
- Seyed Mobin Khoramjoo
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Kazemifard
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Shaghayegh Baradaran Ghavami
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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26
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Extending the viability of human precision-cut intestinal slice model for drug metabolism studies. Arch Toxicol 2022; 96:1815-1827. [PMID: 35428896 PMCID: PMC9095520 DOI: 10.1007/s00204-022-03295-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/24/2022] [Indexed: 11/09/2022]
Abstract
Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.
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27
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Zhang L, Huang Z, Cai Q, Zhao C, Xiao Y, Quan X, Tang C, Gao J. Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer. Front Med (Lausanne) 2022; 9:837143. [PMID: 35280908 PMCID: PMC8905541 DOI: 10.3389/fmed.2022.837143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) remains a heavy health burden worldwide. Transketolase (TKT) is a crucial enzyme in the non-oxidative phase of the Pentose Phosphate Pathway (PPP), and is up-regulated in multiple cancer types. However, the role of TKT in the prognosis of CRC remains unclear. We aimed to explore whether TKT expression is altered in CRC, how TKT is associated with the prognosis of CRC, and whether the regulation of TKT might have an impact on CRC. Differentially expressed genes (DEGs) were identified using bioinformatics analysis. TKT expression was examined in the human colon adenocarcinoma tissue microarray and xenografts. Cell viability, proliferation, migration, and apoptosis assays in vitro were applied to evaluate the protumoral effects of TKT on CRC. TKT was found to be a risk factor for the poor prognosis of CRC by bioinformatics analysis among the DEGs. TKT was significantly up-regulated in colon adenocarcinoma tissues compared with normal colon tissues in patients. Moreover, similar results were found in HCT116 and RKO human colon adenocarcinoma xenografts in nude mice. TKT expression was positively associated with advanced TNM stage, positive lymph nodes, and poor 5 or 10-year overall survival of CRC patients. In vitro, inhibition of TKT reduced cell viability, proliferation, and migration, and induced cell apoptosis. In addition, inhibition of TKT decreased the protein levels of NICD and Hes1. In conclusion, high TKT expression was associated with the poor prognosis of CRC patients. The protumoral effects of downregulating TKT may be realized by suppressing the Notch signaling pathway. TKT may be a new prognostic biomarker and therapeutic target for CRC.
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Affiliation(s)
- Linhao Zhang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuyu Cai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Xiao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Quan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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Bravo Iniguez A, Tian Q, Du M, Zhu MJ. Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice. Nutrients 2022; 14:nu14061148. [PMID: 35334805 PMCID: PMC8951758 DOI: 10.3390/nu14061148] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
The metabolite, alpha-ketoglutarate (aKG), shows promise as an approach for ameliorating colitis, but much remains unknown about the full extent of its effects on the metabolome and mucosal barrier. To further elucidate this matter, C57BL/6 male mice received drinking water with or without 1% aKG for three weeks, then were subjected to 2.5% dextran sulfate sodium (DSS) induction for 7 days followed by 7 days of recovery. Cecal content and intestinal tissue samples were analyzed for changes in metabolite profile and signaling pathways. Gas chromatography-mass spectrometry (GC-MS) metabolomics revealed a separation between the metabolome of mice treated with or without aKG; putrescine and glycine were significantly increased; and ornithine and amide products, oleamide and urea were significantly decreased. Based on a pathway analysis, aKG treatment induced metabolite changes and enriched glutathione metabolism and the urea cycle. Additionally, signaling pathways committing epithelial cells to the secretory lineage were elevated in aKG-treated mice. Consistently, aKG supplementation increased goblet cells staining, mRNA expression of mucin 2, and, trefoil factor 3 and Krüppel-like factor 4, markers of goblet cell differentiation. These data suggest the ameliorating the effects of aKG against chemically induced colitis involves a reduction in harmful metabolites and the promotion of goblet cell differentiation, resulting in a more-fortified mucus layer.
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Affiliation(s)
- Alejandro Bravo Iniguez
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (A.B.I.); (Q.T.)
| | - Qiyu Tian
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (A.B.I.); (Q.T.)
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA;
| | - Min Du
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA;
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (A.B.I.); (Q.T.)
- Correspondence: ; Tel.: +1-509-335-4016
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29
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Sun Y, Liu B, Chen Y, Xing Y, Zhang Y. Multi-Omics Prognostic Signatures Based on Lipid Metabolism for Colorectal Cancer. Front Cell Dev Biol 2022; 9:811957. [PMID: 35223868 PMCID: PMC8874334 DOI: 10.3389/fcell.2021.811957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The potential biological processes and laws of the biological components in malignant tumors can be understood more systematically and comprehensively through multi-omics analysis. This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics. Methods: We performed K-means unsupervised clustering algorithm and t test to identify the differential lipid metabolites determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of 236 CRC patients of the First Hospital of Jilin University (JLUFH). Cox regression analysis was used to identify prognosis-associated lipid metabolites and to construct multi-lipid-metabolite prognostic signature. The composite nomogram composed of independent prognostic factors was utilized to individually predict the outcome of CRC patients. Glycerophospholipid metabolism was the most significant enrichment pathway for lipid metabolites in CRC, whose related hub genes (GMRHGs) were distinguished by gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were utilized to develop the prognostic signature. Results: Six-lipid-metabolite and five-GMRHG prognostic signatures were developed, indicating favorable survival stratification effects on CRC patients. Using the independent prognostic factors as variables, we established a composite nomogram to individually evaluate the prognosis of CRC patients. The AUCs of one-, three-, and five-year ROC curves were 0.815, 0.815, and 0.805, respectively, showing auspicious prognostic accuracy. Furthermore, we explored the potential relationship between tumor microenvironment (TME) and immune infiltration. Moreover, the mutational frequency of TP53 in the high-risk group was significantly higher than that in the low-risk group (p < 0.001), while in the coordinate mutational status of TP53, the overall survival of CRC patients in the high-risk group was significantly lower than that in low-risk group with statistical differences. Conclusion: We identified the significance of lipid metabolism for the prognosis of CRC from the aspects of metabonomics and transcriptomics, which can provide a novel perspective for promoting individualized treatment and revealing the potential molecular biological characteristics of CRC. The composite nomogram including a six-lipid-metabolite prognostic signature is a promising predictor of the prognosis of CRC patients.
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30
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Quach A, Jayaratne RR, Lee BJ, Ibeawuchi SR, Lim E, Das S, Barrett KE. Diarrheal pathogenesis in Salmonella infection may result from an imbalance in intestinal epithelial differentiation through reduced Notch signaling. J Physiol 2022; 600:1851-1865. [PMID: 35100665 DOI: 10.1113/jp282585] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/20/2022] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Salmonella is a leading foodborne pathogen known to cause high chloride content diarrhea. Salmonella infection of murine enteroid-derived monolayers decreased DRA expression. Salmonella infection resulted in upregulation of the secretory epithelial marker ATOH1, the goblet cell marker Muc2, and the enteroendocrine cell marker ChgA. Downregulation of DRA may result from infection-induced Notch inhibition, as reflected by decreased expression of Notch intracellular domain and Hes1, as well as from decreased HNF1α signaling. The imbalance in intestinal epithelial differentiation favoring secretory over absorptive cell types is a possible mechanism by which Salmonella elicits diarrhea and may be relevant therapeutically. ABSTRACT Infections with non-typhoidal Salmonella spp. represent the most burdensome foodborne illnesses worldwide, yet despite their prevalence, the mechanism through which Salmonella elicits diarrhea is not entirely known. Intestinal ion transporters play important roles in fluid and electrolyte homeostasis in the intestine. We have previously shown that infection with Salmonella caused decreased colonic expression of the chloride/bicarbonate exchanger SLC26A3 (Down-Regulated in Adenoma; DRA) in a mouse model. In this study, we focused on the mechanism of DRA downregulation during Salmonella infection, by using murine epithelial enteroid-derived monolayers (EDM). The decrease in DRA expression caused by infection was recapitulated in EDM and accompanied by increased expression of ATOH1, the goblet cell marker Muc2, and the enteroendocrine cell marker ChgA. This suggested biased epithelial differentiation towards the secretory, rather than absorptive phenotype. In addition, the downstream Notch effector, Notch Intracellular Domain (NICD) and Hes1 were decreased following Salmonella infection. The relevance of Notch signaling was further investigated using a γ-secretase inhibitor, which recapitulated the downregulation in Hes1 and DRA as well as upregulation in ATOH1 and Muc2 seen following infection. Our findings suggest that Salmonella infection may result in a shift from absorptive to secretory cell types through Notch inhibition, which explains why there is a decreased capacity for absorption and ultimately the accumulation of diarrheal fluid. Our work also shows the value of EDM as a model to investigate mechanisms that might be targeted for therapy of diarrhea caused by Salmonella infection. Abstract figure legend Upon infection of the intestinal epithelium with Salmonella, diarrhea may be explained by an imbalance of intestinal epithelial differentiation. Downregulation of cell-fate commitment to the absorptive lineage, as reflected by decreased Hes1 and DRA, was observed. Conversely, upregulation of epithelial differentiation into secretory cell types was observed, as reflected by increased ATOH1, Muc2, and ChgA. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Andrew Quach
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Rashini R Jayaratne
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Beom Jae Lee
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA.,Department of Gastroenterology, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Stella-Rita Ibeawuchi
- Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Eileen Lim
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Soumita Das
- Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Kim E Barrett
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA.,Current affiliation: UC Davis School of Medicine, Education Building, 4610 X Street, Sacramento, CA, 95817, USA
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31
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Watanabe S, Hibiya S, Katsukura N, Kitagawa S, Sato A, Okamoto R, Watanabe M, Tsuchiya K. Importance of Telomere Shortening in the Pathogenesis of Ulcerative Colitis: A New Treatment From the Aspect of Telomeres in Intestinal Epithelial Cells. J Crohns Colitis 2022; 16:109-121. [PMID: 34180971 DOI: 10.1093/ecco-jcc/jjab115] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with frequent relapses. Telomere shortening in intestinal epithelial cells has been reported in severe or longstanding cases. However, its influence on UC pathogenesis remains unelucidated. To this end, we evaluated telomere shortening using a long-term organoid inflammation model that we had originally established. METHODS A UC model using human colon organoids was established to assess telomere changes chronologically. MST-312 was used for the telomerase inhibition assay. The potential of telomerase activators as a novel UC treatment was evaluated with an in vitro model, including microarray analysis, and histological changes were assessed using xenotransplantation into mouse colonic mucosa. RESULTS Our UC model reproduced telomere shortening in vitro, which was induced by the continuous suppression of telomerase activity via P53. MST-312-based analysis revealed that telomere shortening was involved in the pathogenesis of UC. Madecassoside [MD] improved the telomere length of the UC model and UC patient-derived organoids, which further promoted cell proliferation in vitro and improved the graft take-rate of xenotransplantation. Moreover, histological analysis revealed that MD induced normal crypt structure with abundant goblet cells. CONCLUSIONS This study is the first to reveal the mechanism and importance of telomere shortening in the pathogenesis of UC. MD could be a novel candidate for UC treatment beyond endoscopic mucosal healing.
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Affiliation(s)
- Sho Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nobuhiro Katsukura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sayuki Kitagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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Nighot M, Ganapathy AS, Saha K, Suchanec E, Castillo EF, Gregory A, Shapiro S, Ma T, Nighot P. Matrix Metalloproteinase MMP-12 Promotes Macrophage Transmigration Across Intestinal Epithelial Tight Junctions and Increases Severity of Experimental Colitis. J Crohns Colitis 2021; 15:1751-1765. [PMID: 33836047 PMCID: PMC8495490 DOI: 10.1093/ecco-jcc/jjab064] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Matrix metalloproteinases [MMPs] play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 [human macrophage elastase] has been reported in inflammatory bowel disease [IBD] which is characterised by the loss of epithelial tight junction [TJ] barrier function and an excessive inflammatory response. The aim of this study was to investigate the role of MMP-12 in intestinal TJ barrier function and inflammation. METHODS Wild type [WT] and MMP-12-/- mice were subjected to experimental acute or chronic dextran sodium sulphate [DSS] colitis. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon and ex vivo by Ussing chamber studies. RESULTS DSS administration increased colonic permeability through modulation of TJ proteins and also increased MMP-12 expression in the colonic mucosa of WT mice. The acute as well as chronic DSS-induced increase in colonic TJ permeability and the severity of DSS colitis was found to be markedly attenuated in MMP-12-/- mice. The resistance of MMP-12-/- mice to DSS colitis was characterised by reduced macrophage infiltration and transmigration, and reduced basement membrane laminin degradation. Further in vitro and in vivo studies show that macrophage transmigration across the epithelial layer is MMP-12 dependent and the epithelial TJ barrier is compromised during macrophage transmigration. Conclusions: Together, these data demonstrate that MMP-12 mediated degradation of basement membrane laminin, macrophage transmigration, and associated loss of intestinal TJ barrier are key pathogenic factors for intestinal inflammation.
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Affiliation(s)
- Meghali Nighot
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | | | - Kushal Saha
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Eric Suchanec
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Eliseo F Castillo
- University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
| | - Alyssa Gregory
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven Shapiro
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thomas Ma
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Prashant Nighot
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
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33
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Watanabe S, Nishimura R, Shirasaki T, Katsukura N, Hibiya S, Kirimura S, Negi M, Okamoto R, Matsumoto Y, Nakamura T, Watanabe M, Tsuchiya K. Schlafen 11 Is a Novel Target for Mucosal Regeneration in Ulcerative Colitis. J Crohns Colitis 2021; 15:1558-1572. [PMID: 33596306 DOI: 10.1093/ecco-jcc/jjab032] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with an intractable course. Although the goal of UC therapy is to achieve mucosal healing, the pathogenesis of mucosal injury caused by chronic inflammation remains unknown. We therefore aim to elucidate molecular mechanisms of mucosal injury by establishing in vitro and in vivo humanised UC-mimicking models. METHODS An in vitro model using human colon organoids was established by 60 weeks of inflammatory stimulation. The key gene for mucosal injury caused by long-term inflammation was identified by microarray analysis. An in vivo model was established by xenotransplantation of organoids into mouse colonic mucosa. RESULTS An in vitro model demonstrated that long-term inflammation induced irrecoverable changes in organoids: inflammatory response and apoptosis with oxidative stress and suppression of cell viability. This model also mimicked organoids derived from patients with UC at the gene expression and phenotype levels. Microarray analysis revealed Schlafen11 [SLFN11] was irreversibly induced by long-term inflammation. Consistently, SLFN11 was highly expressed in UC mucosa but absent in normal mucosa. The knockdown of SLFN11 [SLFN11-KD] suppressed apoptosis of intestinal epithelial cells [IECs] induced by inflammation. Moreover, SLFN11-KD improved the take rates of xenotransplantation and induced the regenerative changes of crypts observed in patients with UC in remission. CONCLUSIONS In vitro and in vivo UC-mimicking models were uniquely established using human colonic organoids. They revealed that SLFN11 is significant for mucosal injury in UC, and demonstrated its potential as a novel target for mucosal regeneration.
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Affiliation(s)
- Sho Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryu Nishimura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoaki Shirasaki
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobuhiro Katsukura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Susumu Kirimura
- Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mariko Negi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuka Matsumoto
- Department of Research and Development for Organoids, Juntendo University, Tokyo, Japan
| | - Tetsuya Nakamura
- Department of Research and Development for Organoids, Juntendo University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Advanced Research Institute, Tokyo Medical and Dental University [TMDU], Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Oss-Ronen L, Cohen I. Epigenetic regulation and signalling pathways in Merkel cell development. Exp Dermatol 2021; 30:1051-1064. [PMID: 34152646 DOI: 10.1111/exd.14415] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/20/2022]
Abstract
Merkel cells are specialized epithelial cells connected to afferent nerve endings responsible for light-touch sensations, formed at specific locations in touch-sensitive regions of the mammalian skin. Although Merkel cells are descendants of the epidermal lineage, little is known about the mechanisms responsible for the development of these unique mechanosensory cells. Recent studies have highlighted that the Polycomb group (PcG) of proteins play a significant role in spatiotemporal regulation of Merkel cell formation. In addition, several of the major signalling pathways involved in skin development have been shown to regulate Merkel cell development as well. Here, we summarize the current understandings of the role of developmental regulators in Merkel cell formation, including the interplay between the epigenetic machinery and key signalling pathways, and the lineage-specific transcription factors involved in the regulation of Merkel cell development.
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Affiliation(s)
- Liat Oss-Ronen
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Idan Cohen
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva, Israel
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35
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Watanabe S, Hibiya S, Katsukura N, Kitagawa S, Sato A, Okamoto R, Watanabe M, Tsuchiya K. Influence of chronic inflammation on the malignant phenotypes and the plasticity of colorectal cancer cells. Biochem Biophys Rep 2021; 26:101031. [PMID: 34095556 PMCID: PMC8167241 DOI: 10.1016/j.bbrep.2021.101031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/13/2021] [Accepted: 05/17/2021] [Indexed: 11/17/2022] Open
Abstract
Sporadic adenoma or adenocarcinoma is often detected during endoscopic surveillance of patients with ulcerative colitis (UC). However, it is occasionally difficult to distinguish these neoplasms from dysplasia or colitis-associated cancers because of the influence of inflammation. However, the influence of inflammation on sporadic neoplasms is not well characterised. To assess this influence, we established a long-term inflammation model of colon cancer cells by inflammatory stimulation with tumour necrosis factor-α, flagellin and interleukin-1β for 60 weeks. Then, the malignant phenotypes were evaluated using the MTS assay, Annexin V fluorescence assay, cell migration assay and sphere formation assay. The influence of P53 function on these phenotypes was assessed with a TP53 mutation model using the CRISPR/Cas9 system. A long-term inflammation model of LS174T cells was established for the first time with continuous inflammatory signalling. Chronic inflammation induced apoptosis and suppressed the proliferation and stemness of these cancer cells via the action of P53. It also enhanced the invasiveness of LS174T cells. Moreover, these phenotypic changes and changes in inflammatory signalling were recoverable after the removal of inflammatory stimuli, suggesting that colon cancer cells have higher plasticity than normal intestinal epithelial cells. In conclusion, our results suggest that sporadic neoplasms in patients with UC are affected by chronic inflammation but are not essentially altered.
Chronic inflammation model of colon cancer cells is established for the first time. Chronic inflammation (CI) suppresses the viability of cancer cells via P53. CI also alters the malignant phenotypes: stemness and invasiveness. P53 mutation under CI acquires higher malignant phenotypes. Changes of malignant phenotypes are recoverable after the removal of CI.
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Affiliation(s)
- Sho Watanabe
- Department of Gastroenterology and Hepatology, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Japan
| | | | | | - Ayako Sato
- Department of Gastroenterology and Hepatology, Japan
| | | | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Japan.,Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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Qiu F, Zhang Z, Yang L, Li R, Ma Y. Combined effect of vitamin C and vitamin D 3 on intestinal epithelial barrier by regulating Notch signaling pathway. Nutr Metab (Lond) 2021; 18:49. [PMID: 33964955 PMCID: PMC8105975 DOI: 10.1186/s12986-021-00576-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Background Tight junction proteins play crucial roles in maintaining the intestinal mucosal barrier. Although previous studies have shown that Notch signaling is closely related to tight junction proteins, the mechanism remains unclear. This study was performed to investigate whether vitamin C combined with vitamin D3 affects intestinal mucosal barrier stability via the Notch signaling pathway. Methods Intestinal epithelial barrier and notch signaling pathway were studied using guinea pig and SW480 cells. The guinea pigs were randomized into four groups (n = 6 in each group): control group (C, 200 IU/kg d VD3 + 100 mg/kg d VC), low VC group (LVC, 200 IU/kg d VD3 + 10 mg/kg d VC), medium VC group (MVC, 200 IU/kg d VD3 + 100 mg/kg d VC), and high VC group (HVC, 200 IU/kg d VD3 + 200 mg/kg d VC). Except for the control group, the other three groups were freely drinked with 2% dextran sodium sulfate solution for 4 days. And the control group was free to drink distilled water. The following cell groups were used: control group (SW480 cells without intervention); LPS group (100 ng/mL LPS); VD3 group (0.1 μmol/L VD3); VC + VD3 group (0.1, 1, 5, 10 μmol/mL VC + 0.1 μmol/L VD3). Results Electron microscopy analysis revealed that both low and high doses of vitamin C combined with vitamin D3 maintained dextran sodium sulfate-induced ulcerative colitis in the guinea pig intestinal epithelium tight junction. Compared with the control group, the expression level of ZO-1 mRNA in the colon tissue of the high-dose vitamin C group was significantly increased. In SW480 cell experiments, compared with the control group, cell migration and repair following treatment with different concentrations of vitamin C combined with vitamin D3 were significantly improved and the protein expression of Notch-1 was increased, whereas the protein expression of claudin-2 was significantly decreased. Thus, our results demonstrate that an appropriate amount of vitamin C combined with vitamin D3 can regulate the expression of claudin-2 by regulating Notch-1, relieve destruction of the intestinal mucosal barrier, and promote the repair of damage to the cell mucosal barrier. Conclusions We found that vitamin C combined with vitamin D3 protected against dextran sodium sulfate-induced ulcerative colitis in the guinea pig intestinal mucosa.
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Affiliation(s)
- Fubin Qiu
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China.
| | - Zehui Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Linxue Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Rui Li
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Ying Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
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Treveil A, Sudhakar P, Matthews ZJ, Wrzesiński T, Jones EJ, Brooks J, Ölbei M, Hautefort I, Hall LJ, Carding SR, Mayer U, Powell PP, Wileman T, Di Palma F, Haerty W, Korcsmáros T. Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches. Mol Omics 2021; 16:39-58. [PMID: 31819932 DOI: 10.1039/c9mo00130a] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn's disease or ulcerative colitis.
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Affiliation(s)
- A Treveil
- Earlham Institute, Norwich Research Park, Norwich, Norfolk NR4 7UZ, UK.
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38
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Wu H, Chen QY, Wang WZ, Chu S, Liu XX, Liu YJ, Tan C, Zhu F, Deng SJ, Dong YL, Yu T, Gao F, He HX, Leng XY, Fan H. Compound sophorae decoction enhances intestinal barrier function of dextran sodium sulfate induced colitis via regulating notch signaling pathway in mice. Biomed Pharmacother 2021; 133:110937. [PMID: 33217689 DOI: 10.1016/j.biopha.2020.110937] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 10/18/2020] [Accepted: 10/25/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Compound sophorae decoction (CSD), a Chinese Herbal decoction, is frequently clinically prescribed for patients suffered from ulcerative colitis (UC) characterized by bloody diarrhea. Yet, the underlying mechanism about how this formulae works is remain elusive. METHODS In the present study, the experimental colitis in C57BL/6 J mice was induced by oral administration of standard diets containing 3% dextran sodium sulfate (DSS), and CSD was given orally for treatment at the same time. The clinical symptoms including stool and body weight were recorded each day, and colon length and its histopathological changes were observed. Apoptosis of colonic epithelium was studied by detecting protein expression of cleaved caspase-3, and cell proliferation by Ki-67 immunohistochemistry. Tight junction complex like ZO-1 and occludin were also determined by transmission electron microscope and immunofluorescence. The concentration of FITC-dextran 4000 was measured to evaluate intestinal barrier permeability and possible signaling pathway was investigated. Mucin2 (MUC2) and notch pathway were tested through western blot. The M1/M2 ratio in spleen and mesenteric lymph nodes were detected by flow cytometry. And the mRNA levels of iNOS and Arg1 were examined by qRT-PCR. RESULTS CSD could significantly alleviate the clinical manifestations and pathological damage. Body weight loss and DAI score of mice with colitis were improved and shortening of colon was inhibited. The administration of CSD was able to reduce apoptotic epithelial cells and facilitate epithelial cell regeneration. Increased intestinal permeability was reduced in DSS-induced colitis mice. In addition, CSD treatment obviously up-regulated the expression of ZO-1 and occludin and the secretion of MUC2, regulated notch signaling, and decreased the ratio of M1/M2. CONCLUSIONS These data together suggest that CSD can effectively mitigate intestinal inflammation, promote phenotypic change in macrophage phenotype and enhance colonic mucosal barrier function by, at least in part, regulating notch signaling in mice affected by DSS-induced colitis.
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Affiliation(s)
- Hui Wu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qian-Yun Chen
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wen-Zhu Wang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Si Chu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xing-Xing Liu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yu-Jin Liu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chen Tan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Feng Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shuang-Jiao Deng
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ya-Lan Dong
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ting Yu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fei Gao
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hong-Xia He
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xue-Yuan Leng
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Heng Fan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Zhang L, Tai Y, Tang S, Zhao C, Tong H, Gao J, Tang C. Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats. Dig Dis Sci 2021; 66:131-142. [PMID: 32144600 DOI: 10.1007/s10620-020-06178-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/25/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.
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Affiliation(s)
- Linhao Zhang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Yang Tai
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Shihang Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Chong Zhao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Guo Xue Lane 37#, Chengdu, 610041, People's Republic of China.
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40
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Katsukura N, Watanabe S, Shirasaki T, Hibiya S, Kano Y, Akahoshi K, Tanabe M, Kirimura S, Akashi T, Kitagawa M, Okamoto R, Watanabe M, Tsuchiya K. Intestinal phenotype is maintained by Atoh1 in the cancer region of intraductal papillary mucinous neoplasm. Cancer Sci 2020; 112:932-944. [PMID: 33275808 PMCID: PMC7894004 DOI: 10.1111/cas.14755] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/20/2020] [Accepted: 11/29/2020] [Indexed: 12/11/2022] Open
Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a precancerous lesion of pancreatic cancer. Although there are 4 types of IPMN, among which intestinal-type IPMN is likely to progress into invasive cancer known as colloid carcinoma, no information regarding the involvement of the intestinal phenotype in the carcinogenesis of IPMN exists. The present study was conducted to explore how the intestinal differentiation system is maintained during the tumor progression of intestinal-type IPMN using surgical resection specimens. Results showed that Atoh1, a critical transcriptional factor for intestinal differentiation toward the secretory lineages of intestinal epithelial cells, was expressed in an invasive-grade IPMN. To determine the function of Atoh1 in pancreatic cancer, we generated a pancreatic ductal adenocarcinoma (PDAC) cell line overexpressing Atoh1. In a xenograft model, we successfully induced an IPMN phenotype in PDAC cells via Atoh1 induction. Finally, for the first time, we discovered that GPA33 is expressed in intestinal-type IPMN, thereby suggesting a novel target for cancer therapy. In conclusion, the intestinal differentiation system might be maintained during tumor progression of intestinal-type IPMN. Further analysis of the function of Atoh1 in IPMN might be useful for understanding the molecular mechanism underlying the malignant potential during the tumor progression of IPMN.
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Affiliation(s)
- Nobuhiro Katsukura
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sho Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoaki Shirasaki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihito Kano
- Department of Clinical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Precision Cancer Medicine, Graduate School, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichi Akahoshi
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Susumu Kirimura
- Department of Surgical Pathology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takumi Akashi
- Department of Surgical Pathology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Stem Cell and Regenerative Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Advanced Research Institute, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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Li Y, Zhang T, Guo C, Geng M, Gai S, Qi W, Li Z, Song Y, Luo X, Zhang T, Wang N. Bacillus subtilis RZ001 improves intestinal integrity and alleviates colitis by inhibiting the Notch signalling pathway and activating ATOH-1. Pathog Dis 2020; 78:5804729. [PMID: 32166323 DOI: 10.1093/femspd/ftaa016] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Intestinal mucosal barriers help the body resist many intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). In this study, we identified a novel bacterium promoting the repair of intestinal mucosa and investigated the potential mechanisms underlying its activity. Culture supernatant of Bacillus subtilis RZ001 upregulated the expression of mucin 2 (MUC2) and tight junction (TJ) proteins in HT-29 cells in vitro. Oral administration of B. subtilis RZ001 may have significantly reduced symptoms such as the dextran sulfate sodium (DSS)-induced decrease in body weight, shortening of colon length and overproduction of proinflammatory factors. The number of goblet cells and levels of MUC2 and TJ proteins were significantly increased in adult mice fed with B. subtilis RZ001. B. subtilis RZ001 cells upregulated the levels of MUC2 in the intestinal organoids. Furthermore, culture supernatant of B. subtilis RZ001 could suppress the Notch signalling pathway and activate the expression of atonal homolog 1 (Atoh1). The transcription factor Atoh1 is required for intestinal secretory cell differentiation and activates transcription of MUC2 via binding to E-boxes on the MUC2 promoter. Taken together, B. subtilis strain RZ001 has the potential for treating IBD. The present study is helpful to elucidate the mechanisms of B. subtilis action.
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Affiliation(s)
- Yanru Li
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Tengxun Zhang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Congcong Guo
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Meng Geng
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Sailun Gai
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Wei Qi
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Zhongyuan Li
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Yajian Song
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Xuegang Luo
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Tongcun Zhang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
| | - Nan Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, China. Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, Tianjin 300457, China
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42
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Frick A, Khare V, Jimenez K, Dammann K, Lang M, Krnjic A, Gmainer C, Baumgartner M, Mesteri I, Gasche C. A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation. Cell Mol Gastroenterol Hepatol 2020; 11:892-907.e1. [PMID: 33189893 PMCID: PMC7900837 DOI: 10.1016/j.jcmgh.2020.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS p21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/β-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice. METHODS IL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT. RESULTS When compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased β-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation. CONCLUSIONS PAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.
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Affiliation(s)
- Adrian Frick
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kristine Jimenez
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kyle Dammann
- Department of Surgery, Saint Luke's University Hospital Bethlehem, Bethlehem, Pennsylvania
| | - Michaela Lang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Anita Krnjic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christina Gmainer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximilian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Wu Y, Li Y, Ruan Z, Li J, Zhang L, Lu H, Xu Z. Puerarin Rebuilding the Mucus Layer and Regulating Mucin-Utilizing Bacteria to Relieve Ulcerative Colitis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:11402-11411. [PMID: 32864960 DOI: 10.1021/acs.jafc.0c04119] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The colonic mucus barrier serves as a primary defense against enteric pathogens; destruction of this mucus layer has been observed in ulcerative colitis patients. This study aims to investigate the possibility of rebuilding the colon mucus layer through puerarin supplementation, which can stimulate mucin secretion and goblet cells differentiation. After puerarin supplementation, the thickness of colon mucus layer was increased and the permeability was reduced. The erosion of intestinal epithelium by bacteria was blocked, and the loss of epithelial integrity was alleviated. Puerarin also altered the composition of mucin-utilizing bacteria, which influenced the mucus permeability. Levels of short-chain fatty acids (SCFAs) were increased after puerarin supplementation, which as a direct source of energy for the proliferation of epithelia and goblet cells. This study demonstrated that enhancement of mucin secretion to relieve ulcerative colitis (UC) by puerarin supplementation is feasible, and the regulation of mucin-utilizing bacteria and the increased levels of SCFAs may be the main reasons.
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Affiliation(s)
- Yi Wu
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Yafei Li
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
- University Campus Hospital and Jiangxi Academy of Medical Science, Nanchang University, Nanchang 330006, China
| | - Zheng Ruan
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
| | - Jiaojiao Li
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
| | - Li Zhang
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
| | - Hui Lu
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
| | - Zhenjiang Xu
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China
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Colquhoun C, Duncan M, Grant G. Inflammatory Bowel Diseases: Host-Microbial-Environmental Interactions in Dysbiosis. Diseases 2020; 8:E13. [PMID: 32397606 PMCID: PMC7348996 DOI: 10.3390/diseases8020013] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Crohn's Disease (CD) and Ulcerative Colitis (UC) are world-wide health problems in which intestinal dysbiosis or adverse functional changes in the microbiome are causative or exacerbating factors. The reduced abundance and diversity of the microbiome may be a result of a lack of exposure to vital commensal microbes or overexposure to competitive pathobionts during early life. Alternatively, many commensal bacteria may not find a suitable intestinal niche or fail to proliferate or function in a protective/competitive manner if they do colonize. Bacteria express a range of factors, such as fimbriae, flagella, and secretory compounds that enable them to attach to the gut, modulate metabolism, and outcompete other species. However, the host also releases factors, such as secretory IgA, antimicrobial factors, hormones, and mucins, which can prevent or regulate bacterial interactions with the gut or disable the bacterium. The delicate balance between these competing host and bacteria factors dictates whether a bacterium can colonize, proliferate or function in the intestine. Impaired functioning of NOD2 in Paneth cells and disrupted colonic mucus production are exacerbating features of CD and UC, respectively, that contribute to dysbiosis. This review evaluates the roles of these and other the host, bacterial and environmental factors in inflammatory bowel diseases.
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Affiliation(s)
| | | | - George Grant
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; (C.C.); (M.D.)
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Todorov H, Kollar B, Bayer F, Brandão I, Mann A, Mohr J, Pontarollo G, Formes H, Stauber R, Kittner JM, Endres K, Watzer B, Nockher WA, Sommer F, Gerber S, Reinhardt C. α-Linolenic Acid-Rich Diet Influences Microbiota Composition and Villus Morphology of the Mouse Small Intestine. Nutrients 2020; 12:nu12030732. [PMID: 32168729 PMCID: PMC7146139 DOI: 10.3390/nu12030732] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 12/14/2022] Open
Abstract
α-Linolenic acid (ALA) is well-known for its anti-inflammatory activity. In contrast, the influence of an ALA-rich diet on intestinal microbiota composition and its impact on small intestine morphology are not fully understood. In the current study, we kept adult C57BL/6J mice for 4 weeks on an ALA-rich or control diet. Characterization of the microbial composition of the small intestine revealed that the ALA diet was associated with an enrichment in Prevotella and Parabacteroides. In contrast, taxa belonging to the Firmicutes phylum, including Lactobacillus, Clostridium cluster XIVa, Lachnospiraceae and Streptococcus, had significantly lower abundance compared to control diet. Metagenome prediction indicated an enrichment in functional pathways such as bacterial secretion system in the ALA group, whereas the two-component system and ALA metabolism pathways were downregulated. We also observed increased levels of ALA and its metabolites eicosapentanoic and docosahexanoic acid, but reduced levels of arachidonic acid in the intestinal tissue of ALA-fed mice. Furthermore, intestinal morphology in the ALA group was characterized by elongated villus structures with increased counts of epithelial cells and reduced epithelial proliferation rate. Interestingly, the ALA diet reduced relative goblet and Paneth cell counts. Of note, high-fat Western-type diet feeding resulted in a comparable adaptation of the small intestine. Collectively, our study demonstrates the impact of ALA on the gut microbiome and reveals the nutritional regulation of gut morphology.
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Affiliation(s)
- Hristo Todorov
- Institute for Developmental Biology and Neurobiology, Faculty of Biology and Center for Computational Sciences in Mainz, Johannes Gutenberg-University Mainz, Staudingerweg 9, 55128 Mainz, Germany; (H.T.); (S.G.)
- Fresenius Kabi Deutschland GmbH, Borkenberg 14, 61440 Oberursel, Germany
| | - Bettina Kollar
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Franziska Bayer
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Inês Brandão
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
- Centro de Apoio Tecnológico Agro Alimentar (CATAA), Zona Industrial de Castelo Branco, Rua A, 6000-459 Castelo Branco, Portugal
| | - Amrit Mann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Julia Mohr
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Giulia Pontarollo
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Henning Formes
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
| | - Roland Stauber
- Nanobiomedicine, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany;
| | - Jens M. Kittner
- Medical Department 2 (Gastroenterology, Hepatology, Pneumology, Endocrinology) Klinikum Darmstadt GmbH, Grafenstr. 9, 64283 Darmstadt, Germany;
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
| | - Bernhard Watzer
- Metabolomics Core Facility, Philipps-University, 35043 Marburg, Germany;
| | - Wolfgang Andreas Nockher
- Institute of Laboratory Medicine and Pathobiochemistry, Philipps-University, 35043 Marburg, Germany;
| | - Felix Sommer
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, 24105 Kiel, Germany;
| | - Susanne Gerber
- Institute for Developmental Biology and Neurobiology, Faculty of Biology and Center for Computational Sciences in Mainz, Johannes Gutenberg-University Mainz, Staudingerweg 9, 55128 Mainz, Germany; (H.T.); (S.G.)
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (B.K.); (I.B.); (A.M.); (J.M.); (G.P.)
- German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-6131-17-8280
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Heib M, Rose-John S, Adam D. Necroptosis, ADAM proteases and intestinal (dys)function. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 353:83-152. [PMID: 32381179 DOI: 10.1016/bs.ircmb.2020.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Recently, an unexpected connection between necroptosis and members of the a disintegrin and metalloproteinase (ADAM) protease family has been reported. Necroptosis represents an important cell death routine which helps to protect from viral, bacterial, fungal and parasitic infections, maintains adult T cell homeostasis and contributes to the elimination of potentially defective organisms before parturition. Equally important for organismal homeostasis, ADAM proteases control cellular processes such as development and differentiation, immune responses or tissue regeneration. Notably, necroptosis as well as ADAM proteases have been implicated in the control of inflammatory responses in the intestine. In this review, we therefore provide an overview of the physiology and pathophysiology of necroptosis, ADAM proteases and intestinal (dys)function, discuss the contribution of necroptosis and ADAMs to intestinal (dys)function, and review the current knowledge on the role of ADAMs in necroptotic signaling.
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Affiliation(s)
- Michelle Heib
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Dieter Adam
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
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Inflammatory bowel disease and targeted oral anti-TNFα therapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 119:157-198. [PMID: 31997768 DOI: 10.1016/bs.apcsb.2019.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Antibodies have provided invaluable treatment options for many diseases, with immunotherapy revolutionising the treatment of several inflammatory disorders including inflammatory bowel disease (IBD). Accumulating evidence suggests that IBD results from an inappropriate response to intestinal microbes and environmental factors in genetically susceptible individuals, with overactivity of the pro-inflammatory pathways. On a pathophysiological level, IBD is a complex disease with intestinal fibrosis, stenosis and an increased incidence of cancer observed in those whose disease is inadequately controlled over time. Regulating the actions of the pro-inflammatory cytokine human tumor necrosis factor-alpha (hTNFα) through the use of anti-TNFα monoclonal antibodies (e.g. infliximab, certolizumab, adalimumab and golimumab) has proven an effective intervention for IBD with their increased use a testament of their effectiveness. These agents are administered systemically thereby causing their distribution throughout the body in a condition that is localised to the gastrointestinal (GI) tract. Immunogenicity, the induction of anti-drug antibodies (ADAs), serum sickness and other undesirable side effects limit their use, whilst up to 50% of patients do not respond to initial therapy. Diseases confined to the GI tract are ideal for targeting by oral therapy which mitigates side effects and allows for lower doses to be administered. Several oral anti-TNFα agents have been investigated with success but are not yet in general clinical use. This partially reflects the fact that the oral administration of antibodies has many barriers including the harsh environment of the GI tract and the presence of enzymes including pepsin, trypsin and chymotrypsin in the intestine which provide significant challenges to targeted oral therapy.
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Hou Q, Huang Y, Zhu Z, Liao L, Chen X, Han Q, Liu F. Tong-Xie-Yao-Fang improves intestinal permeability in diarrhoea-predominant irritable bowel syndrome rats by inhibiting the NF-κB and notch signalling pathways. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:337. [PMID: 31775739 PMCID: PMC6882330 DOI: 10.1186/s12906-019-2749-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Tong-Xie-Yao-Fang (TXYF) has been shown to be effective in diarrhoea-predominant irritable bowel syndrome (IBS-D) patients. However, the underlying mechanism remains to be clarified. The aim of this study was to investigate the efficacy and related mechanisms of TXYF in an IBS-D rat model. METHODS The IBS-D rat model was established with 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. Then, IBS-D rats were divided into control, TXYF and rifaximin groups and treated intragastrically with normal saline, TXYF and rifaximin, respectively, for 14 days. The following indicators were measured before and after treatment: defecation frequency, faecal water content (FWC) and colorectal distension (CRD). Histopathological changes in the distal colon were observed after treatment. The expression of OCLN and ZO1 in the distal colon of IBS-D rats reflected the intestinal mucosal permeability, as measured by qRT-PCR, western blot, and enzyme-linked immunosorbent assays (ELISAs). The NF-κB and Notch signalling pathways and inflammation-related factors were investigated. RESULTS After treatment with TXYF, the defecation frequency, FWC and CRD were significantly lower than those in the model group (P < 0.05). HE staining showed that colonic epithelial cells (CECs) in the IBS-D rats displayed significant oedema, impaired intestinal mucosal integrity and an increased influx of inflammatory cells. A significant reduction in granulocyte and CEC oedema was observed after the administration of TXYF and rifaximin compared to that of the model group and blank group (P < 0.05). TXYF significantly upregulated the expression of OCLN and ZO-1 and downregulated inflammation-related factors (IL-6, IL-1β, and TNF-α and the chemokine KC) in IBS-D rats compared to those in the model group rats (P < 0.05). In terms of the NF-κB and Notch signalling pathways, the expression of NICD, p-ERK, Hes-1 and p-P65 decreased significantly in the TXYF and rifaximin groups, while the expression of ATOH1 increased significantly compared to that in the model group (P < 0.05). CONCLUSION TXYF can effectively improve intestinal permeability and enhance intestinal mucosal barrier function, which may be related to inhibition of the inflammatory cascade and the NF-κB and Notch signalling pathways.
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Affiliation(s)
- Qiuke Hou
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yongquan Huang
- Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhaoyang Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Liu Liao
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Xinlin Chen
- Department of Preventive Medicine and Health Statistics, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Quanbin Han
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Fengbin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
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Yi J, Bergstrom K, Fu J, Shan X, McDaniel JM, McGee S, Qu D, Houchen CW, Liu X, Xia L. Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. Cell Death Differ 2019; 26:1656-1669. [PMID: 30478383 PMCID: PMC6748088 DOI: 10.1038/s41418-018-0237-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/28/2018] [Accepted: 10/22/2018] [Indexed: 12/16/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1ΔIEC) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3-4-week-old DKO;Dclk1ΔIEC mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1ΔIEC relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1ΔIEC mice at 3-6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa.
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Affiliation(s)
- Jun Yi
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Kirk Bergstrom
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Jianxin Fu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Xindi Shan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - J Michael McDaniel
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Samuel McGee
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Dongfeng Qu
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Courtney W Houchen
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China.
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
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Kaur H, Moreau R. Role of mTORC1 in intestinal epithelial repair and tumorigenesis. Cell Mol Life Sci 2019; 76:2525-2546. [PMID: 30944973 PMCID: PMC11105546 DOI: 10.1007/s00018-019-03085-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 03/08/2019] [Accepted: 03/25/2019] [Indexed: 12/15/2022]
Abstract
mTORC1 signaling is the prototypical pathway regulating protein synthesis and cell proliferation. mTORC1 is active in stem cells located at the base of intestinal crypts but silenced as transit-amplifying cells differentiate into enterocytes or secretory cells along the epithelium. After an insult or injury, self-limiting and controlled activation of mTORC1 is critical for the renewal and repair of intestinal epithelium. mTORC1 promotes epithelial cell renewal by driving cryptic stem cell division, and epithelial cell repair by supporting the dedifferentiation and proliferation of enterocytes or secretory cells. Under repeated insult or injury, mTORC1 becomes constitutively active, triggering an irreversible return to stemness, cell division, proliferation, and inflammation among dedifferentiated epithelial cells. Epithelium-derived cytokines promulgate inflammation within the lamina propria, which in turn releases inflammatory factors that act back on the epithelium where undamaged intestinal epithelial cells participate in the pervading state of inflammation and become susceptible to tumorigenesis.
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Affiliation(s)
- Harleen Kaur
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA
| | - Régis Moreau
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
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