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1
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Gao X, Yang C, Feng Z, Liu P, Liu Z. The signature of the small intestinal epithelial and immune cells in health and diseases. Chin Med J (Engl) 2025; 138:1288-1300. [PMID: 40394804 DOI: 10.1097/cm9.0000000000003615] [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: 12/05/2024] [Indexed: 05/22/2025] Open
Abstract
ABSTRACT The small intestine is essential for digestion, nutrient absorption, immune regulation, and microbial balance. Its epithelial lining, containing specialized cells like Paneth cells and tuft cells, is crucial for maintaining intestinal homeostasis. Paneth cells produce antimicrobial peptides and growth factors that support microbial regulation and intestinal stem cells, while tuft cells act as chemosensors, detecting environmental changes and modulating immune responses. Along with immune cells such as intraepithelial lymphocytes, innate lymphoid cells, T cells, and macrophages, they form a strong defense system that protects the epithelial barrier. Disruptions in this balance contribute to chronic inflammation, microbial dysbiosis, and compromised barrier function-key features of inflammatory bowel disease, celiac disease, and metabolic syndromes. Furthermore, dysfunctions in the small intestine and immune cells are linked to systemic diseases like obesity, diabetes, and autoimmune disorders. Recent research highlights promising therapeutic strategies, including modulation of epithelial and immune cell functions, probiotics, and gene editing to restore gut health and address systemic effects. This review emphasizes the pivotal roles of small intestinal epithelia and immune cells in maintaining intestinal homeostasis, their involvement in disease development, and emerging treatments for intestinal and systemic disorders.
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Affiliation(s)
- Xiang Gao
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Cuiping Yang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201801, China
| | - Zhongsheng Feng
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ping Liu
- Department of Gastroenterology, Wuhu First People's Hospital, Wuhu, Anhui 241000, China
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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2
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Meerschaert KA, Chiu IM. The gut-brain axis and pain signalling mechanisms in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2025; 22:206-221. [PMID: 39578592 DOI: 10.1038/s41575-024-01017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 11/24/2024]
Abstract
Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut-brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell-cell communication is integrated into this gut-brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain.
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Affiliation(s)
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
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3
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Pratt ML, Plumb AN, Manjrekar A, Cardona LM, Chan CK, John JM, Sadler KE. Microbiome contributions to pain: a review of the preclinical literature. Pain 2025; 166:262-281. [PMID: 39258679 PMCID: PMC11723818 DOI: 10.1097/j.pain.0000000000003376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/28/2024] [Indexed: 09/12/2024]
Abstract
ABSTRACT Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments.
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Affiliation(s)
- McKenna L Pratt
- Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
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4
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Karaboycheva G, Conrad ML, Dörr P, Dittrich K, Murray E, Skonieczna-Żydecka K, Kaczmarczyk M, Łoniewski I, Klawitter H, Buss C, Entringer S, Binder E, Winter SM, Heim C. Altered Gut Microbiota Patterns in Young Children with Recent Maltreatment Exposure. Biomolecules 2024; 14:1313. [PMID: 39456245 PMCID: PMC11506340 DOI: 10.3390/biom14101313] [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: 06/23/2024] [Revised: 09/30/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND The brain and the intestinal microbiota are highly interconnected and especially vulnerable to disruptions in early life. Emerging evidence indicates that psychosocial adversity detrimentally impacts the intestinal microbiota, affecting both physical and mental health. This study aims to investigate the gut microbiome in young children in the immediate aftermath of maltreatment exposure. METHODS Maltreatment exposure was assessed in 88 children (ages 3-7) using the Maternal Interview for the Classification of Maltreatment [MICM]. Children were allocated to three groups according to the number of experienced maltreatment categories: no maltreatment, low maltreatment, and high maltreatment exposures. Stool samples were collected and analyzed by 16S rRNA sequencing. RESULTS Children subjected to high maltreatment exposure exhibited lower alpha diversity in comparison to those with both no and low maltreatment exposure (Simpson Index, Tukey post hoc, p = 0.059 and p = 0.007, respectively). No significant distinctions in beta diversity were identified. High maltreatment exposure was associated with the enrichment of several genera from the class Clostridia (Clostridium, Intestinibacter, Howardella and Butyrivibrio) and the depletion of the genus Phocaeicola (class Bacteriodia). CONCLUSIONS Severe maltreatment exposure is associated with alterations in the gut microbiota of young children. Longitudinal trajectories of intestinal microbiota composition in the context of maltreatment may reveal important insights related to psychiatric and somatic health outcomes.
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Affiliation(s)
- Gergana Karaboycheva
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
- Department of Child & Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (P.D.); (K.D.); (E.M.); (S.M.W.)
| | - Melanie L. Conrad
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
- Department of Microbiology, Infectious Diseases and Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Peggy Dörr
- Department of Child & Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (P.D.); (K.D.); (E.M.); (S.M.W.)
| | - Katja Dittrich
- Department of Child & Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (P.D.); (K.D.); (E.M.); (S.M.W.)
| | - Elena Murray
- Department of Child & Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (P.D.); (K.D.); (E.M.); (S.M.W.)
| | - Karolina Skonieczna-Żydecka
- Department of Biochemical Research, Pomeranian Medical University, Szczecin, Poland; (K.S.-Ż.); (M.K.); (I.Ł.)
| | - Mariusz Kaczmarczyk
- Department of Biochemical Research, Pomeranian Medical University, Szczecin, Poland; (K.S.-Ż.); (M.K.); (I.Ł.)
| | - Igor Łoniewski
- Department of Biochemical Research, Pomeranian Medical University, Szczecin, Poland; (K.S.-Ż.); (M.K.); (I.Ł.)
| | - Heiko Klawitter
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
| | - Claudia Buss
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - Sonja Entringer
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | | | - Sibylle M. Winter
- Department of Child & Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (P.D.); (K.D.); (E.M.); (S.M.W.)
| | - Christine Heim
- Institute of Medical Psychology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; (G.K.); (M.L.C.); (H.K.); (C.B.); (S.E.)
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence, Berlin, Germany
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5
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Wu X, Cao Y, Liu Y, Zheng J. A New Strategy for Dietary Nutrition to Improve Intestinal Homeostasis in Diarrheal Irritable Bowel Syndrome: A Perspective on Intestinal Flora and Intestinal Epithelial Interaction. Nutrients 2024; 16:3192. [PMID: 39339792 PMCID: PMC11435304 DOI: 10.3390/nu16183192] [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: 08/22/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Although a reasonable diet is essential for promoting human health, precise nutritional regulation presents a challenge for different physiological conditions. Irritable Bowel Syndrome (IBS) is characterized by recurrent abdominal pain and abnormal bowel habits, and diarrheal IBS (IBS-D) is the most common, seriously affecting patients' quality of life. Therefore, the implementation of precise nutritional interventions for IBS-D has become an urgent challenge in the fields of nutrition and food science. IBS-D intestinal homeostatic imbalance involves intestinal flora disorganization and impaired intestinal epithelial barrier function. A familiar interaction is evident between intestinal flora and intestinal epithelial cells (IECs), which together maintain intestinal homeostasis and health. Dietary patterns, such as the Mediterranean diet, have been shown to regulate gut flora, which in turn improves the body's health by influencing the immune system, the hormonal system, and other metabolic pathways. METHODS This review summarized the relationship between intestinal flora, IECs, and IBS-D. It analyzed the mechanism behind IBS-D intestinal homeostatic imbalance by examining the interactions between intestinal flora and IECs, and proposed a precise dietary nutrient intervention strategy. RESULTS AND CONCLUSION This increases the understanding of the IBS-D-targeted regulation pathways and provides guidance for designing related nutritional intervention strategies.
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Affiliation(s)
- Xinyu Wu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Yilong Cao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Yixiang Liu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Jie Zheng
- School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China
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6
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Kwon MS, Chung HK, Xiao L, Yu TX, Sharma S, Cairns CM, Chen T, Chae S, Turner DJ, Wang JY. Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation. Am J Physiol Cell Physiol 2024; 327:C817-C829. [PMID: 39099425 PMCID: PMC11427006 DOI: 10.1152/ajpcell.00325.2024] [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: 05/15/2024] [Revised: 07/25/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024]
Abstract
Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.
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Affiliation(s)
- Min S Kwon
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Hee K Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States
| | - Ting-Xi Yu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Shweta Sharma
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Cassandra M Cairns
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Ting Chen
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Songah Chae
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - Douglas J Turner
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States
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Xu J, Han J, Jin S, Yu B, Li X, Ma X, Sun L, Li C, Zhao L, Ni X. Modulation of mercaptopurine intestinal toxicity and pharmacokinetics by gut microbiota. Biomed Pharmacother 2024; 177:116975. [PMID: 38925017 DOI: 10.1016/j.biopha.2024.116975] [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: 02/18/2024] [Revised: 06/04/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.
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Affiliation(s)
- Jiamin Xu
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China; Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Jiaqi Han
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Siyao Jin
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Boran Yu
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Xiaona Li
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Xiangyu Ma
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | | | | | - Libo Zhao
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China; Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.
| | - Xin Ni
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
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8
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De Santa F, Strimpakos G, Marchetti N, Gargari G, Torcinaro A, Arioli S, Mora D, Petrella C, Farioli-Vecchioli S. Effect of a multi-strain probiotic mixture consumption on anxiety and depression symptoms induced in adult mice by postnatal maternal separation. MICROBIOME 2024; 12:29. [PMID: 38369490 PMCID: PMC10875865 DOI: 10.1186/s40168-024-01752-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 01/04/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND Intestinal microbial composition not only affects the health of the gut but also influences centrally mediated systems involved in mood, through the "gut-brain" axis, a bidirectional communication between gut microbiota and the brain. In this context, the modulation of intestinal microbiota and its metabolites through the administration of probiotics seems to represent a very promising approach in the treatment of the central nervous system alterations. Early postnatal life is a critical period during which the brain undergoes profound and essential modulations in terms of maturation and plasticity. Maternal separation (MS), i.e., the disruption of the mother-pup interaction, represents a pivotal paradigm in the study of stress-related mood disorders, by inducing persistent changes in the immune system, inflammatory processes, and emotional behavior in adult mammals. RESULTS We conducted experiments to investigate whether sustained consumption of a multi-strain probiotic formulation by adult male mice could mitigate the effects of maternal separation. Our data demonstrated that the treatment with probiotics was able to totally reverse the anxiety- and depressive-like behavior; normalize the neuro-inflammatory state, by restoring the resting state of microglia; and finally induce a proneurogenic effect. Mice subjected to maternal separation showed changes in microbiota composition compared to the control group that resulted in permissive colonization by the administered multi-strain probiotic product. As a consequence, the probiotic treatment also significantly affected the production of SCFA and in particular the level of butyrate. CONCLUSION Gut microbiota and its metabolites mediate the therapeutic action of the probiotic mix on MS-induced brain dysfunctions. Our findings extend the knowledge on the use of probiotics as a therapeutic tool in the presence of alterations of the emotional sphere that significantly impact on gut microbiota composition. Video Abstract.
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Affiliation(s)
- Francesca De Santa
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Via E. Ramarini, 32, Monterotondo, Rome, 00015, Italy
| | - Georgios Strimpakos
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Via E. Ramarini, 32, Monterotondo, Rome, 00015, Italy
| | - Nicole Marchetti
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Via E. Ramarini, 32, Monterotondo, Rome, 00015, Italy
- Sciences of Nutrition, Aging, Metabolism and Gender Pathologies, Catholic University of Roma, Rome, 00100, Italy
| | - Giorgio Gargari
- Department of Food Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Alessio Torcinaro
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Via E. Ramarini, 32, Monterotondo, Rome, 00015, Italy
| | - Stefania Arioli
- Department of Food Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Diego Mora
- Department of Food Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Carla Petrella
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Policlinico Umberto I, Rome, Italy
| | - Stefano Farioli-Vecchioli
- Institute of Biochemistry and Cell Biology, IBBC, CNR, Via E. Ramarini, 32, Monterotondo, Rome, 00015, Italy.
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9
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Zhang Z, Du L, Ji Q, Liu H, Ren Z, Ji G, Bian ZX, Zhao L. The Landscape of Gut Microbiota and Its Metabolites: A Key to Understanding the Pathophysiology of Pattern in Chinese Medicine. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:89-122. [PMID: 38351704 DOI: 10.1142/s0192415x24500046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Liver Stagnation and Spleen Deficiency (LSSD) is a Chinese Medicine (CM) pattern commonly observed in gastrointestinal (GI) diseases, yet its biological nature remains unknown. This limits the global use of CM medications for treating GI diseases. Recent studies emphasize the role of gut microbiota and their metabolites in the pathogenesis and treatment of LSSD-associated GI diseases. There is increasing evidence supporting that an altered gut microbiome in LSSD patients or animals contributes to GI and extra-intestinal symptoms and affects the effectiveness of CM therapies. The gut microbiota is considered to be an essential component of the biological basis of LSSD. This study aims to provide an overview of existing research findings and gaps for the pathophysiological study of LSSD from the gut microbiota perspective in order to understand the relationship between the CM pattern and disease progression and to optimize CM-based diagnosis, prevention, and therapy.
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Affiliation(s)
- Zhaozhou Zhang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Liqing Du
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Qiuchen Ji
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Hao Liu
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Zhenxing Ren
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P. R. China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Zhao-Xiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P. R. China
| | - Ling Zhao
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
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10
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Tang D, Qiu R, Qiu X, Sun M, Su M, Tao Z, Zhang L, Tao S. Dietary restriction rescues 5-fluorouracil-induced lethal intestinal toxicity in old mice by blocking translocation of opportunistic pathogens. Gut Microbes 2024; 16:2355693. [PMID: 38780487 PMCID: PMC11123560 DOI: 10.1080/19490976.2024.2355693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in ad libitum (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial Lactobacillus genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or Lactobacillus gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.
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Affiliation(s)
- Duozhuang Tang
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Rongrong Qiu
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingxing Qiu
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Man Sun
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mingyue Su
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhendong Tao
- Department of Medical Laboratory Medicine, Jiangxi Province Hospital of Integrated Chinese & Western Medicine, Nanchang, Jiangxi, China
| | - Liu Zhang
- Intensive Care Unit, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Si Tao
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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11
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Garrett S, Asada MC, Sun J. Axin1's mystique in manipulating microbiome amidst colitis. Gut Microbes 2023; 15:2286674. [PMID: 38010886 PMCID: PMC10730173 DOI: 10.1080/19490976.2023.2286674] [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] [Indexed: 11/29/2023] Open
Abstract
Classically, Axin1 is considered a regulator of Wnt/β-catenin signaling. However, Axin1's roles in host-microbial interactions have been unknown. Our recent study has demonstrated that deletion of intestinal epithelial Axin1 in epithelial cells and Paneth cells protects the host against colitis by enhancing Akkermansia muciniphila. Loss of intestinal epithelial or Paneth cell Axin1 results in increased Wnt/β-catenin signaling, proliferation, and cell migration. This is associated with morphologically altered goblet and Paneth cells, including increased Muc2 and decreased lysozyme. Axin1 deletion specifically enriched Akkermansia muciniphila. Akkermansia muciniphila in Axin1 knockout mice is the driver of protection against DSS-induced inflammation. Here, we feature several significant conceptual changes, such as differences between Axin1 and Axin2, Axin1 in innate immunity and microbial homeostasis, and Axin1 reduction of Akkermansia muciniphila. We discuss an important trend in the field related to Paneth cells and tissue-specific Axin1 manipulation of microbiome in health and inflammation.
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Affiliation(s)
- Shari Garrett
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
| | - Monica C. Asada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
- UIC Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA
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12
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Liu XY, Wu SD. Fecal microbiota transplantation for treatment of irritable bowel syndrome: Current advances and future perspectives. Shijie Huaren Xiaohua Zazhi 2023; 31:922-932. [DOI: 10.11569/wcjd.v31.i22.922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/19/2023] [Indexed: 11/28/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a kind of functional gastroin-testinal disorder, characterized by recurrent abdominal pain and altered bowel habits. IBS adversely affects the quality of life of patients for the lack of effective treatment. The etiology of IBS remains poorly known. Previous studies suggested a possible role of gut dysbiosis in IBS pathogenesis. Fecal microbiota transplantation (FMT), which aims to reverse the gut dysbiosis, is a promising strategy in IBS management. In this review, we summarize the role of the gut microbiota in IBS pathogenesis from different aspects. We also review recent studies on efficacy evaluation of FMT in IBS. Besides, we discuss factors affecting the efficacy of FMT, hoping to provide a reference for future IBS treatment strategies targeting the gut microbiota.
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Affiliation(s)
- Xin-Yi Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Sheng-Di Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
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13
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Xu Y, Yu Z, Li S, Zhang T, Zhu F, Gong J. Pouchitis Is Associated with Paneth Cell Dysfunction and Ameliorated by Exogenous Lysosome in a Rat Model Undergoing Ileal Pouch Anal Anastomosis. Microorganisms 2023; 11:2832. [PMID: 38137976 PMCID: PMC10745344 DOI: 10.3390/microorganisms11122832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/05/2023] [Accepted: 11/09/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Pouchitis is a common complication of restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC), significantly affecting the postoperative quality of life. Paneth cells play an important role in the maintenance of gut homeostasis. This study aimed to investigate the role of Paneth cells in the pathogenesis of pouchitis. METHOD Endoscopic biopsies from the pouch body and terminal ileum of UC patients undergoing IPAA with or without pouchitis were obtained to analyze Paneth cell function. Acute pouchitis was induced with 5% dextran sulfate sodium (DSS) for seven consecutive days in a rat model of IPAA. The Paneth cell morphology was examined by immunofluorescence and electron microscopy. The effect of exogenous lysozyme supplementation on pouchitis was also investigated. The fecal microbiota profile after DSS and lysozyme treatment was determined by 16s rRNA ITS2 sequence analysis. RESULT Abnormal mucosal lysozyme expression was observed in patients with pouchitis. The rat model of pouchitis showed increased pouch inflammation, increased CD3+ and CD45+ T cell infiltration, and decreased tight junction proteins, including ZO-1 and Occludin. There is a significant deficiency of Paneth cell-derived lysozyme granules in the rat model of pouchitis. Supplementation with exogenous lysozyme significantly ameliorated pouchitis, lowering the levels of inflammatory cytokines such as TNF-α and IL-6 in the pouch tissue. 16s rRNA analysis revealed a higher Lachnospiraceae level after lysosome treatment. CONCLUSIONS Paneth cell dysfunction is prominent in patients and rat models of pouchitis and may be one of its causes. The decrease in Lachnospiraceae, a characteristic of dysbiosis in pouchitis, could be reserved by lysosome treatment. Lysozyme supplementation shows promise as a novel treatment strategy for pouchitis.
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Affiliation(s)
| | | | | | | | | | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China; (Y.X.); (Z.Y.); (S.L.); (T.Z.); (F.Z.)
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14
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Qin D, Wang R, Ji J, Wang D, Lu Y, Cao S, Chen Y, Wang L, Chen X, Zhang L. Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function. Cell Biosci 2023; 13:159. [PMID: 37649095 PMCID: PMC10468867 DOI: 10.1186/s13578-023-01104-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND AND AIMS Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. RESULTS We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future.
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Affiliation(s)
- Dan Qin
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Rui Wang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Jinwei Ji
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Duo Wang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yuanyuan Lu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Shiyao Cao
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yaqing Chen
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Liqiang Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
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15
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Yang Q, Zhao Y, Zhao X, Sun S, Chen Y, Chen J, Zou D, Zhang L. Exploring the potential targets of Biling Weitong Granules on visceral hypersensitivity through integration of network pharmacology and in vivo analysis. JOURNAL OF ETHNOPHARMACOLOGY 2023:116701. [PMID: 37257703 DOI: 10.1016/j.jep.2023.116701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/13/2023] [Accepted: 05/28/2023] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Biling Weitong Granules(BLWTG) are a newly developed traditional Chinese medicine prescription based on the ancient prescription Jinlingzi San and Zuojin Wan. It is used for the treatment of functional gastrointestinal disorders (FGIDs) featured as visceral hypersensitivity(VH). However, its active ingredients and protein targets involved still remain unknown. AIM OF THE STUDY To explore the potential targets of BLWTG for the treatment of visceral hypersensitivity. MATERIALS AND METHODS Active components and their protein targets of BLWTG were screened from TCMSP database and the component-target network were constructed with Cytoscape software. Irritable bowel syndrome (IBS) was the representative disease in this study and information on its linked pathways was obtained from NCBI, Drugbank and Genecard. Target pathways of BLWTG were analyzed through KEGG to verify the correlation with IBS related pathways.Then, the VH mouse models was induced by maternal separation(MS), randomly divided into normal saline(NS),BLWTG1(low-dosage) and BLWTG2(high-dosage) group. After intervention, threshold intensity of colorectal distension (CRD) and body weight were measured to evaluate relief of IBS symptoms. Elisa was performed to evaluate 5-HT concentration changes of colon tissues. Flow cytometry was performed to assess changes of colon eosinophils and mast cells proportion. Transcriptome sequencing was employed to analyze changes of pathways and differential genes. RESULTS 199 protein targets and 132 active components of BLWTG were identified. KEGG analysis revealed the overlap between BLWTG target pathways and IBS related pathways such as neuroactive ligand-receptor interaction, tryptophan metabolism and inflammatory reaction. 34 genes were not only BLWTG target proteins but also recognized targets for treating IBS. After maternal separation(MS), the mice showed a significant decrease in threshold intensity of CRD, a progressive decrease in body weight and an increase of 5-HT concentration of colon tissue. The proportion of mast cells and eosinophils in the colon increased. Differential genes including Hp,Ido1 and Aqp7 were significantly increased in MS mice group and IBS-related pathways were upregulated. After treatment of BLWTG, threshold intensity of CRD and body weight were significantly improved and IBS related pathways were downregulated. In addition, among BLWTG protein targets, Il1b,Tnf,Adrb1 and Nos2 were found upregulated in MS + NS mice and downregulated after BLWTG intervention through combination of transcriptome sequencing. CONCLUSIONS In maternal separation-induced mouse models, BLWTG could alleviate visceral hypersensitivity, possibly through downregulation of 5-HT concentration and eosinophils and mast cells proportion in colon and critical pathways such as neuroactive ligand-receptor pathway. Potential targets of BLWTG including Il1b,Tnf,Adrb1 and Nos2 were found through integration of network pharmacology database and transcriptome sequencing, providing evidence for further study on mechanisms underlying visceral hypersensitivity.
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Affiliation(s)
- Qidi Yang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Yizhou Zhao
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Xiangyu Zhao
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Sishen Sun
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Yifei Chen
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Jiayin Chen
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Ling Zhang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
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16
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Yang J, Shi Y. Paneth cell development in the neonatal gut: pathway regulation, development, and relevance to necrotizing enterocolitis. Front Cell Dev Biol 2023; 11:1184159. [PMID: 37266449 PMCID: PMC10231676 DOI: 10.3389/fcell.2023.1184159] [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: 03/11/2023] [Accepted: 05/09/2023] [Indexed: 06/03/2023] Open
Abstract
Paneth cells (PCs) are intestinal epithelial cells (IECs) that contain eosinophilic granules, which are located in Lieberkühn crypts. An increasing number of animal and human experiments have indicated that PCs are involved in the progression of a variety of intestinal as well as systemic inflammatory responses including necrotizing enterocolitis (NEC). NEC is an enteric acquired disease with high mortality that usually occurs in premature infants and neonates, however the underlying mechanisms remain unclear. In this review, we summarize the features of PCs, including their immune function, association with gut microbiota and intestinal stem cells, and their mechanism of regulating IEC death to explore the possible mechanisms by which PCs affect NEC.
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17
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Zhao Y, Zou DW. Gut microbiota and irritable bowel syndrome. J Dig Dis 2023; 24:312-320. [PMID: 37458142 DOI: 10.1111/1751-2980.13204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/11/2023] [Accepted: 07/13/2023] [Indexed: 07/18/2023]
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that poses a significant health concern. Although its etiology remains unknown, there is growing evidence that gut dysbiosis is involved in the development and exacerbation of IBS. Previous studies have reported altered microbial diversity, abundance, and composition in IBS patients when compared to controls. However, whether dysbiosis or aberrant changes in the intestinal microbiota can be used as a hallmark of IBS remains inconclusive. We reviewed the literatures on changes in and roles of intestinal microbiota in relation to IBS and discussed various gut microbiota manipulation strategies. Gut microbiota may affect IBS development by regulating the mucosal immune system, brain-gut-microbiome interaction, and intestinal barrier function. The advent of high-throughput multi-omics provides important insights into the pathogenesis of IBS and promotes the development of individualized treatment for IBS. Despite advances in currently available microbiota-directed therapies, large-scale, well-organized, and long-term randomized controlled trials are highly warranted to assess their clinical effects. Overall, gut microbiota alterations play a critical role in the pathophysiology of IBS, and modulation of microbiota has a significant therapeutic potential that requires to be further verified.
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Affiliation(s)
- Ye Zhao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duo Wu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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18
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Cui C, Wang X, Li L, Wei H, Peng J. Multifaceted involvements of Paneth cells in various diseases within intestine and systemically. Front Immunol 2023; 14:1115552. [PMID: 36993974 PMCID: PMC10040535 DOI: 10.3389/fimmu.2023.1115552] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn’s disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.
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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
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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Chamniansawat S, Suksridechacin N, Thongon N. Current opinion on the regulation of small intestinal magnesium absorption. World J Gastroenterol 2023; 29:332-342. [PMID: 36687126 PMCID: PMC9846944 DOI: 10.3748/wjg.v29.i2.332] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/25/2022] [Accepted: 11/19/2022] [Indexed: 01/06/2023] Open
Abstract
Magnesium (Mg2+) has an important role in numerous biological functions, and Mg2+ deficiency is associated with several diseases. Therefore, adequate intestinal absorption of Mg2+ is vital for health. The small intestine was previously thought to absorb digested Mg2+ exclusively through an unregulated paracellular mechanism, which is responsible for approximately 90% of total Mg2+ absorption. Recent studies, however, have revealed that the duodenum, jejunum, and ileum absorb Mg2+ through both transcellular and paracellular routes. Several regulatory factors of small intestinal Mg2+ uptake also have been explored, e.g., parathyroid hormone, fibroblast growth factor-23, apical acidity, proton pump inhibitor, and pH-sensing channel and receptors. The mechanistic factors underlying proton pump inhibitor suppression of small intestinal Mg2+, such as magnesiotropic protein dysfunction, higher mucosal bicarbonate secretion, Paneth cell dysfunction, and intestinal inflammation, are currently being explored. The potential role of small intestinal microbiomes in Mg2+ absorption has also been proposed. In this article, we reviewed the current knowledge on the mechanisms and regulatory factors of small intestinal Mg2+ absorption.
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Affiliation(s)
- Siriporn Chamniansawat
- Division of Anatomy, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, Muang 20131, Chonburi, Thailand
| | - Nasisorn Suksridechacin
- Biodiversity Research Centre, Thailand Institute of Scientific and Technological Research, Khlong Luang 12120, Pathum Thani, Thailand
| | - Narongrit Thongon
- Division of Physiology, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, Muang 20131, Chonburi, Thailand
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Saqib Z, De Palma G, Lu J, Surette M, Bercik P, Collins SM. Alterations in fecal β-defensin-3 secretion as a marker of instability of the gut microbiota. Gut Microbes 2023; 15:2233679. [PMID: 37464450 PMCID: PMC10355691 DOI: 10.1080/19490976.2023.2233679] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/29/2023] [Accepted: 07/03/2023] [Indexed: 07/20/2023] Open
Abstract
Compositional changes in the microbiota (dysbiosis) may be a basis for Irritable Bowel Syndrome (IBS), but biomarkers are currently unavailable to direct microbiota-directed therapy. We therefore examined whether changes in fecal β-defensin could be a marker of dysbiosis in a murine model. Experimental dysbiosis was induced using four interventions relevant to IBS: a mix of antimicrobials, westernized diets (high-fat/high-sugar and high salt diets), or mild restraint stress. Fecal mouse β-defensin-3 and 16S rRNA-based microbiome profiles were assessed at baseline and during and following these interventions. Each intervention, except for mild restraint stress, altered compositional and diversity profiles of the microbiota. Exposure to antimicrobials or a high-fat/high-sugar diet, but not mild restraint stress, resulted in decreased fecal β-defensin-3 compared to baseline. In contrast, exposure to the high salt diet increased β-defensin-3 compared to baseline. Mice exposed to the mix of antimicrobials showed the largest compositional changes and the most significant correlations between β-defensin-3 levels and bacterial diversity. The high salt diet was also associated with significant correlations between changes in β-defensin-3 and bacterial diversity, and this was not accompanied by discernible inflammatory changes in the host. Thus, dietary change or antimicrobial exposure, both recognized factors in IBS exacerbations, induced marked dysbiosis that was accompanied by changes in fecal β-defensin-3 levels. We propose that serial monitoring of fecal β-defensins may serve as a marker of dysbiosis and help identify those IBS patients who may benefit from microbiota-directed therapeutic interventions.
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Affiliation(s)
- Zarwa Saqib
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Jun Lu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Michael Surette
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Stephen Michael Collins
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
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21
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Schreiber R, Cabrita I, Kunzelmann K. Paneth Cell Secretion in vivo Requires Expression of Tmem16a and Tmem16f. GASTRO HEP ADVANCES 2022; 1:1088-1098. [PMID: 39131261 PMCID: PMC11308424 DOI: 10.1016/j.gastha.2022.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/03/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Paneth cells play a central role in intestinal innate immune response. These cells are localized at the base of small intestinal crypts of Lieberkuhn. The calcium-activated chloride channel TMEM16A and the phospholipid scramblase TMEM16F control intracellular Ca2+ signaling and exocytosis. We analyzed the role of TMEM16A and TMEM16F for Paneth cells secretion. Methods Mice with intestinal epithelial knockout of Tmem16a (Tmem16a-/-) and Tmem16f (Tmem16f-/-) were generated. Tissue structures and Paneth cells were analyzed, and Paneth cell exocytosis was examined in small intestinal organoids in vitro. Intracellular Ca2+ signals were measured and were compared between wild-type and Tmem16 knockout mice. Bacterial colonization and intestinal apoptosis were analyzed. Results Paneth cells in the crypts of Lieberkuhn from Tmem16a-/- and Tmem16f-/- mice demonstrated accumulation of lysozyme. Tmem16a and Tmem16f were localized in wild-type Paneth cells but were absent in cells from knockout animals. Paneth cell number and size were enhanced in the crypt base and mucus accumulated in intestinal goblet cells of knockout animals. Granule fusion and exocytosis on cholinergic and purinergic stimulation were examined online. Both were strongly compromised in the absence of Tmem16a or Tmem16f and were also blocked by inhibition of Tmem16a/f. Purinergic Ca2+ signaling was largely inhibited in Tmem16a knockout mice. Jejunal bacterial content was enhanced in knockout mice, whereas cellular apoptosis was inhibited. Conclusion The present data demonstrate the role of Tmem16 for exocytosis in Paneth cells. Inhibition or activation of Tmem16a/f is likely to affect microbial content and immune functions present in the small intestine.
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Affiliation(s)
- Rainer Schreiber
- Institut für Physiologie, Universität Regensburg, Regensburg, Bavaria, Germany
| | - Ines Cabrita
- Nephrologisches Forschungslabor, University of Cologne, Köln, NRW, Germany
| | - Karl Kunzelmann
- Institut für Physiologie, Universität Regensburg, Regensburg, Bavaria, Germany
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22
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Krela-Kaźmierczak I, Zakerska-Banaszak O, Skrzypczak-Zielińska M, Łykowska-Szuber L, Szymczak-Tomczak A, Zawada A, Rychter AM, Ratajczak AE, Skoracka K, Skrzypczak D, Marcinkowska E, Słomski R, Dobrowolska A. Where Do We Stand in the Behavioral Pathogenesis of Inflammatory Bowel Disease? The Western Dietary Pattern and Microbiota-A Narrative Review. Nutrients 2022; 14:nu14122520. [PMID: 35745251 PMCID: PMC9230670 DOI: 10.3390/nu14122520] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the increasing knowledge with regard to IBD (inflammatory bowel disease), including ulcerative colitis (UC) and Crohn’s disease (CD), the etiology of these conditions is still not fully understood. Apart from immunological, environmental and nutritional factors, which have already been well documented, it is worthwhile to look at the possible impact of genetic factors, as well as the composition of the microbiota in patients suffering from IBD. New technologies in biochemistry allow to obtain information that can add to the current state of knowledge in IBD etiology.
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Affiliation(s)
- Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
- Correspondence: (I.K.-K.); (O.Z.-B.); (D.S.)
| | - Oliwia Zakerska-Banaszak
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznań, Poland; (M.S.-Z.); (R.S.)
- Correspondence: (I.K.-K.); (O.Z.-B.); (D.S.)
| | | | - Liliana Łykowska-Szuber
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
| | - Aleksandra Szymczak-Tomczak
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
| | - Agnieszka Zawada
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
| | - Anna Maria Rychter
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznań, Poland
| | - Alicja Ewa Ratajczak
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznań, Poland
| | - Kinga Skoracka
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznań, Poland
| | - Dorota Skrzypczak
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
- Correspondence: (I.K.-K.); (O.Z.-B.); (D.S.)
| | - Emilia Marcinkowska
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznań, Poland; (M.S.-Z.); (R.S.)
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznań, Poland; (L.Ł.-S.); (A.S.-T.); (A.Z.); (A.M.R.); (A.E.R.); (K.S.); (E.M.); (A.D.)
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23
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Abstract
We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our
in vivo
research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder.
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24
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Sakata N, Mantani Y, Nakanishi S, Morishita R, Yokoyama T, Hoshi N. Histological study of diurnal changes in bacterial settlement in the rat alimentary tract. Cell Tissue Res 2022; 389:71-83. [PMID: 35403967 DOI: 10.1007/s00441-022-03626-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 03/30/2022] [Indexed: 11/28/2022]
Abstract
The composition of fecal bacteria is reported to change throughout the day, whereas the circadian rhythmicity of indigenous bacteria that settle on the epithelium is mostly unknown. The present study aimed to clarify the diurnal changes in the settlement of indigenous bacteria in the rat alimentary tract using histological analysis. The settlement of indigenous bacteria on the mucosal epithelium throughout the day and the diurnal changes in settlement levels were observed in the esophagus, the nonglandular area of the stomach, and the ileum. The peak of zeitgeber time (ZT) in the settlement level differed by segment: ZT 12 in the esophagus, ZT 6 in the nonglandular area of the stomach, and ZT 0 in the ileum. Moreover, 16S rRNA amplicon sequencing using tissue sections revealed that the compositions of the indigenous bacteria in the ileum differed among ZT. In the intervillous spaces of the ileum, the formation level of the mucus layer, one of the most fundamental host defenses against bacteria, was lowest at ZT 0. Bacteria were preferentially adjacent to the villous epithelium in the area without coverage by the mucus layer at ZT 0. These findings collectively suggest that the settlement level and possibly the composition of the indigenous bacteria changed diurnally in various segments of the alimentary tract, and the formation of the mucus layer might be the most likely to lead to such diurnal changes in indigenous bacteria, at least in the ileum.
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Affiliation(s)
- Nanami Sakata
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
| | - Youhei Mantani
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan.
| | - Satoki Nakanishi
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
| | - Rinako Morishita
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
| | - Toshifumi Yokoyama
- Laboratory of Animal Molecular Morphology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
| | - Nobuhiko Hoshi
- Laboratory of Animal Molecular Morphology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
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25
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Tao E, Long G, Yang T, Chen B, Guo R, Ye D, Fang M, Jiang M. Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice. Front Neurosci 2022; 15:803957. [PMID: 35153662 PMCID: PMC8831756 DOI: 10.3389/fnins.2021.803957] [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: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Early life stress (ELS) disposes to functional gastrointestinal diseases in adult, such as irritable bowel syndrome (IBS). Maternal separation (MS) is a well-known animal model of IBS and has been shown to induce visceral hypersensitivity in adult rats and mice. However, to the best of our knowledge, it has not been reported whether MS induces visceral hypersensitivity in young mice, such as the post-weaning mice. Moreover, the method for evaluation of visceral sensitivity also has not been described. Accordingly, the present study aims to evaluate the visceral sensitivity caused by MS in post-weaning mice and develop a novel and small size distention balloon for assessment of visceral sensitivity of such mice. Male pups of C57BL/6 mice were randomly divided into two groups, MS (n = 12) and non-separation (NS) (n = 10). MS pups were separated from the dams through postnatal days (PND) 2 to 14, while NS pups were undisturbed. After, all pups stayed with respective dams and were weaned at PND 22. Visceral sensitivity was evaluated by colorectal distention (CRD) with a novel and small size distention balloon at PND 25. The threshold of abdominal withdrawal reflex (AWR) scores were significantly lower in MS than NS. In addition, AWR scores at different pressures of CRD were significantly higher in MS than NS. The results demonstrate that MS induced visceral hypersensitivity in post-weaning mice. The designed small size distention balloon for evaluation of visceral sensitivity is of significance to further study the pathophysiology of IBS from early life to adulthood.
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Affiliation(s)
- Enfu Tao
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- Department of Pediatrics, Wenling Maternal and Child Health Care Hospital, Wenling, China
| | - Gao Long
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Ting Yang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Bo Chen
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Rui Guo
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Diya Ye
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Marong Fang
- Institute of Neuroscience and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mizu Jiang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- *Correspondence: Mizu Jiang,
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26
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Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases. Biomedicines 2022; 10:biomedicines10020289. [PMID: 35203499 PMCID: PMC8869546 DOI: 10.3390/biomedicines10020289] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance.
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27
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Huo J, Wu Z, Sun W, Wang Z, Wu J, Huang M, Wang B, Sun B. Protective Effects of Natural Polysaccharides on Intestinal Barrier Injury: A Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:711-735. [PMID: 35078319 DOI: 10.1021/acs.jafc.1c05966] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Owing to their minimal side effects and effective protection from oxidative stress, inflammation, and malignant growth, natural polysaccharides (NPs) are a potential adjuvant therapy for several diseases caused by intestinal barrier injury (IBI). More studies are accumulating on the protective effects of NPs with respect to IBI, but the underlying mechanisms remain unclear. Thus, this review aims to represent current studies that investigate the protective effects of NPs on IBI by directly maintaining intestinal epithelial barrier integrity (inhibiting oxidative stress, regulating inflammatory cytokine expression, and increasing tight junction protein expression) and indirectly regulating intestinal immunity and microbiota. Furthermore, the mechanisms underlying IBI development are briefly introduced, and the structure-activity relationships of polysaccharides with intestinal barrier protection effects are discussed. Potential developments and challenges associated with NPs exhibiting protective effects against IBI have also been highlighted to guide the application of NPs in the treatment of intestinal diseases caused by IBI.
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Affiliation(s)
- Jiaying Huo
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, People's Republic of China
| | - Ziyan Wu
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Weizheng Sun
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, People's Republic of China
| | - Zhenhua Wang
- Center for Mitochondria and Healthy Aging, College of Life Science, Yantai University, Yantai, Shandong 264005, People's Republic of China
| | - Jihong Wu
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Mingquan Huang
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Bowen Wang
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Baoguo Sun
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
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28
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Dai X, Wang C, Guo Z, Li Y, Liu T, Jin G, Wang S, Wang B, Jiang K, Cao H. Maternal sucralose exposure induces Paneth cell defects and exacerbates gut dysbiosis of progeny mice. Food Funct 2021; 12:12634-12646. [PMID: 34821899 DOI: 10.1039/d1fo02921e] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Research has shown that maternal sucralose (MS) exposure alters the gut microbiota of offspring at weaning and predisposes the offspring to developing obesity, non-alcoholic fatty liver disease and metabolic syndrome later in life. However, the underlying mechanism remains unclear. Paneth cells are thought to critically influence the gut microbiota. This study aimed to investigate whether MS exposure induced Paneth cell defects and exacerbated gut dysbiosis of offspring. Female C57BL/6 mice were divided into the MS and control (water) groups during pregnancy and lactation. Progeny mice were fed a normal sucralose-free diet after weaning until adulthood. MS inhibited intestinal development and increased the expression of proinflammatory cytokines in the small intestines of 3-week-old progeny mice. MS increased the proportions of abnormal granule secretion by Paneth cells. The number of Paneth cells and mRNA expression of AMPs such as cryptdins and lysozyme were reduced in the MS group. MS disturbed the gut microbiota composition and diversity in the 3-week-old offspring mice. The relative abundances of pro-inflammatory bacteria, such as Desulfovibrionales, Helicobacter, Pasteurellales and Campylobacterales were significantly increased in the MS group, while anti-inflammatory bacteria, including Clostridium XI, were decreased. This dysbiosis continued into adulthood. These findings showed that MS exposure induced Paneth cell defects and exacerbated gut dysbiosis in offspring mice. Sucralose should be consumed with caution, especially during pregnancy and in early life.
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Affiliation(s)
- Xin Dai
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Chen Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Zixuan Guo
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Yun Li
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Ge Jin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
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29
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Ma Y, Nenkov M, Chen Y, Press AT, Kaemmerer E, Gassler N. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis. World J Hepatol 2021; 13:1512-1533. [PMID: 34904027 PMCID: PMC8637682 DOI: 10.4254/wjh.v13.i11.1512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/28/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
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Affiliation(s)
- Yunxia Ma
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Miljana Nenkov
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Elke Kaemmerer
- Department of Pediatrics, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
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30
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Wahida A, Müller M, Hiergeist A, Popper B, Steiger K, Branca C, Tschurtschenthaler M, Engleitner T, Donakonda S, De Coninck J, Öllinger R, Pfautsch MK, Müller N, Silva M, Usluer S, Thiele Orberg E, Böttcher JP, Pfarr N, Anton M, Slotta-Huspenina JB, Nerlich AG, Madl T, Basic M, Bleich A, Berx G, Ruland J, Knolle PA, Rad R, Adolph TE, Vandenabeele P, Kanegane H, Gessner A, Jost PJ, Yabal M. XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells. Sci Immunol 2021; 6:eabf7235. [PMID: 34739338 DOI: 10.1126/sciimmunol.abf7235] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap−/− mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap−/− mice. Consequently, both Tnfr1−/−Xiap−/− and Tnfr2−/−Xiap−/− mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap−/− mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis.
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MESH Headings
- Animals
- Dendritic Cells/immunology
- Dysbiosis/immunology
- Humans
- Immunity, Innate/immunology
- Inflammation/immunology
- Intestines/immunology
- Mice
- Mice, Knockout
- Paneth Cells/immunology
- Receptors, Tumor Necrosis Factor, Type I/deficiency
- Receptors, Tumor Necrosis Factor, Type I/immunology
- Receptors, Tumor Necrosis Factor, Type II/deficiency
- Receptors, Tumor Necrosis Factor, Type II/immunology
- Toll-Like Receptor 5/immunology
- X-Linked Inhibitor of Apoptosis Protein/deficiency
- X-Linked Inhibitor of Apoptosis Protein/immunology
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Affiliation(s)
- Adam Wahida
- Medical Department III for Hematology and Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
| | - Madeleine Müller
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Hiergeist
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
| | - Bastian Popper
- Biomedical Center, Core Facility Animal Models, Ludwig-Maximilians-University, Planegg-Martinsried, Germany
| | - Katja Steiger
- Institute of Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany
- Comparative Experimental Pathology and Digital Pathology, Institute for Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany
| | - Caterina Branca
- Medical Department III for Hematology and Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
| | - Markus Tschurtschenthaler
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Translational Cancer Research and Experimental Cancer Therapy, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Thomas Engleitner
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Sainitin Donakonda
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Jordy De Coninck
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Rupert Öllinger
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Marie K Pfautsch
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Nicole Müller
- Medical Department III for Hematology and Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Miguel Silva
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Sinem Usluer
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Erik Thiele Orberg
- Medical Department III for Hematology and Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
| | - Jan P Böttcher
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Nicole Pfarr
- Institute of Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany
| | - Martina Anton
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia B Slotta-Huspenina
- Institute of Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany
| | - Andreas G Nerlich
- Institute of Pathology, Academic Clinic Munich-Bogenhausen, Munich, Germany
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Marijana Basic
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - André Bleich
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Jürgen Ruland
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Percy A Knolle
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Roland Rad
- TranslaTUM, Center for Translational Cancer Research, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Timon E Adolph
- Department of Internal Medicine I for Gastroenterology, Hepatology, and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Vandenabeele
- Cell Death and Inflammation Unit, VIB-Center for Inflammation Research (IRC), VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology (DBMB), Ghent University, Ghent, Belgium
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - André Gessner
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
| | - Philipp J Jost
- Medical Department III for Hematology and Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Monica Yabal
- Institute of Molecular Immunology and Experimental Oncology, TUM School of Medicine, Technical University of Munich, Munich, Germany
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31
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Wei L, Singh R, Ro S, Ghoshal UC. Gut microbiota dysbiosis in functional gastrointestinal disorders: Underpinning the symptoms and pathophysiology. JGH Open 2021; 5:976-987. [PMID: 34584964 PMCID: PMC8454481 DOI: 10.1002/jgh3.12528] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Functional gastrointestinal disorders (FGIDs), currently known as disorders of gut-brain interaction, are emerging microbiota-gut-brain abnormalities that are prevalent worldwide. The pathogenesis of FGIDs is heterogeneous and is intertwined with gut microbiota and its derived molecule-modulated mechanisms, including gut dysmotility, visceral hypersensitivity, gut immune abnormalities, abnormal secretion, and impaired barrier function. There has been phenomenal progress in understanding the role of gut microbiota in FGIDs by underpinning the species alternations between healthy and pathological conditions such as FGIDs. However, the precise gut microbiota-directed cellular and molecular pathogeneses of FGIDs are yet enigmatic. Determining the mechanistic link between the gut microbiota and gastrointestinal (GI) diseases has been difficult due to (i) the lack of robust animal models imitating the various aspects of human FGID pathophysiology; (ii) the absence of longitudinal human and/or animal studies to unveil the interaction of the gut microbiota with FGID-relevant pathogenesis; (iii) uncertainty about connections between human and animal studies; and (iv) insufficient data supporting a holistic view of disease-specific pathophysiological changes in FGID patients. These unidentified gaps open possibilities to explore pathological mechanisms directed through gut microbiota dysbiosis in FGIDs. The current treatment options for dysbiotic gut microbiota are limited; dietary interventions, antibiotics, probiotics, and fecal microbiota transplantation are the front-line clinical options. Here, we review the contribution of gut microbiota and its derived molecules in gut homeostasis and explore the possible pathophysiological mechanisms involved in FGIDs leading to potential therapeutics options.
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Affiliation(s)
- Lai Wei
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Rajan Singh
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Seungil Ro
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Uday C Ghoshal
- Department of GastroenterologySanjay Gandhi Postgraduate Institute of Medical SciencesLucknowIndia
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32
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Regulation of Paneth Cell Function by RNA-Binding Proteins and Noncoding RNAs. Cells 2021; 10:cells10082107. [PMID: 34440876 PMCID: PMC8392049 DOI: 10.3390/cells10082107] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 12/20/2022] Open
Abstract
Paneth cells are specialized intestinal epithelial cells that are located at the base of small intestinal crypts and play a vital role in preserving the gut epithelium homeostasis. Paneth cells act as a safeguard from bacterial translocation across the epithelium and constitute the niche for intestinal stem cells in the small intestine by providing multiple niche signals. Recently, Paneth cells have become the focal point of investigations defining the mechanisms underlying the epithelium-microbiome interactions and pathogenesis of chronic gut mucosal inflammation and bacterial infection. Function of Paneth cells is tightly regulated by numerous factors at different levels, while Paneth cell defects have been widely documented in various gut mucosal diseases in humans. The post-transcription events, specific change in mRNA stability and translation by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) are implicated in many aspects of gut mucosal physiology by modulating Paneth cell function. Deregulation of RBPs and ncRNAs and subsequent Paneth cell defects are identified as crucial elements of gut mucosal pathologies. Here, we overview the posttranscriptional regulation of Paneth cells by RBPs and ncRNAs, with a particular focus on the increasing evidence of RBP HuR and long ncRNA H19 in this process. We also discuss the involvement of Paneth cell dysfunction in altered susceptibility of the intestinal epithelium to chronic inflammation and bacterial infection following disrupted expression of HuR and H19.
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33
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Lee KJ. The Usefulness of Symptom-based Subtypes of Functional Dyspepsia for Predicting Underlying Pathophysiologic Mechanisms and Choosing Appropriate Therapeutic Agents. J Neurogastroenterol Motil 2021; 27:326-336. [PMID: 34210898 PMCID: PMC8266502 DOI: 10.5056/jnm21042] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/01/2021] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
Functional dyspepsia (FD) is considered to be a heterogeneous disorder with different pathophysiological mechanisms or pathogenetic factors. In addition to traditional mechanisms, novel concepts regarding pathophysiologic mechanisms of FD have been proposed. Candidates of therapeutic agents based on novel concepts have also been suggested. FD is a symptom complex and currently diagnosed by symptom-based Rome criteria. In the Rome criteria, symptom-based subtypes of FD including postprandial distress syndrome and epigastric pain syndrome are recommended to be used, based on the assumption that each subtype is more homogenous in terms of underlying pathophysiologic mechanisms than FD as a whole. In this review, the usefulness of symptombased subtypes of FD for predicting underlying pathophysiologic mechanisms and choosing appropriate therapeutic agents was evaluated. Although several classic pathophysiologic mechanisms are suggested to be associated with individual dyspeptic symptoms, symptom-based subtypes of FD are not specific for a certain pathogenetic factor or pathophysiologic mechanism, and may be frequently associated with multiple pathophysiologic abnormalities. Novel concepts on the pathophysiology of FD show complex interactions between pathophysiologic mechanisms and pathogenetic factors, and prediction of underlying mechanisms of individual patients simply by the symptom pattern or symptom-based subtypes may not be accurate in a considerable proportion of cases. Therefore, subtyping by the Rome criteria appears to have limited value to guide therapeutic strategy, suggesting that the addition of objective parameters or subclassification reflecting physiologic or pathologic tests may be necessary for the targeted therapeutic approaches, particularly when therapeutic agents targeting novel mechanisms are available.
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Affiliation(s)
- Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
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34
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Viola MF, Boeckxstaens G. Niche-specific functional heterogeneity of intestinal resident macrophages. Gut 2021; 70:1383-1395. [PMID: 33384336 PMCID: PMC8223647 DOI: 10.1136/gutjnl-2020-323121] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 12/22/2022]
Abstract
Intestinal resident macrophages are at the front line of host defence at the mucosal barrier within the gastrointestinal tract and have long been known to play a crucial role in the response to food antigens and bacteria that are able to penetrate the mucosal barrier. However, recent advances in single-cell RNA sequencing technology have revealed that resident macrophages throughout the gut are functionally specialised to carry out specific roles in the niche they occupy, leading to an unprecedented understanding of the heterogeneity and potential biological functions of these cells. This review aims to integrate these novel findings with long-standing knowledge, to provide an updated overview on our understanding of macrophage function in the gastrointestinal tract and to speculate on the role of specialised subsets in the context of homoeostasis and disease.
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Affiliation(s)
- Maria Francesca Viola
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (Chrometa), KU Leuven, Leuven, Flanders, Belgium
| | - Guy Boeckxstaens
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (Chrometa), KU Leuven, Leuven, Flanders, Belgium
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35
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Guzylack-Piriou L, Ménard S. Early Life Exposure to Food Contaminants and Social Stress as Risk Factor for Metabolic Disorders Occurrence?-An Overview. Biomolecules 2021; 11:687. [PMID: 34063694 PMCID: PMC8147825 DOI: 10.3390/biom11050687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022] Open
Abstract
The global prevalence of obesity has been increasing in recent years and is now the major public health challenge worldwide. While the risks of developing metabolic disorders (MD) including obesity and type 2 diabetes (T2D) have been historically thought to be essentially driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. Based on human epidemiological and pre-clinical experimental studies, this overview questioned the role of non-nutritional components as contributors to the epidemic of MD with a special emphasis on food contaminants and social stress. This overview examines the impact of early life adverse events (ELAE) focusing on exposures to food contaminants or social stress on weight gain and T2D occurrence in the offspring and explores potential mechanisms leading to MD in adulthood. Indeed, summing up data on both ELAE models in parallel allowed us to identify common patterns that appear worthwhile to study in MD etiology. This overview provides some evidence of a link between ELAE-induced intestinal barrier disruption, inflammation, epigenetic modifications, and the occurrence of MD. This overview sums up evidence that MD could have developmental origins and that ELAE are risk factors for MD at adulthood independently of nutritional status.
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Affiliation(s)
| | - Sandrine Ménard
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, 31024 Toulouse, France;
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36
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Chamniansawat S, Kampuang N, Suksridechacin N, Thongon N. Ultrastructural intestinal mucosa change after prolonged inhibition of gastric acid secretion by omeprazole in male rats. Anat Sci Int 2021; 96:142-156. [PMID: 32931001 DOI: 10.1007/s12565-020-00572-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
Abstract
Omeprazole is a potent inhibitor of gastric acid secretion. It was reported that omeprazole induced dramatic gastric mucosa morphologic changes from the resting state to the stimulated state. However, the effect of omeprazole administration on the ultrastructure and absorptive function of small intestines was largely unknown. Here, male Sprague-Dawley rats were daily treated with a single dose of omeprazole for 12 or 24 weeks. Ultrastructure intestinal mucosal change in duodenum, jejunum, and ileum was observed. We also determined small intestine inflammation, using intraepithelial lymphocytes activation. Finally, magnesium levels were measured in plasma, urine, feces, muscle, and bone to determine systemic magnesium balance. Omeprazole-treated rats had significantly decreased the width of tight junction, villous length, and absorptive area of duodenum, jejunum, and ileum compared to control rats. The small intestine of the omeprazole-treated group showed significantly higher intraepithelial lymphocytes activation levels compared with the control group. Lower secretory granules of Paneth cells at the base of the crypts were showed in omeprazole-treated rats. They also had significantly lower plasma, urinary, bone, and muscle Mg2+ contents indicating hypomagnesemia with systemic magnesium deficiency. In conclusion, prolonged omeprazole treatment-induced small intestinal inflammation and villous atrophy, which led to decrease small intestinal magnesium absorption in the condition of proton pump inhibitor-induced hypomagnesemia.
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Affiliation(s)
- Siriporn Chamniansawat
- Division of Anatomy, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chon Buri, 20131, Thailand
| | - Nattida Kampuang
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand
| | - Nasisorn Suksridechacin
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand
| | - Narongrit Thongon
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand.
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37
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Kumari MV, Amarasiri L, Rajindrajith S, Devanarayana NM. Functional abdominal pain disorders and asthma: two disorders, but similar pathophysiology? Expert Rev Gastroenterol Hepatol 2021; 15:9-24. [PMID: 32909837 DOI: 10.1080/17474124.2020.1821652] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Functional abdominal pain disorders (FAPDs) and asthma are common ailments affecting both children and adults worldwide. Multiple studies have demonstrated an association between these two disorders. However, the exact reason for this observed association is not apparent. AREAS COVERED The current review has explored available literature and outlined multiple underlying pathophysiological mechanisms, common to both asthma and FAPDs, as possible reasons for this association. EXPERT OPINION Smooth muscle dysfunction, hypersensitivity and hyper-responsiveness, mucosal inflammation, and barrier dysfunction involving gastrointestinal and respiratory tracts are the main underlying pathophysiological mechanisms described for the generation of symptoms in FAPDs and asthma. In addition, alterations in neuroendocrine regulatory functions, immunological dysfunction, and microbial dysbiosis have been described in both disorders. We believe that the pathophysiological processes that were explored in this article would be able to expand the mechanisms of the association. The in-depth knowledge is needed to be converted to therapeutic and preventive strategies to improve the quality of care of children suffering from FAPDs and asthma.
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Affiliation(s)
- Manori Vijaya Kumari
- Department of Physiology, Faculty of Medicine & Allied Sciences, Rajarata University of Sri Lanka , Anuradhapura, Sri Lanka
| | - Lakmali Amarasiri
- Department of Physiology, Faculty of Medicine, University of Colombo , Colombo, Sri Lanka
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38
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Chen Q, Suzuki K, Sifuentes-Dominguez L, Miyata N, Song J, Lopez A, Starokadomskyy P, Gopal P, Dozmorov I, Tan S, Ge B, Burstein E. Paneth cell-derived growth factors support tumorigenesis in the small intestine. Life Sci Alliance 2020; 4:4/3/e202000934. [PMID: 33372038 PMCID: PMC7772774 DOI: 10.26508/lsa.202000934] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/17/2022] Open
Abstract
Paneth cells, known for their production of antimicrobial peptides and growth factors in the gut epithelium, are found to play a key role in intestinal tumor formation through secretion of Wnt3. Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in ApcMin mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3. We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.
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Affiliation(s)
- Qing Chen
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Kohei Suzuki
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Luis Sifuentes-Dominguez
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA.,Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Naoteru Miyata
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Jie Song
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Adam Lopez
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Petro Starokadomskyy
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Igor Dozmorov
- Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Shuai Tan
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA
| | - Bujun Ge
- Department of General Surgery, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ezra Burstein
- Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas, TX, USA .,Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA
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Zhou C, Fang X, Xu J, Gao J, Zhang L, Zhao J, Meng Y, Zhou W, Han X, Bai Y, Li Z, Zou D. Bifidobacterium longum alleviates irritable bowel syndrome-related visceral hypersensitivity and microbiota dysbiosis via Paneth cell regulation. Gut Microbes 2020; 12:1782156. [PMID: 32584650 PMCID: PMC7524277 DOI: 10.1080/19490976.2020.1782156] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Although the oral administration of Bifidobacterium longum (B. longum) relieves the signs of irritable bowel syndrome (IBS) in clinical settings, the mechanisms underlying its effects are unclear. In this study, we evaluated the precise effects of B. longum on IBS via regulation of Paneth cell function. We confirmed the beneficial effects of B. longum on defecation habits and visceral hypersensitivity in WAS rats. Further analysis revealed that B. longum enhanced mucosal repair, promoted lysozyme production, and ameliorated dysbiosis of the microbiota in WAS rats. These processes are closely correlated with Paneth cell functions. In vitro, we incubated primary cultured enteroids with B. longum and found that B. longum promoted the proliferation of these organoids; this may be attributed to the upregulation of the stem niche factors WNT3A and TGF-β, which are secreted by Paneth cells. Based on our findings, we propose that B. longum relieves IBS by restoring the antimicrobial activity and stem niche maintenance function of Paneth cells.
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Affiliation(s)
- Chunhua Zhou
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China,Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Xue Fang
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jiajia Xu
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jun Gao
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Ling Zhang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Jiulong Zhao
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Yuting Meng
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Wei Zhou
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Xu Han
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China,CONTACT Zhaoshen Li Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China,Duowu Zou Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
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40
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Malaisé Y, Lencina C, Placide F, Bacquié V, Cartier C, Olier M, Buettner M, Wallbrecht M, Ménard S, Guzylack-Piriou L. Oral exposure to bisphenols induced food intolerance and colitis in vivo by modulating immune response in adult mice. Food Chem Toxicol 2020; 146:111773. [PMID: 33011352 DOI: 10.1016/j.fct.2020.111773] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/14/2020] [Accepted: 09/20/2020] [Indexed: 01/09/2023]
Abstract
Bisphenol (BP) A, a known food contaminant, is a possible risk factor in the epidemic of non-communicable diseases (NCD) including food intolerance and inflammatory bowel diseases (IBD). Regulatory restrictions regarding BPA usage led to BPA removal and replacement by poorly described substitutes, like BPS or BPF (few data on occurrence in food and human samples and biological effect). Oral tolerance protocol to ovalbumin (OVA) in WT mice and Il10-/- mice prone to IBD were used respectively to address immune responses towards food and microbial luminal antigens following BP oral exposure. Both mice models were orally exposed for five weeks to BPA, BPS or BPF at 0.5, 5 and 50 μg/kg of body weight (bw)/day (d). Oral exposure to BPs at low doses (0.5 and 5 μg/kg bw/d) impaired oral tolerance as indicated by higher humoral and pro-inflammatory cellular responses in OVA-tolerized mice. However, only BPF exacerbate colitis in Il10-/- prone mice associated with a defect of fecal IgA and increased secretion of TNF-α in colon. These findings provide a unique comparative study on effects of adult oral exposure to BPs on immune responses and its consequences on NCD related to intestinal luminal antigen development.
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Affiliation(s)
- Yann Malaisé
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Corinne Lencina
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Fanny Placide
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Valérie Bacquié
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Christel Cartier
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Maïwenn Olier
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Manuela Buettner
- Hannover Medical School, Institute for Laboratory Animal Science, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Markus Wallbrecht
- Hannover Medical School, Institute for Laboratory Animal Science, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Sandrine Ménard
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Laurence Guzylack-Piriou
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France.
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41
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Hassan M, Moghadamrad S, Sorribas M, Muntet SG, Kellmann P, Trentesaux C, Fraudeau M, Nanni P, Wolski W, Keller I, Hapfelmeier S, Shroyer NF, Wiest R, Romagnolo B, De Gottardi A. Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals. J Hepatol 2020; 73:628-639. [PMID: 32205193 DOI: 10.1016/j.jhep.2020.03.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/27/2020] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.
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Affiliation(s)
- Mohsin Hassan
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Sheida Moghadamrad
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Marcel Sorribas
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland
| | - Sergi G Muntet
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Philipp Kellmann
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Coralie Trentesaux
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Marie Fraudeau
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Paolo Nanni
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Witold Wolski
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Irene Keller
- Department for Biomedical Research and Swiss Institute of Bioinformatics, University of Bern, Switzerland
| | | | - Noah F Shroyer
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - Reiner Wiest
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Beatrice Romagnolo
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Andrea De Gottardi
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland); Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland.
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Ilchmann-Diounou H, Menard S. Psychological Stress, Intestinal Barrier Dysfunctions, and Autoimmune Disorders: An Overview. Front Immunol 2020; 11:1823. [PMID: 32983091 PMCID: PMC7477358 DOI: 10.3389/fimmu.2020.01823] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Autoimmune disorders (ADs) are multifactorial diseases involving, genetic, epigenetic, and environmental factors characterized by an inappropriate immune response toward self-antigens. In the past decades, there has been a continuous rise in the incidence of ADs, which cannot be explained by genetic factors alone. Influence of psychological stress on the development or the course of autoimmune disorders has been discussed for a long time. Indeed, based on epidemiological studies, stress has been suggested to precede AD occurrence and to exacerbate symptoms. Furthermore, compiling data showed that most of ADs are associated with gastrointestinal symptoms, that is, microbiota dysbiosis, intestinal hyperpermeability, and intestinal inflammation. Interestingly, social stress (acute or chronic, in adult or in neonate) is a well-described intestinal disrupting factor. Taken together, those observations question a potential role of stress-induced defect of the intestinal barrier in the onset and/or the course of ADs. In this review, we aim to present evidences supporting the hypothesis for a role of stress-induced intestinal barrier disruption in the onset and/or the course of ADs. We will mainly focus on autoimmune type 1 diabetes, multiple sclerosis and systemic lupus erythematosus, ADs for which we could find sufficient circumstantial data to support this hypothesis. We excluded gastrointestinal (GI) ADs like coeliac disease to privilege ADs not focused on intestinal disorders to avoid confounding factors. Indeed, GIADs are characterized by antibodies directed against intestinal barrier actors.
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MESH Headings
- Animals
- Autoimmune Diseases/epidemiology
- Autoimmune Diseases/immunology
- Autoimmune Diseases/metabolism
- Autoimmune Diseases/microbiology
- Autoimmunity
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/microbiology
- Dysbiosis
- Gastrointestinal Microbiome
- Host-Pathogen Interactions
- Humans
- Intestinal Mucosa/immunology
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/microbiology
- Lupus Erythematosus, Systemic/epidemiology
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/metabolism
- Lupus Erythematosus, Systemic/microbiology
- Multiple Sclerosis/epidemiology
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/microbiology
- Permeability
- Risk Factors
- Stress, Psychological/epidemiology
- Stress, Psychological/immunology
- Stress, Psychological/metabolism
- Stress, Psychological/microbiology
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Affiliation(s)
| | - Sandrine Menard
- Neuro-Gastroenterology and Nutrition Team, Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
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Impact of PepT1 deletion on microbiota composition and colitis requires multiple generations. NPJ Biofilms Microbiomes 2020; 6:27. [PMID: 32694535 PMCID: PMC7374158 DOI: 10.1038/s41522-020-0137-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 06/26/2020] [Indexed: 12/19/2022] Open
Abstract
Numerous studies of knockout mice find impacts on microbiota composition that influence host phenotype. However, such differences can vanish when KO mice are compared directly to WT littermates, suggesting these differences do not reflect the genetic deletion per se but microbiota composition drifting over generations. Hence, our hypothesis that absence of di/tri-peptide transporter PepT1 altered microbiota composition resulting in resistance to colitis compelled scrutiny. In this study, we used PepT1−/− and WT founder mice bred separately for multiple generations. Such mice were then bred to each other to generate F1 PepT1−/− and WT littermates, which were then bred within their genotype to generate F2, F3, and F4, offspring. Here we report that founder PepT1−/− mice were, relative to their WT counterparts, resistant to DSS colitis. Such resistance was associated with alterations in gut microbiota, which, when transplanted to germfree mice, was sufficient to transfer resistance to colitis. Such differences were not observed when comparing F1 PepT1−/− to F1 WT littermates but rather, returned gradually over subsequent generations such that, relative to their F4 WT controls, F4 PepT1−/− displayed microbiota composition and colitis-resistant phenotype nearly identical to the founder PepT1−/− mice. Our findings indicate a role for PepT1 in influencing microbiota composition and, consequently, proneness to colitis and cancer. Overall, our study indicates that littermate-controlled experiments can be insufficient for assessing microbiota-dependent phenotypes and prevent a full comprehension of genotype-driven phenomena. Rather, impact of a single genetic alteration on microbiota and host phenotype may take generations to manifest.
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van Thiel IAM, de Jonge WJ, Chiu IM, van den Wijngaard RM. Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel. Am J Physiol Gastrointest Liver Physiol 2020; 318:G1034-G1041. [PMID: 32308040 PMCID: PMC7642838 DOI: 10.1152/ajpgi.00196.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mechanisms in visceral hypersensitivity, working toward understanding how gut microbiota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.
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Affiliation(s)
- Isabelle A. M. van Thiel
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Wouter J. de Jonge
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands,3Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands,4Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Isaac M. Chiu
- 5Department of Immunology, Harvard Medical School. Boston, Massachusetts
| | - Rene M. van den Wijngaard
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands,3Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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Theodorou V, Beaufrand C, Yvon S, Laforge G, Burmeister Y, Müller A, Seilheimer B, Bueno L, Eutamene H. The multicomponent medication Spascupreel attenuates stress-induced gut dysfunction in rats. Neurogastroenterol Motil 2020; 32:e13798. [PMID: 32059072 PMCID: PMC7217055 DOI: 10.1111/nmo.13798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/13/2019] [Accepted: 12/23/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common disorder worldwide. It is characterized by abdominal pain/discomfort and changes in bowel habits. Due to the multifactorial pathophysiology and the heterogeneity of IBS patients, appropriate treatment of IBS is still a challenge. Spascupreel (SP-11), as a multicomponent medication, has the potential to modulate multiple pathophysiological pathways simultaneously. Therefore, the objective of the current study was to investigate the effects of oral SP-11 treatment on stress-induced changes of peripheral and central functions in a rat model mimicking human IBS. METHODS Naïve Wistar rats were treated with SP-11 (0.9 tab/kg) or NaCl 0.9% by oral gavage for 4 days before 2-hour partial restraint stress (PRS) procedure. Twenty minutes after PRS, central and peripheral stress-induced changes affecting IBS were assessed. These include the hypothalamic-pituitary-adrenal (HPA) axis response through plasma ACTH and corticosterone measurements, visceral pain in response to colorectal distension, gut permeability, colonic mast cell number, and sensitization as well as gut transit time. RESULTS Treatment with SP-11 reduced the HPA axis activation in response to PRS. At the gut level, a reduction in colonic hypersensitivity to colorectal distension, a normalization of gut transit time acceleration, a reduced mast cell sensitization, and a trend toward reduced gut hyperpermeability were observed. CONCLUSIONS These data suggest that stress-induced IBS signs can be reduced using SP-11 in rats. The observed effects and the good tolerability of the drug make SP-11 an innovative candidate in the management of IBS.
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Affiliation(s)
- Vassilia Theodorou
- INRAToxAlimUMR 1331Neuro‐Gastroenterology and Nutrition GroupENVTINP‐PurpanUPSUniversité de ToulouseToulouseFrance
| | - Catherine Beaufrand
- INRAToxAlimUMR 1331Neuro‐Gastroenterology and Nutrition GroupENVTINP‐PurpanUPSUniversité de ToulouseToulouseFrance
| | - Sophie Yvon
- INRAToxAlimUMR 1331Neuro‐Gastroenterology and Nutrition GroupENVTINP‐PurpanUPSUniversité de ToulouseToulouseFrance
| | - Guylaine Laforge
- INRAToxAlimUMR 1331Neuro‐Gastroenterology and Nutrition GroupENVTINP‐PurpanUPSUniversité de ToulouseToulouseFrance
| | | | | | | | | | - Helene Eutamene
- INRAToxAlimUMR 1331Neuro‐Gastroenterology and Nutrition GroupENVTINP‐PurpanUPSUniversité de ToulouseToulouseFrance
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46
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Wehkamp J, Stange EF. An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease. Front Immunol 2020; 11:646. [PMID: 32351509 PMCID: PMC7174711 DOI: 10.3389/fimmu.2020.00646] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022] Open
Abstract
The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, life-style risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.
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Affiliation(s)
- Jan Wehkamp
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
| | - Eduard F Stange
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
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47
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Inczefi O, Bacquié V, Olier-Pierre M, Rincel M, Ringot-Destrez B, Ellero-Simatos S, Eutamène H, Bétoulières C, Thomas J, Lainé J, Gros L, Lévêque M, Leonard R, Harkat C, Robbe-Masselot C, Róka R, Mercier-Bonin M, Theodorou V, Darnaudéry M, Turner JR, Ferrier L. Targeted Intestinal Tight Junction Hyperpermeability Alters the Microbiome, Behavior, and Visceromotor Responses. Cell Mol Gastroenterol Hepatol 2020; 10:206-208.e3. [PMID: 32147490 PMCID: PMC7296230 DOI: 10.1016/j.jcmgh.2020.02.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/18/2022]
Affiliation(s)
- O Inczefi
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France; First Department of Medicine, University of Szeged, Szeged, Hungary
| | - V Bacquié
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Olier-Pierre
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Rincel
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - B Ringot-Destrez
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - S Ellero-Simatos
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - H Eutamène
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - C Bétoulières
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - J Thomas
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - J Lainé
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - L Gros
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - M Lévêque
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - R Leonard
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - C Harkat
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - C Robbe-Masselot
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - R Róka
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - M Mercier-Bonin
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - V Theodorou
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Darnaudéry
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - J R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - L Ferrier
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France.
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Zhang X, Fisher R, Hou W, Shields D, Epperly MW, Wang H, Wei L, Leibowitz BJ, Yu J, Alexander LM, VAN Pijkeren JP, Watkins S, Wipf P, Greenberger JS. Second-generation Probiotics Producing IL-22 Increase Survival of Mice After Total Body Irradiation. In Vivo 2020; 34:39-50. [PMID: 31882461 PMCID: PMC6984118 DOI: 10.21873/invivo.11743] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/21/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Intestinal damage induced by total body irradiation (TBI) reduces leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-expressing stem cells, goblet, and Paneth cells, breaching the epithelial lining, and facilitating bacterial translocation, sepsis, and death. MATERIALS AND METHODS Survival was measured after TBI in animals that received wild-type or recombinant bacteria producing interleukin-22 (IL-22). Changes in survival due to microbially delivered IL-22 were measured. Lactobacillus reuteri producing IL-22, or Escherichia coli-IL-22 were compared to determine which delivery system is better. RESULTS C57BL/6 mice receiving IL-22 probiotics at 24 h after 9.25 Gy TBI, demonstrated green fluorescent protein-positive bacteria in the intestine, doubled the number of Lgr5+ intestinal stem cells, and increased 30-day survival. Bacteria were localized to the jejunum, ileum, and colon. CONCLUSION Second-generation probiotics appear to be valuable for mitigation of TBI, and radiation protection during therapeutic total abdominal irradiation.
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Affiliation(s)
- Xichen Zhang
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Renee Fisher
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Wen Hou
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Donna Shields
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Michael W Epperly
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A
| | - Hong Wang
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Liang Wei
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Brian J Leibowitz
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Jian Yu
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Laura M Alexander
- Department of Food Science, University of Wisconsin-Madison, Madison, WI, U.S.A
| | | | - Simon Watkins
- Center for Imaging, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Joel S Greenberger
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, U.S.A.
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Dutcher EG, Pama EC, Lynall ME, Khan S, Clatworthy MR, Robbins TW, Bullmore ET, Dalley JW. Early-life stress and inflammation: A systematic review of a key experimental approach in rodents. Brain Neurosci Adv 2020; 4:2398212820978049. [PMID: 33447663 PMCID: PMC7780197 DOI: 10.1177/2398212820978049] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/11/2020] [Indexed: 12/11/2022] Open
Abstract
Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.
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Affiliation(s)
- Ethan G. Dutcher
- Department of Psychology, University of Cambridge, Cambridge, UK
| | | | - Mary-Ellen Lynall
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Shahid Khan
- GlaxoSmithKline Research & Development, Stevenage, UK
| | | | | | | | - Jeffrey W. Dalley
- Department of Psychology, University of Cambridge, Cambridge, UK
- Department of Psychiatry, University of Cambridge, Cambridge, UK
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50
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Yu TX, Chung HK, Xiao L, Piao JJ, Lan S, Jaladanki SK, Turner DJ, Raufman JP, Gorospe M, Wang JY. Long Noncoding RNA H19 Impairs the Intestinal Barrier by Suppressing Autophagy and Lowering Paneth and Goblet Cell Function. Cell Mol Gastroenterol Hepatol 2019; 9:611-625. [PMID: 31862317 PMCID: PMC7078540 DOI: 10.1016/j.jcmgh.2019.12.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The protective intestinal mucosal barrier consists of multiple elements including mucus and epithelial layers and immune defense; nonetheless, barrier dysfunction is common in various disorders. The imprinted and developmentally regulated long noncoding RNA H19 is involved in many cell processes and diseases. Here, we investigated the role of H19 in regulating Paneth and goblet cells and autophagy, and its impact on intestinal barrier dysfunction induced by septic stress. METHODS Studies were conducted in H19-deficient (H19-/-) mice, mucosal tissues from patients with sepsis, primary enterocytes, and Caco-2 cells. Septic stress was induced by cecal ligation and puncture (CLP), and gut permeability was detected by tracer fluorescein isothiocyanate-dextran assays. The function of Paneth and goblet cells was examined by immunostaining for lysozyme and mucin 2, respectively, and autophagy was examined by microtubule-associated proteins 1A/1B light chain 3 II immunostaining and Western blot analysis. Intestinal organoids were isolated from H19-/- and control littermate mice and treated with lipopolysaccharide (LPS). RESULTS Intestinal mucosal tissues in mice 24 hours after exposure to CLP and in patients with sepsis showed high H19 levels, associated with intestinal barrier dysfunction. Targeted deletion of the H19 gene in mice enhanced the function of Paneth and goblet cells and promoted autophagy in the small intestinal mucosa. Knockout of H19 protected Paneth and goblet cells against septic stress, preserved autophagy activation, and promoted gut barrier function after exposure to CLP. Compared with organoids from control littermate mice, intestinal organoids isolated from H19-/- mice had increased numbers of lysozyme- and mucin 2-positive cells and showed increased tolerance to LPS. Conversely, ectopic overexpression of H19 in cultured intestinal epithelial cells prevented rapamycin-induced autophagy and abolished the rapamycin-induced protection of the epithelial barrier against LPS. CONCLUSIONS In investigations of mice, human tissues, primary organoids, and intestinal epithelial cells, we found that increased H19 inhibited the function of Paneth and goblet cells and suppressed autophagy, thus potentially contributing to barrier dysfunction in intestinal pathologies.
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Affiliation(s)
- Ting-Xi Yu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Hee K Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jun-Jie Piao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Shaoyang Lan
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Suraj K Jaladanki
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Douglas J Turner
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jean-Pierre Raufman
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
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