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1
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Thapa D, Ghimire A, Warne LN, Carlessi R. Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease. Pharmaceuticals (Basel) 2025; 18:478. [PMID: 40283915 PMCID: PMC12030576 DOI: 10.3390/ph18040478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including "cannabinoids", "endocannabinoid system", "endocannabinoidome", "inflammatory bowel disease", and "extraintestinal manifestations" were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.
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Affiliation(s)
- Dinesh Thapa
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
| | - Anjali Ghimire
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
| | - Leon N. Warne
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
- The Vet Pharmacist, East Fremantle, WA 6158, Australia
| | - Rodrigo Carlessi
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
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2
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Liu F, Guo C, Liu X, Gu Z, Zou W, Tang X, Tang J. Luteolin in Inflammatory Bowel Disease and Colorectal Cancer: A Disease Continuum Perspective. Curr Issues Mol Biol 2025; 47:126. [PMID: 39996847 PMCID: PMC11853781 DOI: 10.3390/cimb47020126] [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: 01/06/2025] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that may progress to colorectal cancer (CRC), presenting significant challenges to global health. With shifts in lifestyle, the incidence of both conditions continues to rise, underscoring the urgent need for effective treatments. While traditional therapies can be effective, their high recurrence rates and associated adverse reactions limit their broader application. Luteolin, a flavonoid derived from natural plants, has emerged as a promising focus in both IBD and CRC research due to its multi-target therapeutic potential. This article reviews the molecular mechanisms and signaling pathways through which luteolin regulates immune cell differentiation, mitigates inflammation and oxidative stress, modulates gut microbiota, and restores intestinal mucosal barrier function in IBD. In the context of CRC, luteolin demonstrates significant anti-tumor effects by inhibiting cancer cell proliferation, inducing apoptosis, and suppressing cell migration and invasion. Notably, luteolin has demonstrated significant improvements in IBD symptoms by influencing the differentiation of T cell subsets, decreasing the expression of inflammatory mediators, activating antioxidant pathways, and enhancing the structure of gut microbiota. Furthermore, advancements in formulation technology, such as the use of polymer micelles and responsive nanoparticles, have greatly improved the bioavailability and efficacy of luteolin. However, further investigation is needed to address the bioavailability and potential toxicity of luteolin, particularly in the critical transition from IBD to CRC. This article emphasizes the potential of luteolin in the treatment of IBD and CRC and anticipates its promising prospects for future clinical applications as a natural therapeutic agent.
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Affiliation(s)
- Fang Liu
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; (F.L.); (C.G.)
- Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong 637100, China; (X.L.); (Z.G.); (W.Z.)
| | - Cui Guo
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; (F.L.); (C.G.)
| | - Xue Liu
- Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong 637100, China; (X.L.); (Z.G.); (W.Z.)
| | - Zhili Gu
- Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong 637100, China; (X.L.); (Z.G.); (W.Z.)
| | - Wenxuan Zou
- Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong 637100, China; (X.L.); (Z.G.); (W.Z.)
| | - Xuegui Tang
- Clinical Medicine College of Integrated Chinese and Western Medicine, North Sichuan Medical College, Nanchong 637100, China; (X.L.); (Z.G.); (W.Z.)
| | - Jianyuan Tang
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; (F.L.); (C.G.)
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Abstract
Consumption of probiotic products continues to increase, perhaps driven by an interest in gut health. However, the field is filled with controversy, inconsistencies, misuse of terminology, and poor communication. While the probiotic concept is biologically plausible and in some cases mechanistically well established, extrapolation of preclinical results to humans has seldom been proven in well-conducted clinical trials. With noteworthy exceptions, clinical guidance has often been derived not from large, adequately powered clinical trials but rather from comparisons of disparate, small studies with insufficient power to identify the optimal strain. The separation of probiotics from live biotherapeutic products has brought some clarity from a regulatory perspective, but in both cases, consumers should expect scientific rigor and strong supporting evidence for health claims.
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Affiliation(s)
- Eamonn M M Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
| | - Fergus Shanahan
- Department of Medicine and Alimentary Pharmabiotic Centre, Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland;
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4
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Chandwaskar R, Dalal R, Gupta S, Sharma A, Parashar D, Kashyap VK, Sohal JS, Tripathi SK. Dysregulation of T cell response in the pathogenesis of inflammatory bowel disease. Scand J Immunol 2024; 100:e13412. [PMID: 39394898 DOI: 10.1111/sji.13412] [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: 11/20/2023] [Revised: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are gut inflammatory diseases that were earlier prevalent in the Western Hemisphere but now are on the rise in the East, with India standing second highest in the incidence rate in the world. Inflammation in IBD is a cause of dysregulated immune response, wherein helper T (Th) cell subsets and their cytokines play a major role in the pathogenesis of IBD. In addition, gut microbiota, environmental factors such as dietary factors and host genetics influence the outcome and severity of IBD. Dysregulation between effector and regulatory T cells drives gut inflammation, as effector T cells like Th1, Th17 and Th9 subsets Th cell lineages were found to be increased in IBD patients. In this review, we attempted to discuss the role of different Th cell subsets together with other T cells like CD8+ T cells, NKT and γδT cells in the outcome of gut inflammation in IBD. We also highlighted the potential therapeutic candidates for IBD.
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Affiliation(s)
- Rucha Chandwaskar
- Amity Institute of Microbial Technology (AIMT), Amity University Jaipur, Rajasthan, India
| | - Rajdeep Dalal
- Infection and Immunology Lab, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Saurabh Gupta
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Aishwarya Sharma
- Sri Siddhartha Medical College and Research Center, Tumkur, Karnataka, India
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Jagdip Singh Sohal
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Subhash K Tripathi
- Center for Immunity and Immunotherapies and Program for Cell and Gene Therapy, Seattle Children's Research Institute, Seattle, Washington, USA
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5
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Adams L, Li X, Burchmore R, Goodwin RJA, Wall DM. Microbiome-derived metabolite effects on intestinal barrier integrity and immune cell response to infection. MICROBIOLOGY (READING, ENGLAND) 2024; 170:001504. [PMID: 39392674 PMCID: PMC11469068 DOI: 10.1099/mic.0.001504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 09/12/2024] [Indexed: 10/12/2024]
Abstract
The gut microbiota exerts a significant influence on human health and disease. While compositional changes in the gut microbiota in specific diseases can easily be determined, we lack a detailed mechanistic understanding of how these changes exert effects at the cellular level. However, the putative local and systemic effects on human physiology that are attributed to the gut microbiota are clearly being mediated through molecular communication. Here, we determined the effects of gut microbiome-derived metabolites l-tryptophan, butyrate, trimethylamine (TMA), 3-methyl-4-(trimethylammonio)butanoate (3,4-TMAB), 4-(trimethylammonio)pentanoate (4-TMAP), ursodeoxycholic acid (UDCA), glycocholic acid (GCA) and benzoate on the first line of defence in the gut. Using in vitro models of intestinal barrier integrity and studying the interaction of macrophages with pathogenic and non-pathogenic bacteria, we could ascertain the influence of these metabolites at the cellular level at physiologically relevant concentrations. Nearly all metabolites exerted positive effects on barrier function, but butyrate prevented a reduction in transepithelial resistance in the presence of the pathogen Escherichia coli, despite inducing increased apoptosis and exerting increased cytotoxicity. Induction of IL-8 was unaffected by all metabolites, but GCA stimulated increased intra-macrophage growth of E. coli and tumour necrosis-alpha (TNF-α) release. Butyrate, 3,4-TMAB and benzoate all increased TNF-α release independent of bacterial replication. These findings reiterate the complexity of understanding microbiome effects on host physiology and underline that microbiome metabolites are crucial mediators of barrier function and the innate response to infection. Understanding these metabolites at the cellular level will allow us to move towards a better mechanistic understanding of microbiome influence over host physiology, a crucial step in advancing microbiome research.
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Affiliation(s)
- Lauren Adams
- School of Infection and Immunology, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8TA, UK
| | - Xiang Li
- School of Infection and Immunology, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8TA, UK
| | - Richard Burchmore
- School of Infection and Immunology, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8TA, UK
| | - Richard J. A. Goodwin
- School of Infection and Immunology, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8TA, UK
- Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, CB4 0WG, UK
| | - Daniel M. Wall
- School of Infection and Immunology, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8TA, UK
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Hsu CY, Mustafa MA, Moath Omar T, Taher SG, Ubaid M, Gilmanova NS, Nasrat Abdulraheem M, Saadh MJ, Athab AH, Mirzaei R, Karampoor S. Gut instinct: harnessing the power of probiotics to tame pathogenic signaling pathways in ulcerative colitis. Front Med (Lausanne) 2024; 11:1396789. [PMID: 39323474 PMCID: PMC11422783 DOI: 10.3389/fmed.2024.1396789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 08/22/2024] [Indexed: 09/27/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) marked by persistent inflammation of the mucosal lining of the large intestine, leading to debilitating symptoms and reduced quality of life. Emerging evidence suggests that an imbalance of the gut microbiota plays a crucial role in UC pathogenesis, and various signaling pathways are implicated in the dysregulated immune response. Probiotics are live microorganisms that confer health benefits to the host, have attracted significant attention for their potential to restore gut microbial balance and ameliorate inflammation in UC. Recent studies have elucidated the mechanisms by which probiotics modulate these signaling pathways, often by producing anti-inflammatory molecules and promoting regulatory immune cell function. For example, probiotics can inhibit the nuclear factor-κB (NF-κB) pathway by stabilizing Inhibitor of kappa B alpha (IκBα), dampening the production of proinflammatory cytokines. Similarly, probiotics can modulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, suppressing the activation of STAT1 and STAT3 and thus reducing the inflammatory response. A better understanding of the underlying mechanisms of probiotics in modulating pathogenic signaling pathways in UC will pave the way for developing more effective probiotic-based therapies. In this review, we explore the mechanistic role of probiotics in the attenuation of pathogenic signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinases (MAPKs), Wnt/β-catenin, the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, Toll-like receptors (TLRs), interleukin-23 (IL-23)/IL-17 signaling pathway in UC.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ, United States
| | - Mohammed Ahmed Mustafa
- Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Baghdad, Iraq
- Department of Pathological Analyzes, College of Applied Sciences, University of Samarra, Samarra, Iraq
| | - Thabit Moath Omar
- Department of Medical Laboratory Technics, College of Health and Medical Technology, Alnoor University, Mosul, Iraq
| | - Sada Gh Taher
- Department of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammed Ubaid
- Department of MTL, Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Nataliya S. Gilmanova
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | - Aya H. Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
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7
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Li Y, Wang W, Liu Y, Li S, Wang J, Hou L. Diminished Immune Response and Elevated Abundance in Gut Microbe Dubosiella in Mouse Models of Chronic Colitis with GBP5 Deficiency. Biomolecules 2024; 14:873. [PMID: 39062588 PMCID: PMC11274912 DOI: 10.3390/biom14070873] [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: 07/05/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Guanylate binding protein 5 (GBP5) is an emerging immune component that has been increasingly recognized for its involvement in autoimmune diseases, particularly inflammatory bowel disease (IBD). IBD is a complex disease involving inflammation of the gastrointestinal tract. Here, we explored the functional significance of GBP5 using Gbp5 knockout mice and wildtype mice exposed to dextran sulfate sodium (DSS) to generate chronic colitis model. We found that Gbp5 deficiency protected mice from DSS-induced chronic colitis. Transcriptome analysis of colon tissues showed reduced immune responses in Gbp5 knockout mice compared to those in corresponding wildtype mice. We further observed that after repeated DSS exposure, the gut microbiota was altered, both in wildtype mice and Gbp5 knockout mice; however, the gut microbiome health index was higher in the Gbp5 knockout mice. Notably, a probiotic murine commensal bacterium, Dubosiella, was predominantly enriched in these knockout mice. Our findings suggest that GBP5 plays an important role in promoting inflammation and dysbiosis in the intestine, the prevention of which might therefore be worth exploring in regards to IBD treatment.
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Affiliation(s)
- Yichen Li
- Medical College, Jiaying University, Meizhou 514031, China
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, Department of General Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Wenxia Wang
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, Department of General Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Yuxuan Liu
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.L.); (S.L.); (J.W.)
| | - Senru Li
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.L.); (S.L.); (J.W.)
| | - Jingyu Wang
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.L.); (S.L.); (J.W.)
| | - Linlin Hou
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.L.); (S.L.); (J.W.)
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Soni D, Upadhayay S, Dhureja M, Arthur R, Kumar P. Crosstalk between gut-brain axis: unveiling the mysteries of gut ROS in progression of Parkinson's disease. Inflammopharmacology 2024:10.1007/s10787-024-01510-2. [PMID: 38992324 DOI: 10.1007/s10787-024-01510-2] [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: 01/22/2024] [Accepted: 06/06/2024] [Indexed: 07/13/2024]
Abstract
"Path to a good mood lies through the gut." This statement seems to imply that it has long been believed that the gut is connected with the brain. Research has shown that eating food activates the reward system and releases dopamine (DA), establishing a link between the peripheral and central nervous system. At the same time, researchers also trust that the gut is involved in the onset of many diseases, including Parkinson's disease (PD), in which gastrointestinal dysfunction is considered a prevalent symptom. Reports suggest that PD starts from the gut and reaches the brain via the vagus nerve. Recent studies have revealed an intriguing interaction between the gut and brain, which links gut dysbiosis to the etiology of PD. This review aims to explore the mechanistic pathway how reactive oxygen species (ROS) generation in the gut affects the makeup and operation of the dopamine circuitry in the brain. Our primary concern is ROS generation in the gut, which disrupts the gut microbiome (GM), causing α-synuclein accumulation and inflammation. This trio contributes to the loss of DA neurons in the brain, resulting in PD development. This review also compiles pre-clinical and clinical studies on antioxidants, demonstrating that antioxidants reduce ROS and increase DA levels. Collectively, the study highlights the necessity of comprehending the gut-brain axis for unraveling the riddles of PD pathogenesis and considering new therapeutic approaches.
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Affiliation(s)
- Divya Soni
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Shubham Upadhayay
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Maanvi Dhureja
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Richmond Arthur
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India.
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Hara M, Suzuki H, Hayashi D, Morii W, Nakamura T, Kiyoki K, Hara H, Ishii R, Noguchi E, Takada H. Gut microbiota of one-and-a-half-year-old food-allergic and healthy children. Allergol Int 2024:S1323-8930(24)00042-X. [PMID: 38600019 DOI: 10.1016/j.alit.2024.03.004] [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: 06/28/2023] [Revised: 02/29/2024] [Accepted: 03/07/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Intestinal bacteria may play a role in the development of food allergies. This study aimed to analyze and compare the gut microbiota of food-allergic children with that of healthy children of the same age. METHODS Stool samples were collected from one-and-a-half-year-old food-allergic (FA group, n = 29) and healthy controls (HC group, n = 19). A questionnaire was provided to examine the children's birth, dietary, medical, and social histories. The gut microbiota was profiled by 16S rRNA sequencing. Differences in taxonomic composition were assessed using linear discriminant analysis effect size (LEfSe), and microbial functional profiles were predicted with Tax4Fun2. RESULTS No significant difference in the alpha diversity index between the two groups; however, a negative correlation was observed between the Shannon diversity index and the relative abundance of Bacteroides. A significant difference was observed in beta diversity (permutational multivariate analysis of variance) in the bacterial composition between the FA and HC groups (P < 0.05). The FA group had a higher abundance of Escherichia and Anaeromassilibacillus and a lower abundance of Bacteroides, Oscillibacter, Ruminococcus, Hungateiclostridium and Anaerotaenia than the HC group (LEfSe: linear discriminant analysis score >2). The FA group showed a predicted increase in the expression levels of genes associated with intestinal pathogenicity compared with that in the HC group. CONCLUSIONS The gut microbiota of food-allergic children has a higher abundance of bacteria involved in intestinal inflammation and a lower abundance of bacteria involved in immune tolerance than that of healthy children. This dysbiosis may also be associated with food allergies.
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Affiliation(s)
- Monami Hara
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; Department of Child Health, Institute of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hisato Suzuki
- Department of Child Health, Institute of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan; Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Hayashi
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; Department of Pediatrics, Tsukuba Medical Center Hospital, Ibaraki, Japan
| | - Wataru Morii
- Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Takako Nakamura
- Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kaori Kiyoki
- Department of Pediatrics, Tsukuba Medical Center Hospital, Ibaraki, Japan
| | - Hideki Hara
- Department of Pediatrics, Tsukuba Medical Center Hospital, Ibaraki, Japan
| | - Ryota Ishii
- Department of Biostatistics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Emiko Noguchi
- Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
| | - Hidetoshi Takada
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan; Department of Child Health, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
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10
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Gustafson KL, McAdams ZL, Russell AL, Dorfmeyer RA, Turner GM, Ericsson AC. Effect size of delayed freezing, diurnal variation, and hindgut location on the mouse fecal microbiome. iScience 2024; 27:109090. [PMID: 38361608 PMCID: PMC10867441 DOI: 10.1016/j.isci.2024.109090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/09/2023] [Accepted: 01/29/2024] [Indexed: 02/17/2024] Open
Abstract
Practical considerations in fecal sample collection for microbiome research include time to sample storage, time of collection, and hindgut position during terminal collections. Here, parallel experiments were performed to investigate the relative effect of these factors on microbiome composition in mice colonized with two different vendor-origin microbiomes. 16S rRNA amplicon sequencing of immediately flash-frozen feces showed no difference in alpha or beta diversity compared to samples incubated up to 9 h at room temperature. Samples collected in the morning showed greater alpha diversity compared to samples collected in the afternoon. While a significant effect of time was detected in all hindgut regions, the effect increased from cecum to distal colon. This study highlights common scenarios in microbiome research that may affect outcome measures of microbial community analysis. However, we demonstrate a relatively low effect size of these technical factors when compared to a primary experimental factor with large intergroup variability.
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Affiliation(s)
- Kevin L. Gustafson
- University of Missouri (MU) Comparative Medicine Program, Columbia, MO 65201, USA
- Department of Veterinary Pathobiology, MU, Columbia, MO 65201, USA
| | - Zachary L. McAdams
- Molecular Pathogenesis and Therapeutics Program, MU, Columbia, MO 65201, USA
| | - Amber L. Russell
- Department of Veterinary Pathobiology, MU, Columbia, MO 65201, USA
| | - Rebecca A. Dorfmeyer
- MU Metagenomics Center (MUMC), Mutant Mouse Resource and Research Center at the University of Missouri (MU MMRRC), Columbia, MO 65201, USA
| | - Giedre M. Turner
- MU Metagenomics Center (MUMC), Mutant Mouse Resource and Research Center at the University of Missouri (MU MMRRC), Columbia, MO 65201, USA
| | - Aaron C. Ericsson
- University of Missouri (MU) Comparative Medicine Program, Columbia, MO 65201, USA
- Department of Veterinary Pathobiology, MU, Columbia, MO 65201, USA
- Molecular Pathogenesis and Therapeutics Program, MU, Columbia, MO 65201, USA
- MU Metagenomics Center (MUMC), Mutant Mouse Resource and Research Center at the University of Missouri (MU MMRRC), Columbia, MO 65201, USA
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11
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Zamani M, Alizadeh-Tabari S. Does Elderly-Onset Inflammatory Bowel Disease Increase Risk of Colorectal Cancer? A Systematic Review and Meta-Analysis. J Clin Med 2023; 13:148. [PMID: 38202155 PMCID: PMC10779516 DOI: 10.3390/jcm13010148] [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: 11/08/2023] [Revised: 12/07/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Although younger adults with inflammatory bowel disease (IBD) are known to have an increased risk of developing colorectal cancer (CRC), the impact of IBD on CRC risk in elderly patients is not yet fully understood. Therefore, we conducted this systematic review and meta-analysis to address this knowledge gap. METHODS We thoroughly searched Embase, PubMed, and Scopus, covering the literature from inception to 31 August 2023, in any language. We enrolled population-based cohort studies that appraised the risk of CRC development in elderly patients (≥60 years) with IBD as compared to the non-IBD population. Our meta-analysis provided pooled relative risk (RR) with 95% confidence intervals (CIs) using a random-effect model. RESULTS Out of 3904 citations, 3 eligible cohort studies were ultimately included, reporting 694 CRC events in 35,187 patients with IBD. According to analysis, the risk of developing CRC did not increase in patients with elderly-onset IBD (RR = 1.17 [95% CI: 0.86-1.47]; I2 = 62.6%). This lack of a significant association was observed in both patients with Crohn's disease (RR = 1.28 [95% CI: 0.88-1.69]) and ulcerative colitis (RR = 0.99 [95% CI: 0.90-1.09]) (p for interaction = 0.166). CONCLUSION Our findings revealed no significant increase in the risk of incident CRC in patients with elderly-onset IBD, suggesting that intense screening of these patients for CRC may not be necessary.
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Affiliation(s)
- Mohammad Zamani
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
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12
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Yuan S, Wang KS, Meng H, Hou XT, Xue JC, Liu BH, Cheng WW, Li J, Zhang HM, Nan JX, Zhang QG. The gut microbes in inflammatory bowel disease: Future novel target option for pharmacotherapy. Biomed Pharmacother 2023; 165:114893. [PMID: 37352702 DOI: 10.1016/j.biopha.2023.114893] [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: 03/16/2023] [Revised: 05/09/2023] [Accepted: 05/13/2023] [Indexed: 06/25/2023] Open
Abstract
Gut microbes constitute the main microbiota in the human body, which can regulate biological processes such as immunity, cell proliferation, and differentiation, hence playing a specific function in intestinal diseases. In recent years, gut microbes have become a research hotspot in the pharmaceutical field. Because of their enormous number, diversity, and functional complexity, gut microbes have essential functions in the development of many digestive diseases. Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease with a complex etiology, the exact cause and pathogenesis are unclear. There are no medicines that can cure IBD, and more research on therapeutic drugs is urgently needed. It has been reported that gut microbes play a critical role in pathogenesis, and there is a tight and complex association between gut microbes and IBD. The dysregulation of gut microbes may be a predisposing factor for IBD, and at the same time, IBD may exacerbate gut microbes' disorders, but the mechanism of interaction between the two is still not well defined. The study of the relationship between gut microbes and IBD is not only important to elucidate the pathogenesis but also has a positive effect on the treatment based on the regimen of regulating gut microbes. This review describes the latest research progress on the functions of gut microbes and their relationship with IBD, which can provide reference and assistance for further research. It may provide a theoretical basis for the application of probiotics, fecal microbiota transplantation, and other therapeutic methods to regulate gut microbes in IBD.
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Affiliation(s)
- Shuo Yuan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ke-Si Wang
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Huan Meng
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Xiao-Ting Hou
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Jia-Chen Xue
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China; Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, 116001, China
| | - Bao-Hong Liu
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Wen-Wen Cheng
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Jiao Li
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Hua-Min Zhang
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Ji-Xing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - Qing-Gao Zhang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
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13
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Wang Y, He C, Xin S, Liu X, Zhang S, Qiao B, Shang H, Gao L, Xu J. A Deep View of the Biological Property of Interleukin-33 and Its Dysfunction in the Gut. Int J Mol Sci 2023; 24:13504. [PMID: 37686309 PMCID: PMC10487440 DOI: 10.3390/ijms241713504] [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: 07/31/2023] [Revised: 08/19/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Intestinal diseases have always posed a serious threat to human health, with inflammatory bowel disease (IBD) being one of them. IBD is an autoimmune disease characterized by chronic inflammation, including ulcerative colitis (UC) and Crohn's disease (CD). The "alarm" cytokine IL-33, which is intimately associated with Th2 immunity, is a highly potent inflammatory factor that is considered to have dual functions-operating as both a pro-inflammatory cytokine and a transcriptional regulator. IL-33 has been shown to play a crucial role in both the onset and development of IBD. Therefore, this review focuses on the pathogenesis of IBD, the major receptor cell types, and the activities of IL-33 in innate and adaptive immunity, as well as its underlying mechanisms and conflicting conclusions in IBD. We have also summarized different medicines targeted to IL-33-associated diseases. Furthermore, we have emphasized the role of IL-33 in gastrointestinal cancer and parasitic infections, giving novel prospective therapeutic utility in the future application of IL-33.
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Affiliation(s)
- Yi Wang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (Y.W.); (S.Z.); (B.Q.)
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (C.H.); (S.X.); (X.L.)
| | - Shuzi Xin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (C.H.); (S.X.); (X.L.)
| | - Xiaohui Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (C.H.); (S.X.); (X.L.)
| | - Sitian Zhang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (Y.W.); (S.Z.); (B.Q.)
| | - Boya Qiao
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (Y.W.); (S.Z.); (B.Q.)
| | - Hongwei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing 100069, China;
| | - Lei Gao
- Department of Intelligent Medical Engineering, School of Biomedical Engineering, Capital Medical University, Beijing 100069, China
| | - Jingdong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; (C.H.); (S.X.); (X.L.)
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Słoka J, Madej M, Strzalka-Mrozik B. Molecular Mechanisms of the Antitumor Effects of Mesalazine and Its Preventive Potential in Colorectal Cancer. Molecules 2023; 28:5081. [PMID: 37446747 DOI: 10.3390/molecules28135081] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/18/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Chemoprevention is one of the ways to fight colorectal cancer, which is a huge challenge in oncology. Numerous pieces of evidence indicate that chronic inflammation in the course of Crohn's disease or ulcerative colitis (UC) is a significant cancer risk factor. Epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), including mesalazine, has beneficial effects on colitis-associated colorectal cancer. Mesalazine is a first-line therapy for UC and is also widely used for maintaining remission in UC. Data showed that mesalazine has antiproliferative properties associated with cyclooxygenase (COX) inhibition but can also act through COX-independent pathways. This review summarizes knowledge about mesalazine's molecular mechanisms of action and chemopreventive effect by which it could interfere with colorectal cancer cell proliferation and survival.
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Affiliation(s)
- Joanna Słoka
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
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15
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Wang T, Tian J, Su W, Yang F, Yin J, Jiang Q, Li Y, Yao K, Li T, Yin Y. Effect of Ornithine α-Ketoglutarate on Intestinal Microbiota and Serum Inflammatory Cytokines in Dextran Sulfate Sodium Induced Colitis. Nutrients 2023; 15:nu15112476. [PMID: 37299439 DOI: 10.3390/nu15112476] [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: 04/20/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Ornithine α-ketoglutarate (OKG), a nutritional compound, is an amino acid salt with anti-oxidative and anti-inflammatory effects on humans and animals. Ulcerative colitis (UC), as an inflammatory bowel disease (IBD), leads to chronic intestinal inflammatory dysfunction. This study evaluated the optimal dosage of OKG in healthy mice. Then, a mouse model of acute colitis was established using dextran sodium sulfate (DSS), and the preventive effect of OKG on DSS-induced colitis in mice was explored through analysis of serum inflammatory cytokines and fecal microbiota. Initially, the mice were randomly divided into a control group, a group given a low dose of OKG (LOKG: 0.5%), a group given a medium dose of OKG (MOKG: 1%), and a group given a high dose of OKG (HOKG: 1.5%); they remained in these groups for the entire 14-day experimental period. Our results demonstrated that 1% OKG supplementation increased body weight, serum growth hormone (GH), insulin (INS), alkaline phosphatase (ALP), Tyr, and His and decreased urea nitrogen (BUN), NH3L, and Ile. Then, a 2 × 2 factor design was used for a total of 40 mice, with diet (a standard diet or a 1% OKG diet) and challenge (4% DSS or not) as the main factors. During days 14 to 21, the DSS mice were administered 4% DSS to induce colitis. The results revealed that OKG alleviated weight loss and reversed the increases in colonic histological damage induced by DSS. OKG also increased serum IL-10 secretion. Moreover, OKG enhanced the abundance of Firmicutes and decreased that of Bacteriodetes at the phylum level and particularly enhanced the abundance of Alistipes and reduced that of Parabacterioides at the genus level. Our results indicated that OKG promotes growth performance and hormone secretion and regulates serum biochemical indicators and amino acid concentrations. Furthermore, 1% OKG supplementation prevents DSS-induced colitis in mice via altering microbial compositions and reducing the secretion of inflammatory cytokines in serum.
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Affiliation(s)
- Tao Wang
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Junquan Tian
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Wenxuan Su
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Fan Yang
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410125, China
| | - Qian Jiang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410125, China
| | - Yuying Li
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha 410205, China
| | - Kang Yao
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Tiejun Li
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
| | - Yulong Yin
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100008, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410125, China
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Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne) 2023; 10:1089099. [PMID: 36936239 PMCID: PMC10017532 DOI: 10.3389/fmed.2023.1089099] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 02/09/2023] [Indexed: 03/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn's disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients.
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Affiliation(s)
| | | | | | - Natalia Borruel
- Unitat d’Atenció Crohn-Colitis, Digestive System Research Unit, Hospital Universitari Vall d’Hebrón, Barcelona, Spain
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17
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Novichkova E, Nayak S, Boussiba S, Gopas J, Zilberg D, Khozin-Goldberg I. Dietary Application of the Microalga Lobosphaera incisa P127 Reduces Severity of Intestinal Inflammation, Modulates Gut-Associated Gene Expression, and Microbiome in the Zebrafish Model of IBD. Mol Nutr Food Res 2023; 67:e2200253. [PMID: 36683256 DOI: 10.1002/mnfr.202200253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 11/30/2022] [Indexed: 01/24/2023]
Abstract
SCOPE Microalgae are an emerging nutritional resource of biomolecules with potential to alleviate gut inflammation. The study explores the anti-inflammatory and immunomodulatory potential of the microalga Lobosphaera incisa P127, which accumulates a rare omega-6 LC-PUFA dihomo-ɣ-linolenic acid (DGLA) under nitrogen starvation. The therapeutic potential of dietary supplementation with P127 is investigated in the zebrafish model of IBD (TNBS-induced colitis). METHODS AND RESULTS Guts are sampled from zebrafish fed experimental diets for 4 weeks, before and 24 h after TNBS challenge. Diets containing 15% non-starved (Ns) and 7.5% and 15% N-starved (St) algal biomass significantly attenuate the severity of gut injury and goblet cell depletion. In contrast, diets containing 7.5% Ns and DGLA ethyl ester have no effect on gut condition. Fish fed 15% St, high-DGLA biomass, have the fewest individuals with pathological alterations in the gut. Dietary inclusion of Ns and St distinctly modulates gut-associated expression of the immune and inflammatory genes. Fish fed 15% Ns biomass display a coordinated boost in immune gene expression and show major changes in the gut microbiome prior challenge. CONCLUSION Dietary inclusion of L. incisa biomass at two physiological states, ameliorates TNBS-induced gut inflammation, suggesting the synergistic beneficial effects of biomass components not limited to DGLA.
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Affiliation(s)
- Ekaterina Novichkova
- The French Associates Institute for Agriculture and Biotechnology of Drylands, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
- The Albert Katz International School for Desert Studies, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
| | - Sagar Nayak
- The French Associates Institute for Agriculture and Biotechnology of Drylands, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
- The Jacob Blaustein Center for Scientific Cooperation, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
| | - Sammy Boussiba
- The French Associates Institute for Agriculture and Biotechnology of Drylands, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
| | - Jacob Gopas
- Department of Microbiology and Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8400501, Israel
| | - Dina Zilberg
- The French Associates Institute for Agriculture and Biotechnology of Drylands, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
| | - Inna Khozin-Goldberg
- The French Associates Institute for Agriculture and Biotechnology of Drylands, The Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, 8499000, Israel
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Xiong H, Xue G, Zhang Y, Wu S, Zhao Q, Zhao R, Zhou N, Xie Y. Effect of exogenous galectin-9, a natural TIM-3 ligand, on the severity of TNBS- and DSS-induced colitis in mice. Int Immunopharmacol 2023; 115:109645. [PMID: 36610329 DOI: 10.1016/j.intimp.2022.109645] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 01/06/2023]
Abstract
Inflammatory bowel disease (IBD) have a complex pathogenesis that is yet to be completely understood. However, a strong correlation between Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling and IBD has been observed. T-cell immunoglobulin and mucin domain-containing-3 (Tim-3) has been reported to regulate TLR4/NF-κB by interacting with Galectin-9 (Gal-9), and recombinant Gal-9 can activate Tim-3; however, its potential properties in IBD and the underlying mechanism remain unclear. This study aimed to determine how Gal-9 affects experimental colitis in mice. Dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) were used to establish colitis in mice, and the severity of the illness was assessed based on body weight, colon length, and histology. Therefore, we explored the effects of Gal-9 treatment on colitis. Furthermore, we analyzed the effect of Gal-9 on the expression of Tim-3 and TLR4/NF-κB pathway in colonic tissues and the serum levels of interferon-gamma (IFN-γ), interleukin (IL)-1β, and IL-6. Tim-3 expression in the colon was notably decreased in mice with TNBS-induced colitis, whereas TLR4/NF-kB expression was significantly increased. Intraperitoneal injection of Gal-9 dramatically decreased the disease activity index and attenuated the level of intestinal mucosal inflammation in TNBS-induced colitis mice (p < 0.05). Intraperitoneal administration of Gal-9 significantly increased Tim-3 expression in the colon and decreased the serum concentrations of IFN-γ, IL-1β, and IL-6. Additionally, Gal-9 treatment significantly downregulated the expression of TLR4 signaling pathway-related proteins. In contrast, Gal-9 did not reduce the severity of DSS-induced colitis. In summary, exogenous Gal-9 increased Tim-3 expression, inhibited the TLR4/NF-κB pathway, and alleviated TNBS-induced colitis in mice but not DSS-induced colitis in mice, revealing its potential therapeutic ramifications for IBD.
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Affiliation(s)
- Huifang Xiong
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Guohui Xue
- Department of Clinical Laboratory, Jiujiang NO.1 People's Hospital, Jiujiang, Jiangxi 332000, China
| | - Yuting Zhang
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Shuang Wu
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Qiaoyun Zhao
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Rulin Zhao
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China
| | - Nanjin Zhou
- Jiangxi Provincial Academy of Medical Science, Nanchang, Jiangxi 330006, China
| | - Yong Xie
- Department of Gastroenterology, Digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi 330006, China.
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Ribeiro BE, Breves J, de Souza HSP. Pathogenesis: Crohn’s disease and ulcerative colitis. NATURAL PLANT PRODUCTS IN INFLAMMATORY BOWEL DISEASES 2023:9-46. [DOI: 10.1016/b978-0-323-99111-7.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update. Genes (Basel) 2022; 13:genes13122388. [PMID: 36553655 PMCID: PMC9778199 DOI: 10.3390/genes13122388] [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: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and remission of the disease. The etiology of IBD is not fully understood. Many studies point to the presence of genetic, immunological, environmental, and microbiological factors and the interactions between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD predisposition and pharmacogenetics.
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Cerdó T, García-Santos JA, Rodríguez-Pöhnlein A, García-Ricobaraza M, Nieto-Ruíz A, G. Bermúdez M, Campoy C. Impact of Total Parenteral Nutrition on Gut Microbiota in Pediatric Population Suffering Intestinal Disorders. Nutrients 2022; 14:4691. [PMID: 36364953 PMCID: PMC9658482 DOI: 10.3390/nu14214691] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023] Open
Abstract
Parenteral nutrition (PN) is a life-saving therapy providing nutritional support in patients with digestive tract complications, particularly in preterm neonates due to their gut immaturity during the first postnatal weeks. Despite this, PN can also result in several gastrointestinal complications that are the cause or consequence of gut mucosal atrophy and gut microbiota dysbiosis, which may further aggravate gastrointestinal disorders. Consequently, the use of PN presents many unique challenges, notably in terms of the potential role of the gut microbiota on the functional and clinical outcomes associated with the long-term use of PN. In this review, we synthesize the current evidence on the effects of PN on gut microbiome in infants and children suffering from diverse gastrointestinal diseases, including necrotizing enterocolitis (NEC), short bowel syndrome (SBS) and subsequent intestinal failure, liver disease and inflammatory bowel disease (IBD). Moreover, we discuss the potential use of pre-, pro- and/or synbiotics as promising therapeutic strategies to reduce the risk of severe gastrointestinal disorders and mortality. The findings discussed here highlight the need for more well-designed studies, and harmonize the methods and its interpretation, which are critical to better understand the role of the gut microbiota in PN-related diseases and the development of efficient and personalized approaches based on pro- and/or prebiotics.
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Affiliation(s)
- Tomás Cerdó
- Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004 Córdoba, Spain
| | - José Antonio García-Santos
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
| | - Anna Rodríguez-Pöhnlein
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
| | - María García-Ricobaraza
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
| | - Ana Nieto-Ruíz
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
| | - Mercedes G. Bermúdez
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
| | - Cristina Campoy
- EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, 18016 Granada, Spain
- Department of Paediatrics, School of Medicine, University of Granada, Avda. Investigación 11, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria Ibs-GRANADA, Health Sciences Technological Park, 18012 Granada, Spain
- Spanish Network of Biomedical Research in Epidemiology and Public Health (CIBERESP), Granada’s Node, Carlos III Health Institute, Avda. Monforte de Lemos 5, 28028 Madrid, Spain
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22
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Peng K, Xia S, Xiao S, Yu Q. Short-chain fatty acids affect the development of inflammatory bowel disease through intestinal barrier, immunology, and microbiota: A promising therapy? J Gastroenterol Hepatol 2022; 37:1710-1718. [PMID: 35906780 DOI: 10.1111/jgh.15970] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 07/18/2022] [Accepted: 07/27/2022] [Indexed: 12/09/2022]
Abstract
Intestinal metabolites are attracting increasing interest, especially more and more studies have found they are closely related to diseases. Microbial fermentation of indigestible dietary fibers in the gut produces short chain fatty acids (SCFAs) as the main product. SCFAs can exert influences on the integrity of the intestinal epithelial and mucosal barrier, immune reactions, and the diversity of microbiota in humans. Thus, alteration in SCFAs may affect inflammatory bowel disease (IBD). In IBD, SCFAs are involved in the main pathogenic process and play an important role in the development of intestinal inflammation. Although many studies have proved that pretreatment with SCFAs can effectively ameliorate inflammation in the gut, the mechanisms are not fully understood. In this review, we describe the relationship between SCFAs and IBD from the aspects of defense barrier, immune effects, and microbial alterations. We also summarize the effects of SCFAs on comorbidities in IBD via the gut-brain, gut-liver, and gut-lung axis, and we give an overview of the prospects of their clinical application. A better understanding of the relevance of SCFAs in IBD may reveal novel targets for future study.
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Affiliation(s)
- Kaixin Peng
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suhong Xia
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Siqi Xiao
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Zhu R, Tang J, Xing C, Nan Q, Liang G, Luo J, Zhou J, Miao Y, Cao Y, Dai S, Lan D. The Distinguishing Bacterial Features From Active and Remission Stages of Ulcerative Colitis Revealed by Paired Fecal Metagenomes. Front Microbiol 2022; 13:883495. [PMID: 35801108 PMCID: PMC9253600 DOI: 10.3389/fmicb.2022.883495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Ulcerative colitis (UC) is a serious chronic intestinal inflammatory disease, with an increased incidence in recent years. The intestinal microbiota plays a key role in the pathogenesis of UC. However, there is no unified conclusion on how the intestinal microbiota changes. Most studies focus on the change between UC patients and healthy individuals, rather than the active and remission stage of the same patient. To minimize the influences of genetic differences, environmental and dietary factors, we studied the intestinal microbiota of paired fecal samples from 42 UC patients at the active and remission stages. We identified 175 species of microbes from 11 phyla and found no difference of the alpha and beta diversities between the active and remission stages. Paired t-test analysis revealed differential microbiota at levels of the phyla, class, order, family, genus, and species, including 13 species with differential abundance. For example, CAG-269 sp001916005, Eubacterium F sp003491505, Lachnospira sp000436475, et al. were downregulated in the remission, while the species of Parabacteroides distasonis, Prevotellamassilia sp900540885, CAG-495 sp001917125, et al. were upregulated in the remission. The 13 species can effectively distinguish the active and remission stages. Functional analysis showed that the sporulation and biosynthesis were downregulated, and the hydrogen peroxide catabolic process was upregulated in remission of UC. Our study suggests that the 13 species together may serve as a biomarker panel contributing to identify the active and remission stages of UC, which provides a valuable reference for the treatment of UC patients by FMT or other therapeutic methods.
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Affiliation(s)
- Ran Zhu
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Junrui Tang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Chengfeng Xing
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Qiong Nan
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Guili Liang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Jiao Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yu Cao
- Department of Cardiac Surgery, The First People’s Hospital of Yunnan Province, Kunming, China
- Yu Cao,
| | - Shaoxing Dai
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
- Shaoxing Dai,
| | - Danfeng Lan
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
- *Correspondence: Danfeng Lan,
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24
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Rashed R, Valcheva R, Dieleman LA. Manipulation of Gut Microbiota as a Key Target for Crohn's Disease. Front Med (Lausanne) 2022; 9:887044. [PMID: 35783604 PMCID: PMC9244564 DOI: 10.3389/fmed.2022.887044] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) sub-type characterized by transmural chronic inflammation of the gastrointestinal tract. Research indicates a complex CD etiology involving genetic predisposition and immune dysregulation in response to environmental triggers. The chronic mucosal inflammation has been associated with a dysregulated state, or dysbiosis, of the gut microbiome (bacteria), mycobiome (fungi), virome (bacteriophages and viruses), and archeaome (archaea) further affecting the interkingdom syntrophic relationships and host metabolism. Microbiota dysbiosis in CD is largely described by an increase in facultative anaerobic pathobionts at the expense of strict anaerobic Firmicutes, such as Faecalibacterium prausnitzii. In the mycobiome, reduced fungal diversity and fungal-bacteria interactions, along with a significantly increased abundance of Candida spp. and a decrease in Saccharomyces cerevisiae are well documented. Virome analysis also indicates a significant decrease in phage diversity, but an overall increase in phages infecting bacterial groups associated with intestinal inflammation. Finally, an increase in methanogenic archaea such as Methanosphaera stadtmanae exhibits high immunogenic potential and is associated with CD etiology. Common anti-inflammatory medications used in CD management (amino-salicylates, immunomodulators, and biologics) could also directly or indirectly affect the gut microbiome in CD. Other medications often used concomitantly in IBD, such as antibiotics, antidepressants, oral contraceptives, opioids, and proton pump inhibitors, have shown to alter the gut microbiota and account for increased susceptibility to disease onset or worsening of disease progression. In contrast, some environmental modifications through alternative therapies including fecal microbiota transplant (FMT), diet and dietary supplements with prebiotics, probiotics, and synbiotics have shown potential protective effects by reversing microbiota dysbiosis or by directly promoting beneficial microbes, together with minimal long-term adverse effects. In this review, we discuss the different approaches to modulating the global consortium of bacteria, fungi, viruses, and archaea in patients with CD through therapies that include antibiotics, probiotics, prebiotics, synbiotics, personalized diets, and FMT. We hope to provide evidence to encourage clinicians and researchers to incorporate these therapies into CD treatment options, along with making them aware of the limitations of these therapies, and indicate where more research is needed.
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25
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Touch S, Godefroy E, Rolhion N, Danne C, Oeuvray C, Straube M, Galbert C, Brot L, Alonso Salgueiro I, Chadi S, Ledent T, Chatel JM, Langella P, Jotereau F, Altare F, Sokol H. Human CD4+/CD8α+ regulatory T cells induced by Faecalibacterium prausnitzii protect against intestinal inflammation. JCI Insight 2022; 7:154722. [PMID: 35536673 DOI: 10.1172/jci.insight.154722] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 05/06/2022] [Indexed: 11/17/2022] Open
Abstract
Faecalibacterium prausnitzii (F. prausnitzii), a dominant bacterium of the human microbiota, is decreased in patients with inflammatory bowel diseases (IBD) and exhibits anti-inflammatory effects. In human, colonic lamina propria contains IL-10-secreting, Foxp3-negative regulatory T cells (Treg) characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet. Here, using a humanized model of NOD.Prkcscid IL2rγ-/- (NSG) immunodeficient mouse strain that expresses the human leucocyte antigen D-related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401-restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn's disease.
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Affiliation(s)
- Sothea Touch
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | | | - Nathalie Rolhion
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | | | - Cyriane Oeuvray
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | - Marjolène Straube
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | - Chloé Galbert
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | - Loïc Brot
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | | | - Sead Chadi
- UMR1319 Micalis & AgroParisTech, INRAE, Jouy en Josas, France
| | - Tatiana Ledent
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
| | | | | | - Francine Jotereau
- CRCINA, INSERM, University of Nantes, University of Angers, Nantes, France
| | - Frédéric Altare
- CRCINA, INSERM, University of Nantes, University of Angers, Nantes, France
| | - Harry Sokol
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France
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26
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Farooq RK, Alamoudi W, Alhibshi A, Rehman S, Sharma AR, Abdulla FA. Varied Composition and Underlying Mechanisms of Gut Microbiome in Neuroinflammation. Microorganisms 2022; 10:705. [PMID: 35456757 PMCID: PMC9032006 DOI: 10.3390/microorganisms10040705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/21/2022] [Accepted: 03/17/2022] [Indexed: 11/16/2022] Open
Abstract
The human gut microbiome has been implicated in a host of bodily functions and their regulation, including brain development and cognition. Neuroinflammation is a relatively newer piece of the puzzle and is implicated in the pathogenesis of many neurological disorders. The microbiome of the gut may alter the inflammatory signaling inside the brain through the secretion of short-chain fatty acids, controlling the availability of amino acid tryptophan and altering vagal activation. Studies in Korea and elsewhere highlight a strong link between microbiome dynamics and neurocognitive states, including personality. For these reasons, re-establishing microbial flora of the gut looks critical for keeping neuroinflammation from putting the whole system aflame through probiotics and allotransplantation of the fecal microbiome. However, the numerosity of the microbiome remains a challenge. For this purpose, it is suggested that wherever possible, a fecal microbial auto-transplant may prove more effective. This review summarizes the current knowledge about the role of the microbiome in neuroinflammation and the various mechanism involved in this process. As an example, we have also discussed the autism spectrum disorder and the implication of neuroinflammation and microbiome in its pathogenesis.
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Affiliation(s)
- Rai Khalid Farooq
- Department of Neuroscience Research, Institute of Research and Medical Consultations, Imam Abdul Rahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (W.A.); (A.A.); (F.A.A.)
| | - Widyan Alamoudi
- Department of Neuroscience Research, Institute of Research and Medical Consultations, Imam Abdul Rahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (W.A.); (A.A.); (F.A.A.)
| | - Amani Alhibshi
- Department of Neuroscience Research, Institute of Research and Medical Consultations, Imam Abdul Rahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (W.A.); (A.A.); (F.A.A.)
| | - Suriya Rehman
- Department of Epidemic Diseases Research, Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si 24252, Gangwon-do, Korea;
| | - Fuad A. Abdulla
- Department of Neuroscience Research, Institute of Research and Medical Consultations, Imam Abdul Rahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (W.A.); (A.A.); (F.A.A.)
- Department of Physical Therapy, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, P.O. Box 2435, Dammam 31441, Saudi Arabia
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27
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Santana PT, Rosas SLB, Ribeiro BE, Marinho Y, de Souza HSP. Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and Potential Therapeutic Targets. Int J Mol Sci 2022; 23:3464. [PMID: 35408838 PMCID: PMC8998182 DOI: 10.3390/ijms23073464] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022] Open
Abstract
Microbe-host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.
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Affiliation(s)
- Patricia Teixeira Santana
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (P.T.S.); (S.L.B.R.); (B.E.R.); (Y.M.)
| | - Siane Lopes Bittencourt Rosas
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (P.T.S.); (S.L.B.R.); (B.E.R.); (Y.M.)
| | - Beatriz Elias Ribeiro
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (P.T.S.); (S.L.B.R.); (B.E.R.); (Y.M.)
| | - Ygor Marinho
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (P.T.S.); (S.L.B.R.); (B.E.R.); (Y.M.)
| | - Heitor S. P. de Souza
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (P.T.S.); (S.L.B.R.); (B.E.R.); (Y.M.)
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro 22281-100, RJ, Brazil
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28
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Dudek P, Fabisiak A, Zatorski H, Malecka-Wojciesko E, Talar-Wojnarowska R. Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment. J Clin Med 2021; 10:jcm10235660. [PMID: 34884361 PMCID: PMC8658230 DOI: 10.3390/jcm10235660] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/22/2021] [Accepted: 11/28/2021] [Indexed: 12/16/2022] Open
Abstract
Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD.
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Affiliation(s)
- Patrycja Dudek
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Correspondence: ; Tel.: +48-42677-66-67
| | - Adam Fabisiak
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland
| | - Hubert Zatorski
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland
| | - Ewa Malecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
| | - Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
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29
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Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated diseases of the gastrointestinal (GI) tract. Their etiology is complex and involves immune (eg, cytokines) and nonimmune (eg, environment) mediated contributions, causing inflammatory damage to the GI tract. Though cytokines contribute a major role in the inflammatory process of both CD and UC, there are some key differences in which cytokines are involved in the pathobiology of CD and UC. Over the past several years, new biologic-directed therapies have focused on controlling specific aspects of inflammation associated with both conditions. Although these treatments have benefited patients overall, approximately 30% of patients still do not respond to induction (initial) therapy, and up to 50% of patients lose response to treatment over a year. Many of these therapies are administered parenterally and have been associated with adverse events such as serious infections or malignancy. Therefore, there is a significant unmet medical need for these patients to minimize symptoms and promote GI healing. There are several therapeutic agents in the pipeline, including oral, small molecules, which hold much promise. One group of small molecules known as Janus kinase (JAK) inhibitors offers an additional option for treatment of chronic inflammatory conditions, based on currently available data. The article will focus on the potential benefits of JAK inhibitors as oral, small molecules, such as the potential role of selectivity, and potential risks.
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Affiliation(s)
| | - Bruce R Yacyshyn
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
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30
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Day AS. Aspects of the Pathogenesis and Management of Inflammatory Bowel Diseases. GASTROINTESTINAL DISORDERS 2021; 3:96-99. [DOI: 10.3390/gidisord3030010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Over the last two decades, inflammatory bowel disease (IBD) has been diagnosed more often in many countries around the world, including in parts of the world where IBD was previously uncommon [...]
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Affiliation(s)
- Andrew S. Day
- Department of Paediatrics, University of Otago Christchurch, Christchurch 8011, New Zealand
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31
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Mukherjee T, Philpott DJ. gp130 blockade to NOD off Crohn's disease. Trends Immunol 2021; 42:551-553. [PMID: 34103266 DOI: 10.1016/j.it.2021.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 05/24/2021] [Indexed: 11/26/2022]
Abstract
In a recent publication, Nayar et al. uncover specific inflammatory cell populations associated with Crohn's disease (CD) pathogenesis, and a gp130-STAT3 signaling axis linked to disease in anti-TNF antibody treatment-refractory patients. Therefore, gp130 blockade might represent a potential CD therapy approach, perhaps in conjunction with existing anti-TNF treatment regimes.
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Affiliation(s)
- Tapas Mukherjee
- Department of Immunology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Dana J Philpott
- Department of Immunology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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Lopez LR, Barlogio CJ, Broberg CA, Wang J, Arthur JC. A nadA Mutation Confers Nicotinic Acid Auxotrophy in Pro-carcinogenic Intestinal Escherichia coli NC101. Front Microbiol 2021; 12:670005. [PMID: 34149655 PMCID: PMC8207962 DOI: 10.3389/fmicb.2021.670005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) and inflammation-associated colorectal cancer (CRC) are linked to blooms of adherent-invasive Escherichia coli (AIEC) in the intestinal microbiota. AIEC are functionally defined by their ability to adhere/invade epithelial cells and survive/replicate within macrophages. Changes in micronutrient availability can alter AIEC physiology and interactions with host cells. Thus, culturing AIEC for mechanistic investigations often involves precise nutrient formulation. We observed that the pro-inflammatory and pro-carcinogenic AIEC strain NC101 failed to grow in minimal media (MM). We hypothesized that NC101 was unable to synthesize a vital micronutrient normally found in the host gut. Through nutrient supplementation studies, we identified that NC101 is a nicotinic acid (NA) auxotroph. NA auxotrophy was not observed in the other non-toxigenic E. coli or AIEC strains we tested. Sequencing revealed NC101 has a missense mutation in nadA, a gene encoding quinolinate synthase A that is important for de novo nicotinamide adenine dinucleotide (NAD) biosynthesis. Correcting the identified nadA point mutation restored NC101 prototrophy without impacting AIEC function, including motility and AIEC-defining survival in macrophages. Our findings, along with the generation of a prototrophic NC101 strain, will greatly enhance the ability to perform in vitro functional studies that are needed for mechanistic investigations on the role of intestinal E. coli in digestive disease.
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Affiliation(s)
- Lacey R Lopez
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Cassandra J Barlogio
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Christopher A Broberg
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy Wang
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Janelle C Arthur
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Center for Gastrointestinal Biology and Disease, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Galipeau HJ, Caminero A, Turpin W, Bermudez-Brito M, Santiago A, Libertucci J, Constante M, Raygoza Garay JA, Rueda G, Armstrong S, Clarizio A, Smith MI, Surette MG, Bercik P, Croitoru K, Verdu EF. Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis. Gastroenterology 2021; 160:1532-1545. [PMID: 33310084 DOI: 10.1053/j.gastro.2020.12.004] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. METHODS We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). RESULTS Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. CONCLUSIONS We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
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Affiliation(s)
- Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Alberto Caminero
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Williams Turpin
- Zane Cohen Centre for Digestive Diseases, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Miriam Bermudez-Brito
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Alba Santiago
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Josie Libertucci
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Marco Constante
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Juan Antonio Raygoza Garay
- Zane Cohen Centre for Digestive Diseases, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Gaston Rueda
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Sarah Armstrong
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Alex Clarizio
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Michelle I Smith
- Zane Cohen Centre for Digestive Diseases, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Michael G Surette
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Kenneth Croitoru
- Zane Cohen Centre for Digestive Diseases, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada.
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Zheng L, Wen XL. Gut microbiota and inflammatory bowel disease: The current status and perspectives. World J Clin Cases 2021; 9:321-333. [PMID: 33521100 PMCID: PMC7812881 DOI: 10.12998/wjcc.v9.i2.321] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated disease that affects the gastrointestinal tract. It is argued that environment, microbiome, and immune-mediated factors interact in a genetically susceptible host to trigger IBD. Recently, there has been increased interest in the development, progression, and treatment of IBD because of our understanding of the microbiome. Researchers have proved that some factors can alter the microbiome and the pathogenesis of IBD. As a result, there has been increasing interest in the application of probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and gene manipulation in treating IBD because of the possible curative effect of microbiome-modulating interventions. In this review, we summarize the findings from human and animal studies and discuss the effect of the gut microbiome in treating patients with IBD.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 730000, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 730000, Shaanxi Province, China
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The Antioxidant and Anti-Inflammatory Effects of Quercus brantii Extract on TNBS-Induced Ulcerative Colitis in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:3075973. [PMID: 33505492 PMCID: PMC7808820 DOI: 10.1155/2021/3075973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/15/2020] [Accepted: 12/19/2020] [Indexed: 12/16/2022]
Abstract
Objectives Ulcerative colitis is a common subtype of persistent inflammatory bowel disease with high morbidity consequences. Despite unknown definite pathogenesis, multiple anti-inflammatory medications are used for its treatment. Traditionally, Quercus brantii (QB), mostly available in the Middle East, has been used for gastrointestinal disorders. Other beneficial effects associated with QB include reduction of oxidative stress, inflammations, homeostatic instability, and improvement in clinical conditions. Materials and Methods This experimental study was designed to assess the possible therapeutic effects of QB on UC and compare its effects with those of sulfasalazine. Of the 70 Wistar rats clustered in seven groups, ten received only alcohols and sixty were confirmed to be suffering from trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Four groups received different dosages of QB extract via oral and rectal routes, one received sulfasalazine, and the other remaining two groups received nothing. The effects of QB were evaluated by assessing macroscopic and histologic scoring, measuring inflammatory mediators, and determining oxidative stress markers. Results Comparing to the untreated TNBS-induced control groups, QB-treated groups showed a dose- and route-dependent improvement comparable with sulfasalazine. Treating rats with QB reduced the microscopic and macroscopic damage, decreased TNF-α, IL-6, NO, MPO activity, and MDA content, increased superoxide dismutase (SOD) activity, and reduced body weight loss. Conclusions Our data recommended the anti-inflammatory and antioxidant effects of QB extract in a dose-dependent manner.
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Jourová L, Lišková B, Lněničková K, Zemanová N, Anzenbacher P, Hermanová P, Hudcovic T, Kozáková H, Anzenbacherová E. Presence or absence of microbiome modulates the response of mice organism to administered drug nabumetone. Physiol Res 2020; 69:S583-S594. [PMID: 33646003 DOI: 10.33549/physiolres.934607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The gut microbiota provides a wide range of beneficial functions for the host, and has an immense effect on the host's health status. The presence of microbiome in the gut may often influence the effect of an orally administered drug. Molecular mechanisms of this process are however mostly unclear. We investigated how the effect of a nonsteroidal drug nabumetone on expression of drug metabolizing enzymes (DMEs) in mice intestine and liver is changed by the presence of microbiota, here, using the germ free (GF) and specific pathogen free (SPF) BALB/c mice. First, we have found in a preliminary experiment that in the GF mice there is a tendency to increase bioavailability of the active form of nabumetone, which we have found now to be possibly influenced by differences in expression of DMEs in the GF and SPF mice. Indeed, we have observed that the expression of the most of selected cytochromes P450 (CYPs) was significantly changed in the small intestine of GF mice compared to the SPF ones. Moreover, orally administered nabumetone itself altered the expression of some CYPs and above all, in different ways in the GF and SPF mice. In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance.
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Affiliation(s)
- L Jourová
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
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Cutone A, Ianiro G, Lepanto MS, Rosa L, Valenti P, Bonaccorsi di Patti MC, Musci G. Lactoferrin in the Prevention and Treatment of Intestinal Inflammatory Pathologies Associated with Colorectal Cancer Development. Cancers (Basel) 2020; 12:3806. [PMID: 33348646 PMCID: PMC7766217 DOI: 10.3390/cancers12123806] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 12/20/2022] Open
Abstract
The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.
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Affiliation(s)
- Antimo Cutone
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
| | - Giusi Ianiro
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
| | - Maria Stefania Lepanto
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | - Luigi Rosa
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | - Piera Valenti
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | | | - Giovanni Musci
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
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Day AS, Lemberg DA. Identification and diagnosis of Crohn disease and ulcerative colitis in children. J Paediatr Child Health 2020; 56:1731-1734. [PMID: 32468706 DOI: 10.1111/jpc.14925] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 04/15/2020] [Accepted: 04/17/2020] [Indexed: 12/25/2022]
Abstract
Crohn disease and ulcerative colitis are the two main types of inflammatory bowel disease. High rates of these conditions are seen in Australasian children - furthermore, increasing rates have been evident in recent years. Children can present with typical symptoms of abdominal pain, diarrhoea, haematochezia and/or weight loss. Atypical presentations (such as skin lesions or isolated short stature) can also occur: these may be associated with delays in the consideration and diagnosis of IBD. Initial steps in establishing a diagnosis of IBD include delineation of inflammatory markers exclusion of any other likely aetiology. Definitive diagnosis relies upon key endoscopic, histologic and radiological findings. Overall management of IBD encompasses care within a team-based, child and family-focused, multi-disciplinary setting.
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Affiliation(s)
- Andrew S Day
- Department of Paediatrics, University of Otago Christchurch, Christchurch, New Zealand
- Department of Gastroenterology, Sydney Children's Hospital, Sydney, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Daniel A Lemberg
- Department of Gastroenterology, Sydney Children's Hospital, Sydney, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
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How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children. Int J Mol Sci 2020; 21:ijms21186976. [PMID: 32972031 PMCID: PMC7555399 DOI: 10.3390/ijms21186976] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/04/2020] [Accepted: 09/15/2020] [Indexed: 12/21/2022] Open
Abstract
Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
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Ma R, Yuan D, Guo Y, Yan R, Li K. Immune Effects of γδ T Cells in Colorectal Cancer: A Review. Front Immunol 2020; 11:1600. [PMID: 33013819 PMCID: PMC7509400 DOI: 10.3389/fimmu.2020.01600] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022] Open
Abstract
Gamma delta (γδ) T cells can effectively recognize and kill colorectal cancer (CRC) cells, thereby suppressing tumor progression via multiple mechanisms. They also have abilities to exert a protumor effect via secreting interleukin-17 (IL-17). γδ T cells have been selected as potential immunocytes for antitumor treatment because of their significant cytotoxic activity. Immunotherapy is another potential anti-CRC strategy after an operation, chemotherapy, and radiotherapy. γδ T cell-based immunotherapy for CRC shows fewer side effects and better toleration. This review will outline the immune functions and the mechanisms of γδ T cells in the growth and progression of CRC in recent years, and summarize the immunotherapies based on γδ T cells, thus providing a direction for future γδ T cells in CRC research.
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MESH Headings
- Animals
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Colorectal Neoplasms/etiology
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/therapy
- Cytokines/metabolism
- Cytotoxicity, Immunologic
- Disease Susceptibility/immunology
- Humans
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Inflammatory Bowel Diseases/complications
- Inflammatory Bowel Diseases/etiology
- Inflammatory Bowel Diseases/metabolism
- Intraepithelial Lymphocytes/immunology
- Intraepithelial Lymphocytes/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- Treatment Outcome
- Tumor Escape/immunology
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Affiliation(s)
- Rulan Ma
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dawei Yuan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yizhan Guo
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Rong Yan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Kang Li
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Leccese G, Bibi A, Mazza S, Facciotti F, Caprioli F, Landini P, Paroni M. Probiotic Lactobacillus and Bifidobacterium Strains Counteract Adherent-Invasive Escherichia coli (AIEC) Virulence and Hamper IL-23/Th17 Axis in Ulcerative Colitis, but Not in Crohn's Disease. Cells 2020; 9:cells9081824. [PMID: 32752244 PMCID: PMC7464949 DOI: 10.3390/cells9081824] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023] Open
Abstract
Hypersecretion of proinflammatory cytokines and dysregulated activation of the IL-23/Th17 axis in response to intestinal microbiota dysbiosis are key factors in the pathogenesis of inflammatory bowel diseases (IBD). In this work, we studied how Lactobacillus and Bifidobacterium strains affect AIEC-LF82 virulence mechanisms and the consequent inflammatory response linked to the CCR6–CCL20 and IL-23/Th17 axes in Crohn’s disease (CD) and ulcerative colitis (UC) patients. All Lactobacillus and Bifidobacterium strains significantly reduced the LF82 adhesion and persistence within HT29 intestinal epithelial cells, inhibiting IL-8 secretion while not affecting the CCR6–CCL20 axis. Moreover, they significantly reduced LF82 survival within macrophages and dendritic cells, reducing the secretion of polarizing cytokines related to the IL-23/Th17 axis, both in healthy donors (HD) and UC patients. In CD patients, however, only B. breve Bbr8 strain was able to slightly reduce the LF82 persistence within dendritic cells, thus hampering the IL-23/Th17 axis. In addition, probiotic strains were able to modulate the AIEC-induced inflammation in HD, reducing TNF-α and increasing IL-10 secretion by macrophages, but failed to do so in IBD patients. Interestingly, the probiotic strains studied in this work were all able to interfere with the IL-23/Th17 axis in UC patients, but not in CD patients. The different interaction mechanisms of probiotic strains with innate immune cells from UC and CD patients compared to HD suggest that testing on CD-derived immune cells may be pivotal for the identification of novel probiotic strains that could be effective also for CD patients.
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Affiliation(s)
- Gabriella Leccese
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Alessia Bibi
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.M.); (F.C.)
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy;
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.M.); (F.C.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20135 Milan, Italy
| | - Paolo Landini
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Moira Paroni
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
- Correspondence:
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Paeoniflorin ameliorates ulcerative colitis by modulating the dendritic cell-mediated T H17/T reg balance. Inflammopharmacology 2020; 28:1705-1716. [PMID: 32472435 PMCID: PMC7572351 DOI: 10.1007/s10787-020-00722-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
Immunological tolerance is critical for maintaining gut homeostasis. An imbalance between interleukin-17 (IL-17)-producing T helper 17 (TH17) cells and regulatory T cells (Treg cells) is involved in ulcerative colitis (UC) pathogenesis. Dendritic cells (DCs) are able to induce T cell differentiation. Paeoniflorin (PF) is a monoterpene glucoside that is commonly used for treatment of autoimmune disease. However, the immunological mechanism of PF involvement in UC treatment is unclear. The present study aimed to explore whether PF can restore the TH17/Treg balance by modulating DCs. The effects of PF on DCs, TH17 cells and Treg cells were measured. Furthermore, PF-treated DCs were injected into mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. PF inhibited MHC-II and CD86 expression on the DC surface (P < 0.05), decreased interleukin (IL)-12 secretion in vitro and in vivo (P < 0.05), and restored the TH17/Treg ratio in the mouse model of colitis (P < 0.05). PF-treated DCs diminished TH17 differentiation (4.26% in vitro and 1.64% in vivo) and decreased IL-17 expression (P < 0.05) while inducing CD4+CD25+Foxp3+ Treg differentiation (7.82% in vitro and 6.85% in vivo) and increasing Foxp3 and IL-10 production (P < 0.05). Additionally, both PF and PF-treated DCs improved colonic histopathology in the mouse model of colitis (P < 0.05). In conclusion this study suggested that PF can ameliorate TNBS-induced colitis by modulating the DC-mediated TH17/Treg balance.
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Petersen AM, Mirsepasi-Lauridsen HC, Vester-Andersen MK, Sørensen N, Krogfelt KA, Bendtsen F. High Abundance of Proteobacteria in Ileo-Anal Pouch Anastomosis and Increased Abundance of Fusobacteria Associated with Increased Pouch Inflammation. Antibiotics (Basel) 2020; 9:antibiotics9050237. [PMID: 32397087 PMCID: PMC7277091 DOI: 10.3390/antibiotics9050237] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/03/2020] [Accepted: 05/06/2020] [Indexed: 12/20/2022] Open
Abstract
Low diversity intestinal dysbiosis has been associated with inflammatory bowel disease, including patients with ulcerative colitis with an ileo-anal pouch anastomosis. Furthermore, specific Escherichia coli phylogroups have been linked to inflammatory bowel disease. Our aim was to characterize the differences among microbiota and E. coli phylogroups in active and inactive pouchitis. Disease activity was assessed using the modified pouch disease activity index and by fecal calprotectin. Microbiota diversity was assessed by 16S rDNA MiSeq sequencing. E. coli phylogroup was determined after triplex PCR. Twenty patients with ulcerative colitis with an ileo-anal pouch anastomosis were included, 10 of whom had active pouchitis. Ileo-anal pouch anastomosis patients had an increased abundance of Proteobacteria colonization compared to patients with ulcerative colitis or Crohn's disease and healthy controls, p = 1.4·10-5. No differences in E. coli phylogroup colonization could be determined between cases of active and inactive disease. No significant link was found between α-diversity and pouch inflammation. However, higher levels of Fusobacteria colonization were found in patients with a pouch with a fecal calprotectin level above 500, p = 0.02. In conclusion, patients with a pouch had an increased Proteobacteria abundance, but only Fusobacteria abundance was linked to inflammation.
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Affiliation(s)
- Andreas Munk Petersen
- Gastrounit, Medical Section, Amager-Hvidovre University Hospital, 2650 Copenhagen, Denmark; (M.K.V.-A.); (F.B.)
- Department of Clinical Microbiology, Amager-Hvidovre University Hospital, 2650 Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Correspondence: ; Tel.: +45-38-62-59-60
| | | | - Marianne K. Vester-Andersen
- Gastrounit, Medical Section, Amager-Hvidovre University Hospital, 2650 Copenhagen, Denmark; (M.K.V.-A.); (F.B.)
- Department of Internal Medicine, Zealand University Hospital, 4600 Køge, Denmark
| | - Nikolaj Sørensen
- Clinical-Microbiomics, Ole Maaløes Vej 3, Clinical Microbiomics, 2200 Copenhagen, Denmark;
| | - Karen Angeliki Krogfelt
- Department of Bacteria, Parasites and Fungi, Statens Serum Institut, 2300 Copenhagen, Denmark; (H.C.M.-L.); (K.A.K.)
- Department of Virus and Microbiological Special Diagnostics, Statens Serum Institut, 2300 Copenhagen, Denmark
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Section, Amager-Hvidovre University Hospital, 2650 Copenhagen, Denmark; (M.K.V.-A.); (F.B.)
- Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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44
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Rautava J, Gürsoy UK, Kullström A, Könönen E, Sorsa T, Tervahartiala T, Gürsoy M. An Oral Rinse Active Matrix Metalloproteinase-8 Point-of-Care Immunotest May Be Less Accurate in Patients with Crohn's Disease. Biomolecules 2020; 10:biom10030395. [PMID: 32143418 PMCID: PMC7175303 DOI: 10.3390/biom10030395] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 02/26/2020] [Indexed: 12/11/2022] Open
Abstract
The diagnostic accuracy of point-of-care (PoC) applications may be compromised in individuals with additional inflammatory conditions. This cross-sectional study examined the performance of a commercial oral rinse active matrix metalloproteinase-8 (aMMP-8) PoC immunotest in individuals with (n = 47) and without Crohn's disease (CD) (n = 41). Oral rinse collected from the participants was analyzed by the PoC immunotest. Molecular forms and fragments of salivary MMP-8 were detected by western immunoblotting. The sensitivity of the immunotest for periodontitis was 60.0% in the CD group and 90.0% in the control group. The respective specificity was 75.0% and 80.0%. In both groups, clinical diagnosis of periodontitis exhibited a significant association with the immunotest results, however, the odds ratio (OR) was more than ten-fold in controls (OR 54.3, 95% CI: 3.1-953, p = 0.006) in comparison to CD patients (OR 5.2, 95% CI: 1.3-21.6, p = 0.022). According to Western immunoblot results, the immunotest MMP-8 positivity was not related to elevated levels of molecular forms and fragments of MMP-8 in the CD group, as in the control group. The diagnostic accuracy of the aMMP-8 PoC oral rinse immunotest is reduced in CD patients, which may be related to lower levels or undetectable complexes.
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Affiliation(s)
- Jaana Rautava
- Department of Oral Pathology and Oral Radiology, Institute of Dentistry, University of Turku, 20520 Turku, Finland;
- Department of Pathology, Turku University Hospital, 20521 Turku, Finland
- Correspondence: ; Tel.: +358-29-4505000
| | - Ulvi K. Gürsoy
- Department of Periodontology, Institute of Dentistry, University of Turku, 20520 Turku, Finland; (U.K.G.); (E.K.); (M.G.)
| | - Adrian Kullström
- Department of Oral Pathology and Oral Radiology, Institute of Dentistry, University of Turku, 20520 Turku, Finland;
- Department of Periodontology, Institute of Dentistry, University of Turku, 20520 Turku, Finland; (U.K.G.); (E.K.); (M.G.)
| | - Eija Könönen
- Department of Periodontology, Institute of Dentistry, University of Turku, 20520 Turku, Finland; (U.K.G.); (E.K.); (M.G.)
- Oral Health Care, Welfare Division, City of Turku, 20101 Turku, Finland
| | - Timo Sorsa
- Department of Oral and Maxillofacial Disease, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland; (T.S.); (T.T.)
- Department of Dental Medicine, Karolinska Institute, 14152 Huddinge, Sweden
| | - Taina Tervahartiala
- Department of Oral and Maxillofacial Disease, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland; (T.S.); (T.T.)
| | - Mervi Gürsoy
- Department of Periodontology, Institute of Dentistry, University of Turku, 20520 Turku, Finland; (U.K.G.); (E.K.); (M.G.)
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45
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Milajerdi A, Sadeghi O, Siadat SD, Keshavarz SA, Sima A, Vahedi H, Adibi P, Esmaillzadeh A. A randomized controlled trial investigating the effect of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols on the intestinal microbiome and inflammation in patients with ulcerative colitis: study protocol for a randomized controlled trial. Trials 2020; 21:201. [PMID: 32070388 PMCID: PMC7029518 DOI: 10.1186/s13063-020-4108-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/26/2020] [Indexed: 12/12/2022] Open
Abstract
Background No conclusive treatment is available for irritable bowel disease (IBD). Adherence to a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) might alleviate clinical symptoms of IBD. However, no study has investigated the effect of low FODMAPs diet on the intestinal microbiota and inflammatory biomarkers in patients with IBD. The aim of current study is to examine the effect a low FODMAP diet on IBD symptoms, inflammation, and the intestinal microbiota in patients with ulcerative colitis. Methods and analysis This study is a randomized clinical trial. Thirty patients with mild to moderate ulcerative colitis will be randomly allocated to receive a low FODMAP diet (n = 15) or to continue their usual diet as control (n = 15), for 4 weeks. The quantity of intestinal microbiota including Clostridium cluster IV, Faecalibacterium prausnitzii, Rosburia spp., Lactobacillus spp., Bifidobacteria spp., Akkermansia muciniphila, Bacteroides fragilis, and Ruminococcus spp., and the Firmicutes to Bacteroidetes ratio and calprotectin and lactoferrin levels will be explored in fecal samples from patients. In addition, anthropometric measures and biochemical assessments including serum concentrations of highly sensitive-C reactive protein (hs-CRP), tumour necrosis factor-α (TNF-α) and IL-1β will be taken from patients at baseline and end of the study. The study has been registered in IRCT (IRCT20181126041763N1; registration date: 2019-01-18). Discussion Consumption of a low-FODMAP diet might decrease systemic and intestinal inflammation, change the bacterial population in the gut, and modulate clinical symptoms in patients with ulcerative colitis. Further studies investigating the effect of such a diet on other variables, including other bacterial species and inflammatory cytokines, are required to confirm future findings of this trial.
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Affiliation(s)
- Alireza Milajerdi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, PO Box 81745, Tehran, Iran
| | - Omid Sadeghi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, PO Box 81745, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Ali Keshavarz
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Sima
- Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Homayoon Vahedi
- Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Peyman Adibi
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Esmaillzadeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, PO Box 81745, Tehran, Iran. .,Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. .,Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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46
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Tran V, Shammas RM, Sauk JS, Padua D. Evaluating tofacitinib citrate in the treatment of moderate-to-severe active ulcerative colitis: design, development and positioning of therapy. Clin Exp Gastroenterol 2019; 12:179-191. [PMID: 31118734 PMCID: PMC6507103 DOI: 10.2147/ceg.s150908] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/06/2019] [Indexed: 12/14/2022] Open
Abstract
The etiology of ulcerative colitis (UC) is complex and involves a host of genetic, epigenetic and environmental factors. Over the last thirty years, signaling pathways like the Janus kinase (JAK) signaling pathway have been implicated in its pathogenesis. Pharmacologic blockade of this pathway is available through several small molecule inhibitors, including tofacitinib. Tofacitinib is an orally administered pan-JAK inhibitor that was first approved by the Food and Drug Administration (FDA) for use in rheumatologic disorders such as rheumatoid arthritis and psoriatic arthritis. The FDA approved its use in moderate-to-severe active ulcerative colitis in 2018. The aim of this review will be to discuss the role of tofacitinib in ulcerative colitis. We will discuss the role of JAK-STAT signaling, clinical data available for tofacitinib, and the safety profile for this therapy. Tofacitinib's place in the UC management algorithm is currently being debated. This effective oral therapy is poised to be a mainstay of UC therapeutics. This review will highlight the key clinical features and detail the UC experience to date.
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Affiliation(s)
- Vivy Tran
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Rania M Shammas
- Department of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jenny S Sauk
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Tamar and Vatche Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - David Padua
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Tamar and Vatche Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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47
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M'Koma AE. The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview. GASTROINTESTINAL DISORDERS 2019; 1:75-105. [PMID: 37577036 PMCID: PMC10416806 DOI: 10.3390/gidisord1010007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease.
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Affiliation(s)
- Amosy E M'Koma
- Meharry Medical College School of Medicine, Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Nashville, TN 37208, USA
- Vanderbilt University School of Medicine, Department of Surgery, Colon and Rectal Surgery, Nashville, TN 37232, USA
- The American Society of Colon and Rectal Surgeons (ASCRS), Arlington Heights, IL 60005, USA
- The American Gastroenterological Association (AGA), Bethesda, MD 20814, USA
- Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, USA
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48
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Alves VBF, de Sousa BC, Fonseca MTC, Ogata H, Caliári-Oliveira C, Yaochite JNU, Rodrigues Júnior V, Chica JEL, da Silva JS, Malmegrim KCR, Pernomian L, Cardoso CR. A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis. Clin Exp Immunol 2019; 196:139-154. [PMID: 30663040 DOI: 10.1111/cei.13262] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2019] [Indexed: 12/15/2022] Open
Abstract
Current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for many refractory patients. Mesenchymal stromal cells (MSC) are multi-potent cells with regulatory immunosuppressive activity that may control inflammatory diseases. In this study, we investigated the short- and especially the long-term protective effects of MSC on experimental colitis. We show that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut-draining lymph nodes, together with reduced accumulation of these cells in the colon intraepithelial compartment. Interestingly, there were increased levels of programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor family-related receptor (GITR) in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, T helper type 1 (Th1) and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted long-term, with restored goblet cells, eosinophils and maintenance of elevated gut interleukin (IL)-4, besides increased CD4+ CD25+ PD-1+ cells in the spleen and reduced Th17 response in mesenteric lymph nodes (MLN) of treated mice on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue-derived MSC as a novel therapeutic approach with long-term beneficial regulatory effects in experimental colitis.
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Affiliation(s)
- V B Freitas Alves
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil.,Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - B Coutinho de Sousa
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - M Thaís Costa Fonseca
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil.,Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - H Ogata
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - C Caliári-Oliveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.,In Situ Terapia Celular, SUPERA Parque de Inovação e Tecnologia de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil
| | - J Navarro Ueda Yaochite
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.,Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal do Ceará, Odontologia e Enfermagem, Fortaleza, Ceará, Brazil
| | - V Rodrigues Júnior
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - J E Lazo Chica
- Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - J Santana da Silva
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - K C Ribeiro Malmegrim
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - L Pernomian
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - C Ribeiro Cardoso
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
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49
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Barrett KE. New frontiers in gastrointestinal physiology and pathophysiology. J Physiol 2018; 596:3859-3860. [PMID: 29863278 PMCID: PMC6117559 DOI: 10.1113/jp276454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 12/14/2022] Open
Affiliation(s)
- Kim E. Barrett
- Department of MedicineUniversity of California San DiegoSchool of MedicineLa JollaCAUSA
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50
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Abdelhamid L, Luo XM. Retinoic Acid, Leaky Gut, and Autoimmune Diseases. Nutrients 2018; 10:E1016. [PMID: 30081517 PMCID: PMC6115935 DOI: 10.3390/nu10081016] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/25/2018] [Accepted: 07/25/2018] [Indexed: 12/19/2022] Open
Abstract
A leaky gut has been observed in a number of autoimmune diseases including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Previous studies from our laboratory have shown that lupus mice also bear a leaky gut and that the intestinal barrier function can be enhanced by gut colonization of probiotics such as Lactobacillus spp. Retinoic acid (RA) can increase the relative abundance of Lactobacillus spp. in the gut. Interestingly, RA has also been shown to strengthen the barrier function of epithelial cells in vitro and in the absence of probiotic bacteria. These reports bring up an interesting question of whether RA exerts protective effects on the intestinal barrier directly or through regulating the microbiota colonization. In this review, we will discuss the roles of RA in immunomodulation, recent literature on the involvement of a leaky gut in different autoimmune diseases, and how RA shapes the outcomes of these diseases.
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Affiliation(s)
- Leila Abdelhamid
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Xin M Luo
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA.
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