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Chen Y, Chen X, Lin S, Huang S, Li L, Hong M, Li J, Ma L, Ma J. Effects of psychological stress on inflammatory bowel disease via affecting the microbiota-gut-brain axis. Chin Med J (Engl) 2025; 138:664-677. [PMID: 39965932 PMCID: PMC11925421 DOI: 10.1097/cm9.0000000000003389] [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: 08/25/2024] [Indexed: 02/20/2025] Open
Abstract
ABSTRACT Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory condition with chronic and relapsing manifestations and is characterized by a disturbance in the interplay between the intestinal microbiota, the gut, and the brain. The microbiota-gut-brain axis involves interactions among the nervous system, the neuroendocrine system, the gut microbiota, and the host immune system. Increasing published data indicate that psychological stress exacerbates the severity of IBD due to its negative effects on the microbiota-gut-brain axis, including alterations in the stress response of the hypothalamic-pituitary-adrenal (HPA) axis, the balance between the sympathetic nervous system and vagus nerves, the homeostasis of the intestinal flora and metabolites, and normal intestinal immunity and permeability. Although the current evidence is insufficient, psychotropic agents, psychotherapies, and interventions targeting the microbiota-gut-brain axis show the potential to improve symptoms and quality of life in IBD patients. Therefore, further studies that translate recent findings into therapeutic approaches that improve both physical and psychological well-being are needed.
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Affiliation(s)
- Yuhan Chen
- Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Xiaofen Chen
- Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Suqin Lin
- Medical College, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Shengjun Huang
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Medical College, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Lijuan Li
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Medical College, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Mingzhi Hong
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Medical College, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jianzhou Li
- Department of Diagnosis and Treatment Center of High Altitude Digestive Disease, The Second People’s Hospital of Xining, Xining, Qinghai 810003, China
| | - Lili Ma
- Department of Gastroenterology and Hepatology, Qinghai Provincial People’s Hospital, Xining, Qinghai 810007, China
| | - Juan Ma
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Department of Diagnosis and Treatment Center of High Altitude Digestive Disease, The Second People’s Hospital of Xining, Xining, Qinghai 810003, China
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Kordahi MC, Delaroque C, Bredèche MF, Gewirtz AT, Chassaing B. Vaccination against microbiota motility protects mice from the detrimental impact of dietary emulsifier consumption. PLoS Biol 2023; 21:e3002289. [PMID: 37725584 PMCID: PMC10508614 DOI: 10.1371/journal.pbio.3002289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 08/07/2023] [Indexed: 09/21/2023] Open
Abstract
Dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate 80 (P80), perturb gut microbiota composition and gene expression, resulting in a microbiota with enhanced capacity to activate host pro-inflammatory gene expression and invade the intestine's inner mucus layer. Such microbiota alterations promote intestinal inflammation, which can have a variety of phenotypic consequences including increased adiposity. Bacterial flagellin is a key mediator of emulsifiers' impact in that this molecule enables motility and is itself a pro-inflammatory agonist. Hence, we reasoned that training the adaptive mucosal immune system to exclude microbes that express flagellin might protect against emulsifiers. Investigating this notion found that immunizing mice with flagellin elicited an increase in mucosal anti-flagellin IgA and IgA-coated microbiota that would have otherwise developed in response to CMC and P80 consumption. Yet, eliciting these responses in advance via flagellin immunization prevented CMC/P80-induced increases in microbiota expression of pro-inflammatory agonists including LPS and flagellin. Furthermore, such immunization prevented CMC/P80-induced microbiota encroachment and deleterious pro-inflammatory consequences associated therewith, including colon shortening and increased adiposity. Hence, eliciting mucosal immune responses to pathobiont surface components, including flagellin, may be a means of combatting the array of inflammatory diseases that are promoted by emulsifiers and perhaps other modern microbiota stressors.
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Affiliation(s)
- Melissa C. Kordahi
- INSERM U1016, Team “Mucosal microbiota in chronic inflammatory diseases”, CNRS UMR 8104, Université Paris Cité, Paris, France
| | - Clara Delaroque
- INSERM U1016, Team “Mucosal microbiota in chronic inflammatory diseases”, CNRS UMR 8104, Université Paris Cité, Paris, France
| | - Marie-Florence Bredèche
- INSERM U1016, Team “Robustness and evolvability of life”, CNRS UMR 8104, Université Paris Cité, Paris, France
| | - Andrew T. Gewirtz
- Institute for Biomedical Sciences, Centre for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, Georgia, United States of America
| | - Benoit Chassaing
- INSERM U1016, Team “Mucosal microbiota in chronic inflammatory diseases”, CNRS UMR 8104, Université Paris Cité, Paris, France
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3
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Eshleman EM, Shao TY, Woo V, Rice T, Engleman L, Didriksen BJ, Whitt J, Haslam DB, Way SS, Alenghat T. Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity. J Clin Invest 2023; 133:e162190. [PMID: 36602872 PMCID: PMC9927950 DOI: 10.1172/jci162190] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023] Open
Abstract
Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we found that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibited increased accumulation of commensal-specific CD4+ T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific CD4+ T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelium-intrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensal-specific Th17 cells, and promoted T cell-driven colitis. Mechanistically, HDAC3 was essential for NF-κB-dependent regulation of epithelial MHC class II (MHCII). Epithelium-intrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII expression on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in directing the dynamic balance of tissue-intrinsic CD4+ T cell subsets that recognize commensal microbes and control inflammation.
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Affiliation(s)
| | - Tzu-Yu Shao
- Center for Inflammation and Tolerance
- Division of Infectious Disease, and
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Vivienne Woo
- Division of Immunobiology
- Center for Inflammation and Tolerance
| | - Taylor Rice
- Division of Immunobiology
- Center for Inflammation and Tolerance
| | - Laura Engleman
- Division of Immunobiology
- Center for Inflammation and Tolerance
| | - Bailey J. Didriksen
- Division of Immunobiology
- Center for Inflammation and Tolerance
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Jordan Whitt
- Division of Immunobiology
- Center for Inflammation and Tolerance
| | | | - Sing Sing Way
- Center for Inflammation and Tolerance
- Division of Infectious Disease, and
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4
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Sollid LM, Iversen R. Tango of B cells with T cells in the making of secretory antibodies to gut bacteria. Nat Rev Gastroenterol Hepatol 2023; 20:120-128. [PMID: 36056203 DOI: 10.1038/s41575-022-00674-y] [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] [Accepted: 07/27/2022] [Indexed: 02/03/2023]
Abstract
Polymeric IgA and IgM are transported across the epithelial barrier from plasma cells in the lamina propria to exert a function in the gut lumen as secretory antibodies. Many secretory antibodies are reactive with the gut bacteria, and mounting evidence suggests that these antibodies are important for the host to control gut bacterial communities. However, we have incomplete knowledge of how bacteria-reactive secretory antibodies are formed. Antibodies from gut plasma cells often show bacterial cross-species reactivity, putting the degree of specificity behind anti-bacterial antibody responses into question. Such cross-species reactive antibodies frequently recognize non-genome-encoded membrane glycan structures. On the other hand, the T cell epitopes are peptides encoded in the bacterial genomes, thereby allowing a higher degree of predictable specificity on the T cell side of anti-bacterial immune responses. In this Perspective, we argue that the production of bacteria-reactive secretory antibodies is mainly controlled by the antigen specificity of T cells, which provide help to B cells. To be able to harness this system (for instance, for manipulation with vaccines), we need to obtain insight into the bacterial epitopes recognized by T cells in addition to characterizing the reactivity of the antibodies.
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Affiliation(s)
- Ludvig M Sollid
- K.G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
| | - Rasmus Iversen
- K.G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
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5
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Mölzer C, Liu YH, Muckersie E, Klaska IP, Cornall R, Wilson HM, Kuffová L, Forrester JV. Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel. Sci Rep 2023; 13:1256. [PMID: 36690619 PMCID: PMC9870966 DOI: 10.1038/s41598-022-27018-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 12/23/2022] [Indexed: 01/24/2023] Open
Abstract
Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.
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Affiliation(s)
- C Mölzer
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Y-H Liu
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
- Flow Facility, University of Glasgow, Wolfson Wohl Cancer Research Centre, Switchback Road, Bearsden, G61 1BD, Glasgow, UK
| | - E Muckersie
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - I P Klaska
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
- Centre for Gene Therapy and Regenerative Medicine, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - R Cornall
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7BN, UK
| | - H M Wilson
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - L Kuffová
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
- Eye Clinic, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK
| | - J V Forrester
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
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6
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Hackstein CP, Costigan D, Drexhage L, Pearson C, Bullers S, Ilott N, Akther HD, Gu Y, FitzPatrick MEB, Harrison OJ, Garner LC, Mann EH, Pandey S, Friedrich M, Provine NM, Uhlig HH, Marchi E, Powrie F, Klenerman P, Thornton EE. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice. Nat Commun 2022; 13:7472. [PMID: 36463279 PMCID: PMC9719512 DOI: 10.1038/s41467-022-35126-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 11/20/2022] [Indexed: 12/05/2022] Open
Abstract
Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.
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Affiliation(s)
- Carl-Philipp Hackstein
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Dana Costigan
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Linnea Drexhage
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Claire Pearson
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Samuel Bullers
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Nicholas Ilott
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Hossain Delowar Akther
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Yisu Gu
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Michael E B FitzPatrick
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Oliver J Harrison
- Center for Fundamental Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA
- Department of Immunology, University of Washington, 750 Republican St, Seattle, WA, 98108, USA
| | - Lucy C Garner
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Elizabeth H Mann
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Sumeet Pandey
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Matthias Friedrich
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Nicholas M Provine
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, and Biomedical Research Centre, and Department of Paediatrics, University of Oxford, Oxford, OX39DU, UK
| | - Emanuele Marchi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Emily E Thornton
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
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7
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Morgan NN, Duck LW, Wu J, Rujani M, Thomes PG, Elson CO, Mannon PJ. Crohn's Disease Patients Uniquely Contain Inflammatory Responses to Flagellin in a CD4 Effector Memory Subset. Inflamm Bowel Dis 2022; 28:1893-1903. [PMID: 35931421 DOI: 10.1093/ibd/izac146] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Specific microbial antigens stimulate production of antibodies indicative of the aberrant immune response in Crohn's disease (CD). We tested for T cell reactivity linkage to B cell responses and now report on the prevalence, functionality, and phenotypic differences of flagellin-specific T cells among CD patients, ulcerative colitis (UC) patients, and control subjects and association with clinical features and flagellin seropositivity within CD patients. METHODS Sera from non-inflammatory bowel disease control subjects, CD patients, and UC patients were probed for antibody reactivity to gut bacterial recombinant flagellin antigens. Peripheral blood mononuclear cells were measured for flagellin antigen (CBir1, A4 Fla2, FlaX) or control (Candida albicans, and CytoStim) reactivity analyzed by flow cytometry for CD154 and cytokine expression on CD4+ T cells. Supernatants from post-flagellin-stimulated and unstimulated cells were used to measure effects on epithelial barrier function. RESULTS CD patients had a significantly higher percentage of flagellin-specific CD154+ CD4+ cells that have an effector memory T helper 1 and T helper 17 phenotype compared with UC patients and healthy control subjects. There was a positive correlation between the frequency of flagellin-specific CD154+ CD4+ effector memory T cells and serum levels of anti-flagellin immunoglobulin G in the CD patients. In addition, A4 Fla2-reactive T cells from active CD patients produced cytokines that can decrease barrier function in a gut epithelium. CONCLUSIONS These findings demonstrate a Crohn's-associated flagellin-reactive CD4 cell subset distinct from UC patients and control subjects. There is a link between these cells and flagellin seropositivity. This CD4 cell subset could reflect a particular endophenotype of CD, leading to novel insight into its pathology and treatment.
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Affiliation(s)
- Nadine N Morgan
- Program in Immunology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lennard W Duck
- Program in Immunology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jiongru Wu
- Division of Gastroenterology and Hepatology, Paustian IBD Center, University of Nebraska Medical Center, Omaha, NE, USA.,Medical Service and Department of Medicine, Omaha VA Medical Center, Omaha, NE, USA
| | - Mahmud Rujani
- Medical Service and Department of Medicine, Omaha VA Medical Center, Omaha, NE, USA
| | - Paul G Thomes
- Division of Gastroenterology and Hepatology, Paustian IBD Center, University of Nebraska Medical Center, Omaha, NE, USA.,Medical Service and Department of Medicine, Omaha VA Medical Center, Omaha, NE, USA
| | - Charles O Elson
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Peter J Mannon
- Division of Gastroenterology and Hepatology, Paustian IBD Center, University of Nebraska Medical Center, Omaha, NE, USA.,Medical Service and Department of Medicine, Omaha VA Medical Center, Omaha, NE, USA
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8
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Tange K, Yagi S, Takeshita E, Abe M, Yamamoto Y, Tomida H, Kawamura T, Hanayama M, Matsuura B, Ikeda Y, Hiasa Y. Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model. Sci Rep 2022; 12:17983. [PMID: 36289244 PMCID: PMC9606376 DOI: 10.1038/s41598-022-22455-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 10/14/2022] [Indexed: 01/24/2023] Open
Abstract
The incidence of inflammatory bowel disease (IBD) is increasing; hence, effective treatments are warranted. The therapeutic effect of human carbonic anhydrase I (hCA I) in IBD remains unknown. Therefore, we investigated whether oral tolerization to hCA I would induce antigen-specific protection from intestinal inflammation in vivo. Severe combined immunodeficient mice received hCA I, keyhole limpet hemocyanin (KLH), or phosphate-buffered saline (PBS) orally for 7 days. Colons and mesenteric lymph nodes (MLNs) were collected 4 weeks after cell transfer. Additionally, the mechanisms underlying the therapeutic effects were investigated. The comparison between the effects of well-established drugs and hCA I oral administration was investigated. Oral administration of hCA I ameliorated colitis remarkably. hCA I reached the cecum and ameliorated colitis more effectively than mesalazine and similarly to prednisolone. Compared with PBS treatment, hCA I treatment reduced interleukin (IL)-17a, IL-6, and retinoic acid-related orphan receptor gamma t (RORγt) expression in the colon or MLNs; moreover, hCA I markedly reduced IL-6, IL-17, and interferon-gamma (IFN-γ) levels in the MLN. Oral administration of hCA I induced immune tolerance and suppressed colitis in vivo. Thus, hCA I administration could be proposed as a new treatment option for IBD.
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Affiliation(s)
- Kazuhiro Tange
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Sen Yagi
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, Ehime, Japan
| | - Eiji Takeshita
- Department of Inflammatory Bowel Diseases and Therapeutics, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Hideomi Tomida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Tomoe Kawamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Masakazu Hanayama
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yoshiou Ikeda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon-Shi, Ehime, 791-0295, Japan.
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9
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Wu X, Chen H, Gao X, Gao H, He Q, Li G, Yao J, Liu Z. Natural Herbal Remedy Wumei Decoction Ameliorates Intestinal Mucosal Inflammation by Inhibiting Th1/Th17 Cell Differentiation and Maintaining Microbial Homeostasis. Inflamm Bowel Dis 2022; 28:1061-1071. [PMID: 35092428 DOI: 10.1093/ibd/izab348] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Evidence has shown that the traditional Chinese herbal medicine Wumei decoction (WMD) has a protective effect on ulcerative colitis. Here, we studied the anti-inflammatory effects and potential mechanisms of WMD on chronic colitis in mice. METHODS A dextran sulfate sodium (DSS)-induced chronic colitis model and CD45RBhighCD4+ T cell transfer model were established in mice. Body weight, Disease Activity Index, and colon length were assessed, and histopathology was confirmed by hematoxylin and eosin staining. Colon tissue samples were collected to detect the frequencies of various immune cells, expression of cytokines, and tight junction-related proteins using flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. 16S ribosomal DNA sequencing was performed to distinguish differential microbiota of fecal samples. RESULTS Severe chronic colitis was observed in mice after DSS exposure and in Rag1-/- mice reconstituted with CD45RBhighCD4+ T cells, as manifested by weight loss, hematochezia, and shortening and thickening of the colon, which were reversed by WMD treatment. WMD markedly suppressed intestinal mucosal CD4+ T cell differentiation and the secretion of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin-1β, interferon γ, and IL-17A) by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Moreover, WMD promoted the expression of occludin, zonula occludens-1, and E-cadherin, thereby maintaining the epithelial barrier function. Additionally, 16S ribosomal DNA sequencing revealed that WMD regulated the dysbiosis of gut microbiota in CD45RBhighCD4+ T cell-reconstituted Rag1-/- mice, evidenced by an increase of Allobaculum and Bacteroides and a decrease of Ileibacterium. CONCLUSIONS WMD ameliorates chronic colitis in mice induced by DSS or reconstituted with CD45RBhighCD4+ T cells through suppressing Th1/Th17 cell differentiation and the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving the dysbiosis.
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Affiliation(s)
- Xiaohan Wu
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huimin Chen
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiang Gao
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Han Gao
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qiong He
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Gengfeng Li
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People's Hospital, Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Zhanju Liu
- Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.,Division of Immunology, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, China
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10
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Garabatos N, Santamaria P. Gut Microbial Antigenic Mimicry in Autoimmunity. Front Immunol 2022; 13:873607. [PMID: 35572569 PMCID: PMC9094498 DOI: 10.3389/fimmu.2022.873607] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/14/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota plays a major role in the developmental biology and homeostasis of cells belonging to the adaptive and innate arms of the immune system. Alterations in its composition, which are known to be regulated by both genetic and environmental factors, can either promote or suppress the pathogenic processes underlying the development of various autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis, to just name a few. Cross-recognition of gut microbial antigens by autoreactive T cells as well as gut microbe-driven alterations in the activation and homeostasis of effector and regulatory T cells have been implicated in this process. Here, we summarize our current understanding of the positive and negative associations between alterations in the composition of the gut microbiota and the development of various autoimmune disorders, with a special emphasis on antigenic mimicry.
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Affiliation(s)
- Nahir Garabatos
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Pere Santamaria
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Julia McFarlane Diabetes Research Centre (JMDRC), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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11
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Gehlhaar A, Inala A, Llivichuzhca-Loja D, Silva TN, Adegboye CY, O’Connell AE, Konnikova L. Insights into the Role of Commensal-Specific T Cells in Intestinal Inflammation. J Inflamm Res 2022; 15:1873-1887. [PMID: 35342295 PMCID: PMC8943607 DOI: 10.2147/jir.s288288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/19/2022] [Indexed: 12/21/2022] Open
Abstract
Trillions of microorganisms exist in the human intestine as commensals and contribute to homeostasis through their interactions with the immune system. In this review, we use previous evidence from published papers to elucidate the involvement of commensal-specific T cells (CSTCs) in regulating intestinal inflammatory responses. CSTCs are generated centrally in the thymus or peripherally at mucosal interfaces and present as CD4+ or CD8+ T cells. Bacteria, fungi, and even viruses act commensally with humans, warranting consideration of CSTCs in this critical relationship. Dysregulation of this immunological balance can result in both intestinal inflammation or damaging autoimmune responses elsewhere in the body. Given the relative novelty of CSTCs in the literature, we aim to introduce the importance of their role in maintaining immune homeostasis at barrier sites such as the intestine.
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Affiliation(s)
- Arne Gehlhaar
- Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Ashwin Inala
- Department of Pediatrics, Yale University, New Haven, CT, USA
| | | | - Tatiana N Silva
- Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Comfort Y Adegboye
- Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA
| | - Amy E O’Connell
- Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Liza Konnikova
- Department of Pediatrics, Yale University, New Haven, CT, USA
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, CT, USA
- Program in Human and Translational Immunology, Yale University, New Haven, CT, USA
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12
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Xu H, Cai F, Li P, Wang X, Yao Y, Chang X, Bi Z, Sun H, Zhuang H, Hua ZC. Characterization and Analysis of the Temporal and Spatial Dynamic of Several Enteritis Modeling Methodologies. Front Immunol 2021; 12:727664. [PMID: 35003056 PMCID: PMC8728876 DOI: 10.3389/fimmu.2021.727664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 11/23/2021] [Indexed: 01/22/2023] Open
Abstract
Inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, is a complex disease involving genetic, immune, and microbiological factors. A variety of animal models of IBD have been developed to study the pathogenesis of human IBD, but there is no model that can fully represent the complexity of IBD. In this study, we established two acute enteritis models by oral 3% DSS or intraperitoneal injection of anti-CD3 antibody, and two chronic enteritis models by feeding 3 cycles of 1.5% DSS or 3 months of the high-fat diet, respectively, and then examined the clinical parameters, histological changes, and cytokine expression profiles after the successful establishment of the models. Our results indicated that in 3% DSS-induced acute enteritis, the colorectal injury was significantly higher than that of the small intestine, while in anti-CD3 antibody-induced acute enteritis, the small intestine injury was significantly higher than that of colorectal damage. Besides, in the 1.5% DSS-induced chronic enteritis, the damage was mainly concentrated in the colorectal, while the damage caused by long-term HFD-induced chronic enteritis was more focused on the small intestine. Therefore, our work provides a reference for selecting appropriate models when conducting research on factors related to the pathogenesis of IBD or evaluating the potential diagnosis and treatment possibilities of pharmaceuticals.
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Affiliation(s)
- Huangru Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Fangfang Cai
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
- School of Biopharmacy, China Pharmaceutical University, Nanjing, China
| | - Ping Li
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Xiaoyang Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Yingying Yao
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Xiaoyao Chang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Zhiqian Bi
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Huisong Sun
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Hongqin Zhuang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
- *Correspondence: Hongqin Zhuang, ; Zi-Chun Hua,
| | - Zi-Chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
- School of Biopharmacy, China Pharmaceutical University, Nanjing, China
- Changzhou High-Tech Research Institute of Nanjing University, Changzhou, China
- Jiangsu TargetPharma Laboratories Inc., Changzhou, China
- *Correspondence: Hongqin Zhuang, ; Zi-Chun Hua,
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13
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Muschaweck M, Kopplin L, Ticconi F, Schippers A, Iljazovic A, Gálvez EJC, Abdallah AT, Wagner N, Costa IG, Strowig T, Pabst O. Cognate recognition of microbial antigens defines constricted CD4 + T cell receptor repertoires in the inflamed colon. Immunity 2021; 54:2565-2577.e6. [PMID: 34582747 DOI: 10.1016/j.immuni.2021.08.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 05/27/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022]
Abstract
Key aspects of intestinal T cells, including their antigen specificity and their selection by the microbiota and other intestinal antigens, as well as the contribution of individual T cell clones to regulatory and effector functions, remain unresolved. Here we tracked adoptively transferred T cell populations to specify the interrelation of T cell receptor repertoire and the gut antigenic environment. We show that dominant TCRα clonotypes were shared between interferon-γ- and interleukin-17-producing but not regulatory Foxp3+ T cells. Identical TCRα clonotypes accumulated in the colon of different individuals, whereas antibiotics or defined colonization correlated with the expansion of distinct expanded T cell clonotypes. Our results demonstrate key aspects of intestinal CD4+ T cell activation and suggest that few microbial species exert a dominant effect on the intestinal T cell repertoire during colitis. We speculate that dominant proinflammatory T cell clones might provide a therapeutic target in human inflammatory bowel disease.
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Affiliation(s)
- Moritz Muschaweck
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany; Department of Pediatrics, RWTH Aachen University, Aachen, Germany.
| | - Lydia Kopplin
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
| | - Fabio Ticconi
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany; Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Angela Schippers
- Department of Pediatrics, RWTH Aachen University, Aachen, Germany
| | - Aida Iljazovic
- Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Eric J C Gálvez
- Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany
| | - Ali T Abdallah
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Norbert Wagner
- Department of Pediatrics, RWTH Aachen University, Aachen, Germany
| | - Ivan G Costa
- Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Till Strowig
- Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany
| | - Oliver Pabst
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
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14
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Casalegno Garduño R, Däbritz J. New Insights on CD8 + T Cells in Inflammatory Bowel Disease and Therapeutic Approaches. Front Immunol 2021; 12:738762. [PMID: 34707610 PMCID: PMC8542854 DOI: 10.3389/fimmu.2021.738762] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022] Open
Abstract
CD8+ T cells are involved in the pathogenesis of inflammatory bowel disease (IBD), a complex multifactorial chronic disease. Here, we present an overview of the current research with the controversial findings of CD8+ T cell subsets and discuss some possible perspectives on their therapeutic value in IBD. Studies on the role of CD8+ T cells in IBD have contradictory outcomes, which might be related to the heterogeneity of the cells. Recent data suggest that cytotoxic CD8+ T cells (Tc1) and interleukin (IL) 17-producing CD8+ (Tc17) cells contribute to the pathogenesis of IBD. Moreover, subsets of regulatory CD8+ T cells are abundant at sites of inflammation and can exhibit pro-inflammatory features. Some subsets of tissue resident memory CD8+ T cells (Trm) might be immunosuppressant, whereas others might be pro-inflammatory. Lastly, exhausted T cells might indicate a positive outcome for patients. The function and plasticity of different subsets of CD8+ T cells in health and IBD remain to be further investigated in a challenging field due to the limited availability of mucosal samples and adequate controls.
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Affiliation(s)
- Rosaely Casalegno Garduño
- Mucosal Immunology Group, Department of Pediatrics, Rostock University Medical Center, Rostock, Germany
| | - Jan Däbritz
- Mucosal Immunology Group, Department of Pediatrics, Rostock University Medical Center, Rostock, Germany.,Center for Immunobiology, Blizard Institute, The Barts and the London School of Medicine and Dentistry, Queen Mary University, London, United Kingdom
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15
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Jain N, Sharma P, Kumar D. Murine models for studying immunopathogenesis in gastrointestinal lesions: How to go about it. INDIAN J PATHOL MICR 2021; 64:S58-S62. [PMID: 34135139 DOI: 10.4103/ijpm.ijpm_802_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Gastro-intestinal (GI) lesions are common outcome to diverse etiological agents affecting the GI tract. It requires significant expertise to accurately diagnose the fundamental cause and treat accordingly. A better understanding of the immunological underpinning of these lesions is of great importance to ensure their successful management. Availability of specific animal models allows us to understand the subtle differences among diverse disease conditions and help decide upon the treatment trajectories. Since murine models are best suited for studying the immunopathogenesis of any disease, we will restrict our discussions here to the available murine models and their applications to study gastrointestinal lesions. In this review, we have systematically examined and compared the variety of mice models that are routinely used to study Inflammatory Bowel disease (IBD) and also how they can be leveraged to address specific questions relating to IBD.
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Affiliation(s)
| | - Priya Sharma
- Cellular Immunology Group, ICGEB, New Delhi, India
| | - Dhiraj Kumar
- Cellular Immunology Group, ICGEB, New Delhi, India
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16
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Lee C, Verma R, Byun S, Jeun EJ, Kim GC, Lee S, Kang HJ, Kim CJ, Sharma G, Lahiri A, Paul S, Kim KS, Hwang DS, Iwakura Y, Speciale I, Molinaro A, De Castro C, Rudra D, Im SH. Structural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities. Nat Commun 2021; 12:3611. [PMID: 34127673 PMCID: PMC8203763 DOI: 10.1038/s41467-021-23929-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 05/24/2021] [Indexed: 01/04/2023] Open
Abstract
Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, β-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/β-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.
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Affiliation(s)
- Changhon Lee
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Ravi Verma
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- ImmmunoBiome Inc, Pohang, Republic of Korea
| | - Seohyun Byun
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Eun-Ji Jeun
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Gi-Cheon Kim
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Suyoung Lee
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Hye-Ji Kang
- Advanced convergence, Handong Global University, Pohang, Republic of Korea
- HEM, Pohang, Republic of Korea
| | - Chan Johng Kim
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Garima Sharma
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- ImmmunoBiome Inc, Pohang, Republic of Korea
| | - Abhishake Lahiri
- Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sandip Paul
- Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- JIS Institute of Advanced Studies and Research, JIS University, Kolkata, India
| | - Kwang Soon Kim
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Dong Soo Hwang
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- Division of Environmental Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Yoichiro Iwakura
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
- Center for Experimental Medicine and Systems Biology, Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo, Japan
| | - Immacolata Speciale
- Department of Agricultural Sciences, University of Napoli, Portici, Italy
- Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
| | - Antonio Molinaro
- Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
- Department of Chemical Sciences, University of Napoli, Napoli, Italy
| | - Cristina De Castro
- Department of Agricultural Sciences, University of Napoli, Portici, Italy
- Department of Chemical Sciences, University of Napoli, Napoli, Italy
| | - Dipayan Rudra
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- ImmmunoBiome Inc, Pohang, Republic of Korea.
| | - Sin-Hyeog Im
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- ImmmunoBiome Inc, Pohang, Republic of Korea.
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17
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Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies. J Immunol Res 2021; 2021:8816041. [PMID: 33553436 PMCID: PMC7846404 DOI: 10.1155/2021/8816041] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/15/2020] [Accepted: 01/12/2021] [Indexed: 12/22/2022] Open
Abstract
Autoimmune diseases (such as rheumatoid arthritis, asthma, autoimmune bowel disease) are a complex disease. Improper activation of the immune system or imbalance of immune cells can cause the immune system to transform into a proinflammatory state, leading to autoimmune pathological damage. Recent studies have shown that autoimmune diseases are closely related to CD4+ T helper cells (Th). The original CD4 T cells will differentiate into different T helper (Th) subgroups after activation. According to their cytokines, the types of Th cells are different to produce lineage-specific cytokines, which play a role in autoimmune homeostasis. When Th differentiation and its cytokines are not regulated, it will induce autoimmune inflammation. Autoimmune bowel disease (IBD) is an autoimmune disease of unknown cause. Current research shows that its pathogenesis is closely related to Th17 cells. This article reviews the role and plasticity of the upstream and downstream cytokines and signaling pathways of Th17 cells in the occurrence and development of autoimmune bowel disease and summarizes the new progress of IBD immunotherapy.
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18
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Cassinotti A, Passamonti F, Segato S. CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2021; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.
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Affiliation(s)
| | | | - Sergio Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese Italy
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19
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Inducing a stressed phenotype in healthy recipient mice by adoptively transferring CD4 + lymphocytes from mice undergoing chronic psychosocial stress. Psychoneuroendocrinology 2020; 122:104898. [PMID: 33126029 DOI: 10.1016/j.psyneuen.2020.104898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/01/2020] [Accepted: 10/02/2020] [Indexed: 11/22/2022]
Abstract
Although chronic stress is an acknowledged risk factor for the development of somatic and affective disorders, the cellular and molecular mechanisms underlying stress-induced pathologies are not fully understood. Interestingly, rodent studies involving immune cell transfer suggest that CD4+ T cells might be at least in part involved in reactivation of a chemically-induced colitis by stress. However, until now evidence is lacking that these immune cell types are indeed involved in the development of a "stressed phenotype". The aim of the present study was, therefore, to assess the effects of adoptively transferring total mesenteric lymph node cells (mesLNCs) and CD4+ mesLNCs isolated from chronically-stressed mice into healthy recipient mice on various physiological, immunological and behavioral parameters. To induce chronic psychosocial stress in donor mice we employed the chronic subordinate colony housing (CSC) paradigm. Our data indicate that transfer of total or CD4+ mesLNCs from CSC mice, compared with respective cells from single-housed control (SHC) mice, promoted splenomegaly and interferon (IFN)-γ secretion from in vitro anti-CD3-stimulated mesLNCs in naïve recipient mice. This effect was independent of recipient mice additionally being administered with dextran sulfate sodium (DSS) or not. Transfer of CD4+ mesLNCs additionally increased adrenal weight and secretion of IL-6 from in vitro anti-CD3 stimulated mesLNCs in recipients administered with DSS. Importantly, transfer of neither cell type from CSC vs. SHC donor mice affected anxiety-related behavior of recipient mice in the light-dark box. Taken together, our data demonstrate that typical physiological and immunological, but not behavioral, effects of chronic stress can be induced in naïve recipient mice by adoptively transferring mesLNCs, in particular CD4+ mesLNCs, from chronically stressed donor mice.
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20
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Huang X, Yang W, Yao S, Bilotta AJ, Lu Y, Zhou Z, Kumar P, Dann SM, Cong Y. IL-21 Promotes Intestinal Memory IgA Responses. THE JOURNAL OF IMMUNOLOGY 2020; 205:1944-1952. [PMID: 32859726 DOI: 10.4049/jimmunol.1900766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 08/03/2020] [Indexed: 12/12/2022]
Abstract
The role of IL-21, produced mainly by Th17 cells and T follicular helper cells, has been intensively investigated in B cell differentiation and Ab class switch. However, how IL-21 regulates memory IgA+ B cell development and memory IgA responses in the intestines is still not completely understood. In this study, we found the total IgA+ B cells as well as CD38+CD138-IgA+ memory B cells were significantly increased in intestinal lamina propria (LP) of TCRβxδ-/- mice after transfer of microbiota Ag-specific Th17 cells but not Th1 cells. Although IL-21R-/- mice or IL-17R-/- mice showed decreased Ag-specific memory IgA production in the intestines upon infection with Citrobacter rodentium, the percentage of IgA+CD38+CD138- memory B cells in Peyer's patches and LP was decreased only in IL-21R-/- mice, but not in IL-17R-/- mice, after reinfection with C. rodentium compared with wild-type mice. Blockade IL-21 in vivo suppressed intestinal C. rodentium-specific IgA production as well as IgA+CD38+CD138- memory B cells in Peyer's patches and LP. Furthermore, IL-21 significantly induced B cell IgA production in vitro, with the increased expression of genes related with class-switching and memory B cell development, including Aicda, Ski, Bmi1, and Klf2. Consistently, Aicda and Ski expression was decreased in B cells of IL-21R-/- mice after C. rodentium reinfection. In conclusion, our study demonstrated that IL-21 promotes intestinal memory IgA B cell development, possibly through upregulating differentiation-related and class switching-related genes, indicating a potential role of IL-21 in memory IgA+ B cell responses in the intestines.
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Affiliation(s)
- Xiangsheng Huang
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Wenjing Yang
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Suxia Yao
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Anthony J Bilotta
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Yao Lu
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Zheng Zhou
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Pawan Kumar
- Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794
| | - Sara M Dann
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555; and
| | - Yingzi Cong
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555; .,Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555
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21
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Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020; 20:411-426. [PMID: 32005980 DOI: 10.1038/s41577-019-0268-7] [Citation(s) in RCA: 461] [Impact Index Per Article: 92.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 12/25/2022]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA.
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22
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Ricciuto A, Sherman PM, Laxer RM. Gut microbiota in chronic inflammatory disorders: A focus on pediatric inflammatory bowel diseases and juvenile idiopathic arthritis. Clin Immunol 2020; 215:108415. [DOI: 10.1016/j.clim.2020.108415] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/06/2020] [Accepted: 04/06/2020] [Indexed: 12/16/2022]
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Yu AI, Zhao L, Eaton KA, Ho S, Chen J, Poe S, Becker J, Gonzalez A, McKinstry D, Hasso M, Mendoza-Castrejon J, Whitfield J, Koumpouras C, Schloss PD, Martens EC, Chen GY. Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis. Cell Rep 2020; 31:107471. [PMID: 32268087 PMCID: PMC7934571 DOI: 10.1016/j.celrep.2020.03.035] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 02/13/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023] Open
Abstract
There is increasing evidence that gut microbiome perturbations, also known as dysbiosis, can influence colorectal cancer development. To understand the mechanisms by which the gut microbiome modulates cancer susceptibility, we examine two wild-type mouse colonies with distinct gut microbial communities that develop significantly different tumor numbers using a mouse model of inflammation-associated tumorigenesis. We demonstrate that adaptive immune cells contribute to the different tumor susceptibilities associated with the two microbial communities. Mice that develop more tumors have increased colon lamina propria CD8+ IFNγ+ T cells before tumorigenesis but reduced CD8+ IFNγ+ T cells in tumors and adjacent tissues compared with mice that develop fewer tumors. Notably, intratumoral T cells in mice that develop more tumors exhibit increased exhaustion. Thus, these studies suggest that microbial dysbiosis can contribute to colon tumor susceptibility by hyperstimulating CD8 T cells to promote chronic inflammation and early T cell exhaustion, which can reduce anti-tumor immunity.
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Affiliation(s)
- Amy I Yu
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lili Zhao
- Department of Biostatistics, University of Michigan, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kathryn A Eaton
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sharon Ho
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jiachen Chen
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sara Poe
- Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - James Becker
- Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Allison Gonzalez
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Delaney McKinstry
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Muneer Hasso
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Joel Whitfield
- Cancer Center Immunology Core, University of Michigan, Ann Arbor, MI 48109, USA
| | - Charles Koumpouras
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Patrick D Schloss
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eric C Martens
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Grace Y Chen
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Newman KM, Vaughn BP. Efficacy of intestinal microbiota transplantation in ulcerative colitis: a review of current literature and knowledge. MINERVA GASTROENTERO 2020; 65. [DOI: 10.23736/s1121-421x.19.02610-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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25
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Tran HQ, Ley RE, Gewirtz AT, Chassaing B. Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases. Nat Commun 2019; 10:5650. [PMID: 31827095 PMCID: PMC6906489 DOI: 10.1038/s41467-019-13538-y] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 11/05/2019] [Indexed: 12/22/2022] Open
Abstract
Alterations in gut microbiota composition are associated with metabolic syndrome and chronic inflammatory diseases such as inflammatory bowel disease. One feature of inflammation-associated gut microbiotas is enrichment of motile bacteria, which can facilitate microbiota encroachment into the mucosa and activate pro-inflammatory gene expression. Here, we set out to investigate whether elicitation of mucosal anti-flagellin antibodies by direct administration of purified flagellin might serve as a general vaccine against subsequent development of chronic gut inflammation. We show, in mice, that repeated injection of flagellin elicits increases in fecal anti-flagellin IgA and alterations in microbiota composition, reduces fecal flagellin concentration, prevents microbiota encroachment, protects against IL-10 deficiency-induced colitis, and ameliorates diet-induced obesity. Flagellin's impact on the microbiota is B-lymphocyte dependent and, in humans, obese subjects exhibit increased levels of fecal flagellin and reduced levels of fecal flagellin-specific IgA, relative to normal weight subjects. Thus, administration of flagellin, and perhaps other pathobiont antigens, may confer some protection against chronic inflammatory diseases.
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Affiliation(s)
- Hao Q Tran
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Ruth E Ley
- Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen, Germany
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Benoit Chassaing
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA.
- INSERM, U1016, team "Mucosal microbiota in chronic inflammatory diseases", Paris, France.
- Université de Paris, Paris, France.
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Quraishi MN, Shaheen W, Oo YH, Iqbal TH. Immunological mechanisms underpinning faecal microbiota transplantation for the treatment of inflammatory bowel disease. Clin Exp Immunol 2019; 199:24-38. [PMID: 31777058 DOI: 10.1111/cei.13397] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2019] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease that results from a dysregulated immune response against specific environmental triggers in a genetically predisposed individual. Increasing evidence has indicated a causal role for changes in gut microbiota (dysbiosis) contributing to this immune-mediated intestinal inflammation. These mechanisms involve dysregulation of multiple facets of the host immune pathways that are potentially reversible. Faecal microbiota transplantation (FMT) is the transfer of processed stool from a healthy donor into an individual with an illness. FMT has shown promising results in both animal model experiments and clinical studies in IBD in the resolution of intestinal inflammation. The underlying mechanisms, however, are unclear. Insights from these studies have shown interactions between modulation of dysbiosis via changes in abundances of specific members of the gut microbial community and changes in host immunological pathways. Unravelling these causal relationships has promising potential for a translational therapy role to develop targeted microbial therapies and understand the mechanisms that underpin IBD aetiopathogenesis. In this review, we discuss current evidence for the contribution of gut microbiota in the disruption of intestinal immune homeostasis and immunoregulatory mechanisms that are associated with the resolution of inflammation through FMT in IBD.
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Affiliation(s)
- M N Quraishi
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.,Department of Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK.,University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - W Shaheen
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.,University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Y H Oo
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.,Department of Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK
| | - T H Iqbal
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.,Department of Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK.,University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
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Study on the Mechanism of Fu Zi Li Zhong Decoction in Treating Gastric Ulcer and its Effect on Gastrointestinal Microecology. DIGITAL CHINESE MEDICINE 2019. [DOI: 10.1016/j.dcmed.2019.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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28
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Tran HQ, Mills RH, Peters NV, Holder MK, de Vries GJ, Knight R, Chassaing B, Gonzalez DJ, Gewirtz AT. Associations of the Fecal Microbial Proteome Composition and Proneness to Diet-induced Obesity. Mol Cell Proteomics 2019; 18:1864-1879. [PMID: 31262998 PMCID: PMC6731084 DOI: 10.1074/mcp.ra119.001623] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Indexed: 12/16/2022] Open
Abstract
Consumption of refined high-fat, low-fiber diets promotes development of obesity and its associated consequences. Although genetics play an important role in dictating susceptibility to such obesogenic diets, mice with nearly uniform genetics exhibit marked heterogeneity in their extent of obesity in response to such diets. This suggests non-genetic determinants play a role in diet-induced obesity. Hence, we sought to identify parameters that predict, and/or correlate with, development of obesity in response to an obesogenic diet. We assayed behavior, metabolic parameters, inflammatory markers/cytokines, microbiota composition, and the fecal metaproteome, in a cohort of mice (n = 50) prior to, and the 8 weeks following, administration of an obesogenic high-fat low-fiber diet. Neither behavioral testing nor quantitation of inflammatory markers broadly predicted severity of diet-induced obesity. Although, the small subset of mice that exhibited basal elevations in serum IL-6 (n = 5) were among the more obese mice in the cohort. While fecal microbiota composition changed markedly in response to the obesogenic diet, it lacked the ability to predict which mice were relative prone or resistant to obesity. In contrast, fecal metaproteome analysis revealed functional and taxonomic differences among the proteins associated with proneness to obesity. Targeted interrogation of microbiota composition data successfully validated the taxonomic differences seen in the metaproteome. Although future work will be needed to determine the breadth of applicability of these associations to other cohorts of animals and humans, this study nonetheless highlights the potential power of gut microbial proteins to predict and perhaps impact development of obesity.
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Affiliation(s)
- Hao Q Tran
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA
| | - Robert H Mills
- §Department of Pharmacology, University of California, San Diego, CA; ¶Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA; ‖Department of Pediatrics, and Department of Computer Science and Engineering, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA
| | - Nicole V Peters
- ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA
| | - Mary K Holder
- ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA; §§School of Psychology, Georgia Institute of Technology, Atlanta, GA 30332
| | | | - Rob Knight
- ‖Department of Pediatrics, and Department of Computer Science and Engineering, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA
| | - Benoit Chassaing
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA; ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA
| | - David J Gonzalez
- §Department of Pharmacology, University of California, San Diego, CA; ¶Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA.
| | - Andrew T Gewirtz
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA.
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A gut pathobiont synergizes with the microbiota to instigate inflammatory disease marked by immunoreactivity against other symbionts but not itself. Sci Rep 2017; 7:17707. [PMID: 29255158 PMCID: PMC5735134 DOI: 10.1038/s41598-017-18014-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 12/05/2017] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are likely driven by aberrant immune responses directed against the resident microbiota. Although IBD is commonly associated with a dysbiotic microbiota enriched in putative pathobionts, the etiological agents of IBD remain unknown. Using a pathobiont-induced intestinal inflammation model and a defined bacterial community, we provide new insights into the immune-microbiota interactions during disease. In this model system, the pathobiont Helicobacter bilis instigates disease following sub-pathological dextran sulfate sodium treatment. We show that H. bilis causes mild inflammation in mono-associated mice, but severe disease in the presence of a microbiota, demonstrating synergy between the pathobiont and microbiota in exacerbating pathology. Remarkably, inflammation depends on the presence of H. bilis, but is marked by a predominant Th17 response against specific members of the microbiota and not the pathobiont, even upon the removal of the most immune-dominant taxa. Neither increases in pathobiont burden nor unique changes in immune-targeted microbiota member abundances are observed during disease. Collectively, our findings demonstrate that a pathobiont instigates inflammation without being the primary target of a Th17 response or by altering the microbiota community structure. Moreover, our findings point toward monitoring pathobiont-induced changes in microbiota immune targeting as a new concept in IBD diagnotics.
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30
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Elshal MF, Aldahlawi AM, Saadah OI, Mccoy JP. Expression of CD200R1 and its Ligand CD200 on T-helper Lymphocytes of Pediatric Patients with Ulcerative Colitis and Crohn's Disease. Clin Lab 2017; 62:1521-1529. [PMID: 28164626 DOI: 10.7754/clin.lab.2016.151231] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND CD200 and its receptor CD200R are both type I membrane glycoproteins that modulate the activity of myeloid and lymphoid cells, and their interaction is functionally important in the suppression of effector T-cell responses by regulatory T-cells. We aimed to investigate the extent of expression of CD200 and CD200R1 on CD4+ T-cells in blood of children with ulcerative colitis (UC) and Crohn's disease (CD) and to explore their correlations with effector T cell subsets, regulatory T cells (Treg), and routine clinical and serological markers. METHODS The frequencies of blood CD4+ expressing CD200 and CD200R1 as well as T-helper CD4+CD25+Foxp3+ Treg, CD4+ IL-17+ (Th17), CD4+ IFN-γ + (Th1), and CD4+IL-4+ (Th2) were estimated by flow cytometry in 23 patients with CD, 14 with UC, and 14 healthy volunteers (HCs). The clinical and inflammatory markers were also investigated. RESULTS IBD patients showed decreased CD4+CD200R1+ T-cells, whereas, CD4+CD200+ T-cells were significantly higher in patient groups compared with healthy controls. Treg cells were found significantly decreased in the patients with UC and CD compared with healthy controls (both at p < 0.01). The percentage of Th17 was found significantly increased in CD (p < 0.05) compared with UC patients and healthy subjects (p = 0.014). CD200+CD4+ T-cells showed significant positive correlations with ESR, Th1, and Th17 (r = 0.438, p < 0.05; r = 0.411, p < 0.05; r = 0.492, p < 0.01, respectively). CD200R1+CD4+ T-cells correlated positively with Th2 and Treg (r = 0.482, p < 0.01, and r = 0.457, p < 0.01, respectively) and negatively with ESR (r = -0.387, p < 0.01). CONCLUSIONS Our study demonstrates an aberrant expression of CD200/CD200R1 on CD4+ T-cells in IBD patients and these data may have potent pathological significance in IBD pathophysiology.
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31
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Hegazy AN, West NR, Stubbington MJT, Wendt E, Suijker KIM, Datsi A, This S, Danne C, Campion S, Duncan SH, Owens BMJ, Uhlig HH, McMichael A, Bergthaler A, Teichmann SA, Keshav S, Powrie F. Circulating and Tissue-Resident CD4 + T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation. Gastroenterology 2017; 153:1320-1337.e16. [PMID: 28782508 PMCID: PMC5687320 DOI: 10.1053/j.gastro.2017.07.047] [Citation(s) in RCA: 248] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 07/21/2017] [Accepted: 07/25/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. METHODS We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. RESULTS Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. CONCLUSIONS In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.
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Affiliation(s)
- Ahmed N Hegazy
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom
| | - Nathaniel R West
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom
| | - Michael J T Stubbington
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
| | - Emily Wendt
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom
| | - Kim I M Suijker
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom
| | - Angeliki Datsi
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom
| | - Sebastien This
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom
| | - Camille Danne
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom
| | - Suzanne Campion
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, United Kingdom
| | - Sylvia H Duncan
- Microbial Ecology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
| | - Benjamin M J Owens
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom
| | - Holm H Uhlig
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Oxford, United Kingdom
| | - Andrew McMichael
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, United Kingdom
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Sarah A Teichmann
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
| | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom
| | - Fiona Powrie
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, United Kingdom; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom.
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Bryson JS, Brandon JA, Jennings CD, Kaplan AM. A gut feeling about murine syngeneic GVHD. CHIMERISM 2017; 2:58-60. [PMID: 21912721 DOI: 10.4161/chim.2.2.16783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Accepted: 06/05/2011] [Indexed: 11/19/2022]
Abstract
Murine syngeneic graft-versus-host disease (SGVHD) results in chronic colon and liver inflammation following syngeneic bone marrow transplantation (BMT) and treatment with the calcineurin inhibitor, cyclosporine A (CsA). SGVHD was initially thought to arise as a result of an autoreactive immune response, but more recently it has been shown that enhanced antimicrobial responses develop in SGVHD mice. Consequently, we performed studies to analyze the role of the microbiota in the development of murine SGVHD. Treatment with broad-spectrum antibiotics eliminated disease-associated inflammatory immune responses and pathology, linking the role of the microbiota and microbial-specific immunity to the development of murine SGVHD. In a broader context, these results bring into question the role that anti-microbial immune responses play in post-transplant immune pathologies that develop following allogeneic stem cell transplantation and use of calcineurin inhibitors.
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Affiliation(s)
- J Scott Bryson
- Division of Hematology and Blood & Marrow Transplantation, Department of Internal Medicine; University of Kentucky Medical Center, University of Kentucky, Lexington, KY USA
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Kotredes KP, Thomas B, Gamero AM. The Protective Role of Type I Interferons in the Gastrointestinal Tract. Front Immunol 2017; 8:410. [PMID: 28428788 PMCID: PMC5382159 DOI: 10.3389/fimmu.2017.00410] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/22/2017] [Indexed: 12/18/2022] Open
Abstract
The immune system of the gastrointestinal (GI) tract manages the significant task of recognizing and eliminating pathogens while maintaining tolerance of commensal bacteria. Dysregulation of this delicate balance can be detrimental, resulting in severe inflammation, intestinal injury, and cancer. Therefore, mechanisms to relay important signals regulating cell growth and immune reactivity must be in place to support GI homeostasis. Type I interferons (IFN-I) are a family of pleiotropic cytokines, which exert a wide range of biological effects including promotion of both pro- and anti-inflammatory activities. Using animal models of colitis, investigations into the regulation of intestinal epithelium inflammation highlight the role of IFN-I signaling during fine modulation of the immune system. The intestinal epithelium of the gut guides the immune system to differentiate between commensal and pathogenic microbiota, which relies on intimate links with the IFN-I signal-transduction pathway. The current paradigm depicts an IFN-I-induced antiproliferative state in the intestinal epithelium enabling cell differentiation, cell maturation, and proper intestinal barrier function, strongly supporting its role in maintaining baseline immune activity and clearance of damaged epithelia or pathogens. In this review, we will highlight the importance of IFN-I in intestinal homeostasis by discussing its function in inflammation, immunity, and cancer.
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Affiliation(s)
- Kevin P Kotredes
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Brianna Thomas
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
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Carbonnel F, Soularue E, Coutzac C, Chaput N, Mateus C, Lepage P, Robert C. Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora? Semin Immunopathol 2017; 39:327-331. [PMID: 28093620 DOI: 10.1007/s00281-016-0613-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/06/2016] [Indexed: 12/13/2022]
Abstract
Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident Treg in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.
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Affiliation(s)
- Franck Carbonnel
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
- Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, F-94276, France
| | - Emilie Soularue
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
- Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, F-94276, France
| | - Clélia Coutzac
- Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, and CNRS-UMS 3655 and INSERM-US23, Villejuif, F-94805, France
| | - Nathalie Chaput
- Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, and CNRS-UMS 3655 and INSERM-US23, Villejuif, F-94805, France
- Université Paris-Sud, Faculté de pharmacie, Chatenay-Malabry, Châtenay-Malabry, F-92296, France
| | - Christine Mateus
- Gustave Roussy, Département de Médecine, Service de Dermatologie, et Université Paris-Sud Villejuif, Villejuif, F-94805, France
| | - Patricia Lepage
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France
| | - Caroline Robert
- Gustave Roussy, Département de Médecine, Service de Dermatologie, et Université Paris-Sud Villejuif, Villejuif, F-94805, France.
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Erova TE, Kirtley ML, Fitts EC, Ponnusamy D, Baze WB, Andersson JA, Cong Y, Tiner BL, Sha J, Chopra AK. Protective Immunity Elicited by Oral Immunization of Mice with Salmonella enterica Serovar Typhimurium Braun Lipoprotein (Lpp) and Acetyltransferase (MsbB) Mutants. Front Cell Infect Microbiol 2016; 6:148. [PMID: 27891321 PMCID: PMC5103298 DOI: 10.3389/fcimb.2016.00148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 10/27/2016] [Indexed: 12/12/2022] Open
Abstract
We evaluated the extent of attenuation and immunogenicity of the ΔlppAB and ΔlppAB ΔmsbB mutants of Salmonella enterica serovar Typhimurium when delivered to mice by the oral route. These mutants were deleted either for the Braun lipoprotein genes (lppA and lppB) or in combination with the msbB gene, which encodes an acetyltransferase required for lipid A modification of lipopolysaccharide. Both the mutants were attenuated (100% animal survival) and triggered robust innate and adaptive immune responses. Comparable levels of IgG and its isotypes were produced in mice infected with wild-type (WT) S. typhimurium or its aforementioned mutant strains. The ΔlppAB ΔmsbB mutant-immunized animals resulted in the production of higher levels of fecal IgA and serum cytokines during later stages of vaccination (adaptive response). A significant production of interleukin-6 from T-cells was also noted in the ΔlppAB ΔmsbB mutant-immunized mice when compared to that of the ΔlppAB mutant. On the other hand, IL-17A production was significantly more in the serum of ΔlppAB mutant-immunized mice (innate response) with a stronger splenic T-cell proliferative and tumor-necrosis factor-α production. Based on 2-dimensional gel analysis, alterations in the levels of several proteins were observed in both the mutant strains when compared to that in WT S. typhimurium and could be associated with the higher immunogenicity of the mutants. Finally, both ΔlppAB and ΔlppAB ΔmsbB mutants provided complete protection to immunized mice against a lethal oral challenge dose of WT S. typhimurium. Thus, these mutants may serve as excellent vaccine candidates and also provide a platform for delivering heterologous antigens.
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Affiliation(s)
- Tatiana E Erova
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Michelle L Kirtley
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Eric C Fitts
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Duraisamy Ponnusamy
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Wallace B Baze
- Department of Veterinary Sciences, University of Texas M. D. Anderson Cancer Center Bastrop, TX, USA
| | - Jourdan A Andersson
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical BranchGalveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical BranchGalveston, TX, USA; Sealy Center for Vaccine Development and World Health Organisation Collaborating Center for Vaccine Research, University of Texas Medical BranchGalveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical BranchGalveston, TX, USA
| | - Bethany L Tiner
- Department of Microbiology and Immunology, University of Texas Medical Branch Galveston, TX, USA
| | - Jian Sha
- Department of Microbiology and Immunology, University of Texas Medical BranchGalveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical BranchGalveston, TX, USA
| | - Ashok K Chopra
- Department of Microbiology and Immunology, University of Texas Medical BranchGalveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical BranchGalveston, TX, USA; Sealy Center for Vaccine Development and World Health Organisation Collaborating Center for Vaccine Research, University of Texas Medical BranchGalveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical BranchGalveston, TX, USA
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Rossini V, Radulovic K, Riedel CU, Niess JH. Development of an Antigen-driven Colitis Model to Study Presentation of Antigens by Antigen Presenting Cells to T Cells. J Vis Exp 2016. [PMID: 27684040 DOI: 10.3791/54421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammation which affects the gastrointestinal tract (GIT). One of the best ways to study the immunological mechanisms involved during the disease is the T cell transfer model of colitis. In this model, immunodeficient mice (RAG(-/-) recipients) are reconstituted with naive CD4(+) T cells from healthy wild type hosts. This model allows examination of the earliest immunological events leading to disease and chronic inflammation, when the gut inflammation perpetuates but does not depend on a defined antigen. To study the potential role of antigen presenting cells (APCs) in the disease process, it is helpful to have an antigen-driven disease model, in which a defined commensal-derived antigen leads to colitis. An antigen driven-colitis model has hence been developed. In this model OT-II CD4(+) T cells, that can recognize only specific epitopes in the OVA protein, are transferred into RAG(-/-) hosts challenged with CFP-OVA-expressing E. coli. This model allows the examination of interactions between APCs and T cells in the lamina propria.
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Affiliation(s)
| | | | | | - Jan Hendrik Niess
- Division of Gastroenterology and Hepatology, University Hospital Basel;
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Calderón-Gómez E, Bassolas-Molina H, Mora-Buch R, Dotti I, Planell N, Esteller M, Gallego M, Martí M, Garcia-Martín C, Martínez-Torró C, Ordás I, Singh S, Panés J, Benítez-Ribas D, Salas A. Commensal-Specific CD4(+) Cells From Patients With Crohn's Disease Have a T-Helper 17 Inflammatory Profile. Gastroenterology 2016; 151:489-500.e3. [PMID: 27267052 DOI: 10.1053/j.gastro.2016.05.050] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 05/27/2016] [Accepted: 05/29/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) has been associated with an altered immune response to commensal microbiota, mostly based on increased seroreactivity to microbial proteins. Although T cells are believed to contribute to the development of CD, little is known about the antigens involved. We investigated the antigen-specificity of T cells isolated from patients with CD. METHODS We isolated peripheral blood mononuclear cells from 65 patients with CD and 45 healthy individuals (controls). We investigated T-cell reactivity to commensal microbial antigens using proliferation assays (based on thymidine incorporation and carboxyfluorescein succinimidyl ester dilution). Gene expression patterns were determined using microarray and real-time polymerase chain reaction analyses. Cytokines, chemokines, and antibodies were measured by enzyme-linked immunosorbent assay, flow cytometry, or multiplex cytokine assays. Intestinal crypts were obtained from surgical resection specimens of 7 individuals without inflammatory bowel disease. We examined the effects of commensal-specific CD4(+) T cells on primary intestinal epithelial cells from these samples. RESULTS The bacterial proteins FlaX, A4-fla2, and YidX increased proliferation of CD4(+) T cells isolated from peripheral blood of patients with CD compared with controls. In blood samples from controls, CD4(+) T cells specific for FlaX, A4-fla2, or YidX had a T-helper (Th)1 phenotype; a larger proportion of CD4(+) T cells specific for these proteins in patients with CD had a Th17 phenotype or produced Th1 and Th17 cytokines. When supernatants collected from commensal-specific CD4(+) T cells from patients with CD were applied to healthy intestinal epithelial cells, the epithelial cells increased the expression of the chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL8 and the CC chemokine ligand 20 (CCL20). CONCLUSIONS A larger proportion of commensal-specific CD4(+) T cells from patients with CD have a Th17 phenotype or produce Th1 and Th17 cytokines, compared with T cells from controls; this might contribute to intestinal inflammation in patients with CD. These cells might be targeted for treatment of CD. The transcriptional data of commensal-specific CD4(+) T cells from healthy individuals and CD patients have been deposited in the Gene Expression Omnibus at the National Center for Biotechnology Information (accession no: GSE70469).
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Affiliation(s)
- Elisabeth Calderón-Gómez
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Helena Bassolas-Molina
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Rut Mora-Buch
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Isabella Dotti
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Núria Planell
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Míriam Esteller
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Marta Gallego
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Mercè Martí
- Laboratory of Cellular Immunology, Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
| | - Carme Garcia-Martín
- Laboratory of Cellular Immunology, Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
| | - Carlos Martínez-Torró
- Laboratory of Cellular Immunology, Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
| | - Ingrid Ordás
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Sharat Singh
- Department of Research and Development, Prometheus Laboratories, San Diego, California
| | - Julian Panés
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Daniel Benítez-Ribas
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
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Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2016; 52:183-190. [PMID: 27526283 DOI: 10.1038/bmt.2016.206] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/08/2016] [Accepted: 05/09/2016] [Indexed: 12/15/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota.
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Abstract
Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria under steady conditions. Many studies have demonstrated that microbiota-reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-interleukin-17A or anti-interleukin-17RA antibodies in patients with Crohn's Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both proinflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases.
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Affiliation(s)
- Wei Wu
- *Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; †Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; and ‡Department of Pathology, University of Texas Medical Branch, Galveston, Texas
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Wadwa M, Klopfleisch R, Buer J, Westendorf AM. Targeting Antigens to Dec-205 on Dendritic Cells Induces Immune Protection in Experimental Colitis in Mice. Eur J Microbiol Immunol (Bp) 2016; 6:1-8. [PMID: 27141310 PMCID: PMC4838981 DOI: 10.1556/1886.2015.00048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 12/01/2015] [Indexed: 12/21/2022] Open
Abstract
The endocytotic c-type lectin receptor DEC-205 is highly expressed on immature dendritic cells. In previous studies, it was shown that antigen-targeting to DEC-205 is a useful tool for the induction of antigen-specific Foxp3+ regulatory T cells and thereby can prevent inflammatory processes. However, whether this approach is sufficient to mediate tolerance in mucosal tissues like the gut is unknown. In this study, we established a new mouse model in which the adoptive transfer of naive hemagglutinin (HA)-specific CD4+Foxp3– T cells into VILLIN-HA transgenic mice leads to severe colitis. To analyze if antigen-targeting to DEC-205 could protect against inflammation of the gut, VILLIN-HA transgenic mice were injected with an antibody–antigen complex consisting of the immunogenic HA110–120 peptide coupled to an α-DEC-205 antibody (DEC-HA) before adoptive T cell transfer. DEC-HA-treated mice showed significantly less signs of intestinal inflammation as was demonstrated by reduced loss of body weight and histopathology in the gut. Strikingly, abrogated intestinal inflammation was mediated via the conversion of naive HA-specific CD4+Foxp3– T cells into HA-specific CD4+Foxp3+ regulatory T cells. In this study, we provide evidence that antigen-targeting to DEC-205 can be utilized for the induction of tolerance in mucosal organs that are confronted with large numbers of exogenous antigens.
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Affiliation(s)
- Munisch Wadwa
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg Essen , Essen, Germany
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universität Berlin , Berlin, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg Essen , Essen, Germany
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg Essen , Essen, Germany
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T Lymphocyte Dynamics in Inflammatory Bowel Diseases: Role of the Microbiome. BIOMED RESEARCH INTERNATIONAL 2015; 2015:504638. [PMID: 26583115 PMCID: PMC4637034 DOI: 10.1155/2015/504638] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 05/28/2015] [Indexed: 12/17/2022]
Abstract
Humans have coevolved with a complex community of bacterial species also referred to as the microbiome, which reciprocally provides critical contributions to human metabolism and immune system development. Gut microbiome composition differs significantly between individuals depending on host genetics, diet, and environmental factors. A dysregulation of the symbiotic nature of the intestinal host-microbial relationship and an aberrant and persistent immune response are the fundamental processes involved in inflammatory bowel diseases (IBD). Considering the essential role of T cells in IBD and the contributing role of the microbiome in shaping the immune response during the pathogenesis of IBD, this review focuses on the complex relationship, interplay, and communication between the gut microbiome and T cells, including their differentiation into different subsets of effector or regulatory cells.
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Cao AT, Yao S, Gong B, Nurieva RI, Elson CO, Cong Y. Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal Immunol 2015; 8:1072-82. [PMID: 25586558 PMCID: PMC4501922 DOI: 10.1038/mi.2014.134] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 12/13/2014] [Indexed: 02/04/2023]
Abstract
Commensal microbiota-specific T helper type 17 (Th17) cells are enriched in the intestines, which can convert into T follicular helper (Tfh) in Peyer's patches, and are crucial for production of intestinal immunoglobulin A (IgA) against microbiota; however, the role of Th17 and Tfh cytokines in regulating the mucosal IgA response to enteric microbiota is still not completely known. In this study, we found that intestinal IgA was impaired in mice deficient in interleukin (IL)-17 or IL-21 signaling. IL-21, but not IL-17, is able to augment B-cell differentiation to IgA(+) cells as mediated by transforming growth factor β1 (TGFβ1) and accelerate IgA class switch recombination (CSR). IL-21 and retinoic acid (RA) induce IgA(+) B-cell development and IgA production and drives autocrine TGFβ1 production to initiate IgA CSR. Repletion of T-cell-deficient TCRβxδ(-/-) mice with Th17 cells specific for commensal bacterial antigen increased the levels of IgA(+) B cells and IgA production in the intestine, which was blocked by neutralizing IL-21. Thus IL-21 functions to strongly augment IgA production under intestinal environment. Furthermore, IL-21 promotes intestinal B-cell homing through α4β7 expression, alone or with TGFβ and RA. Together, IL-21 from microbiota-specific Th17 and/or Tfh cells contributes to robust intestinal IgA levels by enhancing IgA(+) CSR, IgA production and B-cell trafficking into the intestine.
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Affiliation(s)
- Anthony T. Cao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555
| | - Suxia Yao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555
| | - Bin Gong
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555
| | - Roza I. Nurieva
- Department of Immunology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030
| | - Charles O. Elson
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555,Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555
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Dann SM, Manthey CF, Le C, Miyamoto Y, Gima L, Abrahim A, Cao AT, Hanson EM, Kolls JK, Raz E, Cong Y, Eckmann L. IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia. Exp Parasitol 2015; 156:68-78. [PMID: 26071205 DOI: 10.1016/j.exppara.2015.06.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 05/14/2015] [Accepted: 06/04/2015] [Indexed: 12/17/2022]
Abstract
Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with G. muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after 2 weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including β-defensin 1 and resistin-like molecule β. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.
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Affiliation(s)
- Sara M Dann
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Carolin F Manthey
- Department of Medicine, University of California, San Diego, CA, USA
| | - Christine Le
- Department of Medicine, University of California, San Diego, CA, USA
| | - Yukiko Miyamoto
- Department of Medicine, University of California, San Diego, CA, USA
| | - Lauren Gima
- Department of Medicine, University of California, San Diego, CA, USA
| | - Andrew Abrahim
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Anthony T Cao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Elaine M Hanson
- Department of Medicine, University of California, San Diego, CA, USA
| | - Jay K Kolls
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eyal Raz
- Department of Medicine, University of California, San Diego, CA, USA
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Lars Eckmann
- Department of Medicine, University of California, San Diego, CA, USA.
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Central role of gimap5 in maintaining peripheral tolerance and T cell homeostasis in the gut. Mediators Inflamm 2015; 2015:436017. [PMID: 25944983 PMCID: PMC4405212 DOI: 10.1155/2015/436017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 09/15/2014] [Indexed: 01/01/2023] Open
Abstract
Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)—including whole exome or genome sequencing—have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of “IBD-prone” animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans, GIMAP5 has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4+ T cell-mediated early-onset colitis.
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TIR-domain-containing adapter-inducing interferon-β (TRIF) regulates Th17-mediated intestinal immunopathology in colitis. Mucosal Immunol 2015; 8:296-306. [PMID: 25073675 PMCID: PMC4326974 DOI: 10.1038/mi.2014.67] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/27/2014] [Indexed: 02/04/2023]
Abstract
Gastrointestinal mucosa reserves abundant Th17 cells where host response to commensal bacteria maintains Th17-cell generation. Although functional heterogeneity and dynamic plasticity of Th17 cells appear to be involved in chronic inflammatory disorders, how their plasticity is regulated in intestinal mucosa is unknown. Here we show that innate TRIF signaling regulates intestinal Th17-cell generation and plasticity during colitis. Absence of TRIF in mice resulted in increased severity of experimental colitis, which was associated with aberrant generation of Th17 cells especially of interferon (IFN)-γ-expressing Th17 cells in the lamina propria. The abnormal generation and plasticity of Th17 cells involved impaired expression of interleukin (IL)-27p28 by lamina propria macrophages but not dendritic cells. Treatment of TRIF-deficient mice with IL-27p28 during colitis reduced the number and IFN-γ expression of Th17 cells in the intestine. In vitro, TRIF-deficient macrophages induced more Th17 cells than wild-type (WT) macrophages during co-culture with WT naive T cells in response to cecal bacterial antigen. Many of Th17 cells induced by TRIF-deficient macrophages expressed IFN-γ due to impaired expression of IL-27p28 by macrophages and defective activation of STAT1 in T cells. These results outline TRIF-dependent regulatory mechanism by which host response to intestinal bacteria maintains Th17-cell-mediated pathology during colitis.
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Henderson AL, Brand MW, Darling RJ, Maas KJ, Detzel CJ, Hostetter J, Wannemuehler MJ, Weaver EM. Attenuation of Colitis by Serum-Derived Bovine Immunoglobulin/Protein Isolate in a Defined Microbiota Mouse Model. Dig Dis Sci 2015; 60:3293-303. [PMID: 26026602 PMCID: PMC4621698 DOI: 10.1007/s10620-015-3726-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 05/21/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND The pathogenesis of inflammatory bowel disease (IBD) is complex and multifaceted including genetic predisposition, environmental components, microbial dysbiosis, and inappropriate immune activation to microbial components. Pathogenic bacterial provocateurs like adherent and invasive E. coli have been reported to increase susceptibility to Crohn's disease. Serum-derived bovine immunoglobulin/protein isolate (SBI) is comprised primarily of immunoglobulins (Igs) that bind to conserved microbial components and neutralize exotoxins. AIM To demonstrate that oral administration of SBI may modulate mucosal inflammation following colonization with E. coli, LF82, and exposure to dextran sodium sulfate (DSS). METHODS Defined microbiota mice harboring the altered Schaedler flora (ASF) were administered SBI or hydrolyzed collagen twice daily starting 7 days prior to challenge with E. coli LF82 and continuing for the remainder of the experiment. Mice were treated with DSS for 7 days and then evaluated for evidence of local and peripheral inflammation. RESULTS Igs within SBI bound multiple antigens from all eight members of the ASF and E. coli LF82 by western blot analysis. Multiple parameters of LF82/DSS-induced colitis were reduced following administration of SBI, including histological lesion scores, secretion of cytokines and chemokines from cecal biopsies, intestinal fatty acid binding protein (I-FABP) and serum amyloid A from plasma. CONCLUSIONS Oral administration of SBI attenuated clinical signs of LF82/DSS-induced colitis in mice. The data are consistent with the hypothesis that SBI immunoglobulin binding of bacterial antigens in the intestinal lumen may inhibit the inflammatory cascades that contribute to IBD, thus attenuating DSS-induced colitis.
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Affiliation(s)
| | - Meghan Wymore Brand
- />Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
| | - Ross J. Darling
- />Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
| | - Kenneth J. Maas
- />Entera Health, Inc., 2575 SE Oak Tree Ct., Ankeny, IA 50023 USA , />Entera Health, Inc., Cary, NC 27518 USA
| | | | - Jesse Hostetter
- />Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
| | - Michael J. Wannemuehler
- />Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011 USA
| | - Eric M. Weaver
- />Entera Health, Inc., 2575 SE Oak Tree Ct., Ankeny, IA 50023 USA
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Dave M, Papadakis KA, Faubion WA. Immunology of inflammatory bowel disease and molecular targets for biologics. Gastroenterol Clin North Am 2014; 43:405-24. [PMID: 25110250 PMCID: PMC4480636 DOI: 10.1016/j.gtc.2014.05.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated disease and involves a complex interplay of host genetics and environmental influences. Recent advances in the field, including data from genome-wide association studies and microbiome analysis, have started to unravel the complex interaction between host genetics and environmental influences in the pathogenesis of IBD. A drawback of current clinical trials is inadequate or lack of immune phenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamic and complex immune system, which may to lead to a more personalized treatment approach in IBD.
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49
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Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity 2014; 40:582-93. [PMID: 24745334 DOI: 10.1016/j.immuni.2014.02.014] [Citation(s) in RCA: 228] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 02/19/2014] [Indexed: 12/18/2022]
Abstract
Although in normal lamina propria (LP) large numbers of eosinophils are present, little is known about their role in mucosal immunity at steady state. Here we show that eosinophils are needed to maintain immune homeostasis in gut-associated tissues. By using eosinophil-deficient ΔdblGATA-1 and PHIL mice or an eosinophil-specific depletion model, we found a reduction in immunoglobulin A(+) (IgA(+)) plasma cell numbers and in secreted IgA. Eosinophil-deficient mice also showed defects in the intestinal mucous shield and alterations in microbiota composition in the gut lumen. In addition, TGF-β-dependent events including class switching to IgA in Peyer's patches (PP), the formation of CD103(+) T cells including Foxp3(+) regulatory (Treg), and also CD103(+) dendritic cells were disturbed. In vitro cultures showed that eosinophils produce factors that promote T-independent IgA class switching. Our findings show that eosinophils are important players for immune homeostasis in gut-associated tissues and add to data suggesting that eosinophils can promote tissue integrity.
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Animal models of inflammatory bowel disease: a review. Inflammopharmacology 2014; 22:219-33. [PMID: 24906689 DOI: 10.1007/s10787-014-0207-y] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 05/09/2014] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) represents a group of idiopathic chronic inflammatory intestinal conditions associated with various areas of the GI tract, including two types of inflammatory conditions, i.e., ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD are chronic inflammatory disorders of the intestine; in UC, inflammation starts in the rectum and generally extends proximally in a continuous manner through the entire colon. Bloody diarrhea, presence of blood and mucus mixed with stool, accompanied by lower abdominal cramping, are the characteristic symptoms of the disease. While in CD, inflammatory condition may affect any part of the GI tract from mouth to anus. It mainly causes abdominal pain, diarrhea, vomiting and weight loss. Although the basic etiology of IBD is unknown, there are several factors that may contribute to the pathogenesis of this disease, such as dysregulation of immune system or commensal bacteria, oxidative stress and inflammatory mediators. In order to understand these different etiological factors, a number of experimental models are available in the scientific research, including chemical-induced, spontaneous, genetically engineered and transgenic models. These models represent a major source of information about biological systems and are clinically relevant to the human IBD. Since there is less collective data available in one single article discussing about all these models, in this review an effort is made to study the outline of pathophysiology and various types of animal models used in the research study of IBD and other disease-related complications.
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