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1
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Arsene D, Tchaptchet SY, Hansen JJ. The global stress response regulator oxyS in an adherent-invasive Escherichia coli strain attenuates experimental colitis. Gut Microbes 2025; 17:2473518. [PMID: 40022675 PMCID: PMC11875499 DOI: 10.1080/19490976.2025.2473518] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 08/12/2024] [Revised: 01/13/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025] Open
Abstract
Crohn's disease and ulcerative colitis in humans and experimental immune-mediated colitis in mice are likely due in part to overactive immune responses to resident intestinal bacteria, including certain strains of adherent-invasive Escherichia coli (E. coli) such as E. coli NC101. We have previously shown that specific E. coli NC101 stress responses are upregulated during experimental colitis and attenuate inflammation. However, the roles of broader stress response pathways in E. coli NC101 during experimental colitis are unknown. We hypothesize that the global stress response regulator in E. coli, oxyS, also reduces experimental colitis. We show that intestinal E. coli NC101 upregulate oxyS expression during colitis in monocolonized interleukin-10 deficient mice. Furthermore, we demonstrate that oxyS-sufficient E. coli NC101 have decreased motility and biofilm formation in vitro and attenuated intestinal translocation and colitogenic potential in vivo compared with oxyS-deficient E. coli. These data suggest that activation of a generalized E. coli stress response, oxyS, reduces experimental colitis and may be a potential therapeutic target.
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Affiliation(s)
- Diana Arsene
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sandrine Y. Tchaptchet
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jonathan J. Hansen
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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2
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Ahn JH, da Silva Pedrosa M, Lopez LR, Tibbs TN, Jeyachandran JN, Vignieri EE, Rothemich A, Cumming I, Irmscher AD, Haswell CJ, Zamboni WC, Yu YRA, Ellermann M, Denson LA, Arthur JC. Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host Microbe 2025; 33:71-88.e9. [PMID: 39701098 DOI: 10.1016/j.chom.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 11/11/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
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Affiliation(s)
- Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marlus da Silva Pedrosa
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lacey R Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor N Tibbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joanna N Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Emily E Vignieri
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Aaron Rothemich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ian Cumming
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
| | - Alexander D Irmscher
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Corey J Haswell
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yen-Rei A Yu
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Melissa Ellermann
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Lee A Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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3
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Zhao Y, Liu Y, Jia L. Gut microbial dysbiosis and inflammation: Impact on periodontal health. J Periodontal Res 2025; 60:30-43. [PMID: 38991951 DOI: 10.1111/jre.13324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024]
Abstract
Periodontitis is widely acknowledged as the most prevalent type of oral inflammation, arising from the dynamic interplay between oral pathogens and the host's immune responses. It is also recognized as a contributing factor to various systemic diseases. Dysbiosis of the oral microbiota can significantly alter the composition and diversity of the gut microbiota. Researchers have delved into the links between periodontitis and systemic diseases through the "oral-gut" axis. However, whether the associations between periodontitis and the gut microbiota are simply correlative or driven by causative mechanistic interactions remains uncertain. This review investigates how dysbiosis of the gut microbiota impacts periodontitis, drawing on existing preclinical and clinical data. This study highlights potential mechanisms of this interaction, including alterations in subgingival microbiota, oral mucosal barrier function, neutrophil activity, and abnormal T-cell recycling, and offers new perspectives for managing periodontitis, especially in cases linked to systemic diseases.
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Affiliation(s)
- Yifan Zhao
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Lu Jia
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
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4
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Biagioli M, Di Giorgio C, Massa C, Marchianò S, Bellini R, Bordoni M, Urbani G, Roselli R, Lachi G, Morretta E, Piaz FD, Charlier B, Fiorillo B, Catalanotti B, Cari L, Nocentini G, Ricci P, Distrutti E, Festa C, Sepe V, Zampella A, Monti MC, Fiorucci S. Microbial-derived bile acid reverses inflammation in IBD via GPBAR1 agonism and RORγt inverse agonism. Biomed Pharmacother 2024; 181:117731. [PMID: 39657506 DOI: 10.1016/j.biopha.2024.117731] [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: 09/20/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 12/12/2024] Open
Abstract
The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Bar Pharmaceuticals s.r.l., Via Gramsci 88/A, Reggio Emilia 42124, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Ginevra Lachi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Fabrizio Dal Piaz
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
| | - Bruno Charlier
- University hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy
| | - Bianca Fiorillo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Luigi Cari
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Nocentini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Carmen Festa
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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5
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Moutusy SI, Ohsako S. Gut Microbiome-Related Anti-Inflammatory Effects of Aryl Hydrocarbon Receptor Activation on Inflammatory Bowel Disease. Int J Mol Sci 2024; 25:3372. [PMID: 38542367 PMCID: PMC10970487 DOI: 10.3390/ijms25063372] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 01/05/2025] Open
Abstract
Inflammatory bowel disease (IBD) is one of the most prevalent chronic inflammations of the gastrointestinal tract (GIT). The gut microbial population, the cytokine milieu, the aryl hydrocarbon receptor (AHR) expressed by immune and nonimmune cells and the intrinsic pathway of Th-cell differentiation are implicated in the immunopathology of IBD. AHR activation requires a delicate balance between regulatory and effector T-cells; loss of this balance can cause local gut microbial dysbiosis and intestinal inflammation. Thus, the study of the gut microbiome in association with AHR provides critical insights into IBD pathogenesis and interventions. This review will focus on the recent advancements to form conceptional frameworks on the benefits of AHR activation by commensal gut bacteria in IBD.
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Affiliation(s)
- Salvinaz Islam Moutusy
- Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA
- VA Palo Alto Health Care System, Palo Alto, CA 94305, USA
| | - Seiichiroh Ohsako
- Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
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Bleich RM, Li C, Sun S, Ahn JH, Dogan B, Barlogio CJ, Broberg CA, Franks AR, Bulik-Sullivan E, Carroll IM, Simpson KW, Fodor AA, Arthur JC. A consortia of clinical E. coli strains with distinct in vitro adherent/invasive properties establish their own co-colonization niche and shape the intestinal microbiota in inflammation-susceptible mice. MICROBIOME 2023; 11:277. [PMID: 38124090 PMCID: PMC10731797 DOI: 10.1186/s40168-023-01710-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/26/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in vitro definition fully predicts mucosal colonization in vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. RESULTS Germ-free inflammation-susceptible interleukin-10-deficient (Il10-/-) and inflammation-resistant WT mice were colonized with a consortium of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10-/- mice. These E. coli expand in Il10-/- mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. CONCLUSIONS Our findings establish the in vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in vivo colonization dynamics of patient-derived bacteria in murine models. Video Abstract.
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Affiliation(s)
- Rachel M Bleich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Biology, Appalachian State University, Boone, NC, USA
| | - Chuang Li
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shan Sun
- College of Computing and Informatics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Belgin Dogan
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Cassandra J Barlogio
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christopher A Broberg
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adrienne R Franks
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily Bulik-Sullivan
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ian M Carroll
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kenneth W Simpson
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Anthony A Fodor
- College of Computing and Informatics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Center for Gastrointestinal Biology & Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Unni R, Andreani NA, Vallier M, Heinzmann SS, Taubenheim J, Guggeis MA, Tran F, Vogler O, Künzel S, Hövener JB, Rosenstiel P, Kaleta C, Dempfle A, Unterweger D, Baines JF. Evolution of E. coli in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance. Gut Microbes 2023; 15:2286675. [PMID: 38059748 PMCID: PMC10730162 DOI: 10.1080/19490976.2023.2286675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/17/2023] [Indexed: 12/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.
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Affiliation(s)
- Rahul Unni
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Nadia Andrea Andreani
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Marie Vallier
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Silke S. Heinzmann
- Research Unit Analytical BioGeoChemistry, Helmholtz Munich, Neuherberg, Germany
| | - Jan Taubenheim
- Research Group Medical Systems Biology, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Martina A. Guggeis
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Olga Vogler
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Sven Künzel
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Jan-Bernd Hövener
- Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Kiel, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Christoph Kaleta
- Research Group Medical Systems Biology, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Daniel Unterweger
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - John F. Baines
- Section Evolutionary Medicine, Max Planck Institute for Evolutionary Biology, Plön, Germany
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
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8
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Bleich RM, Li C, Sun S, Barlogio CJ, Broberg CA, Franks AR, Bulik-Sullivan E, Dogan B, Simpson KW, Carroll IM, Fodor AA, Arthur JC. A consortia of clinical E. coli strains with distinct in-vitro adherent/invasive properties establish their own co-colonization niche and shape the intestinal microbiota in inflammation-susceptible mice. RESEARCH SQUARE 2023:rs.3.rs-2899665. [PMID: 37214858 PMCID: PMC10197778 DOI: 10.21203/rs.3.rs-2899665/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in-vitro definition fully predicts mucosal colonization in-vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10-/-) and inflammation-resistant WT mice were colonized with a consortia of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10-/- mice. These E. coli expand in Il10-/- mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. Conclusions Our findings establish the in-vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in-vivo colonization dynamics of patient-derived bacteria in murine models.
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Affiliation(s)
| | - Chuang Li
- University of North Carolina at Chapel Hill
| | - Shan Sun
- University of North Carolina at Charlotte
| | | | | | | | | | - Belgin Dogan
- Cornell University College of Veterinary Medicine
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9
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Kim SY, Park JH, Leite G, Pimentel M, Rezaie A. Interleukin-10 Knockout Mice Do Not Reliably Exhibit Macroscopic Inflammation: A Natural History Endoscopic Surveillance Study. Dig Dis Sci 2023; 68:1858-1862. [PMID: 36929236 DOI: 10.1007/s10620-023-07871-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 02/06/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Interleukin (IL)-10 knockout (KO) mice, a model for inflammatory bowel disease (IBD), develop chronic enterocolitis due to an aberrant immune response to enteric antigens. Endoscopy, the gold standard for evaluation of human mucosal health, is not widely available for murine models. AIMS To assess the natural history of left-sided colitis in IL-10 KO mice via serial endoscopies. METHODS BALB/cJ IL-10 KO mice underwent regular endoscopic assessments from 2 up to 8 months of age. Procedures were recorded and blindly evaluated using a 4-component endoscopic score: mucosal wall transparency, intestinal bleeding, focal lesions and perianal lesions (0-3 points each). An endoscopic score ≥ 1 point was considered as the presence of colitis/flare. RESULTS IL-10 KO mice (N = 40, 9 female) were assessed. Mean age at first endoscopy was 62.5 ± 2.5 days; average number of procedures per mouse was 6.0 ± 1.3. A total of 238 endoscopies were conducted every 24.8 ± 8.3 days, corresponding to 124.1 ± 45.2 days of surveillance per mouse. Thirty-three endoscopies in 24 mice (60%) detected colitis, mean endoscopy score 2.5 ± 1.3 (range: 1-6.3). Nineteen mice (47.5%) had one episode of colitis and 5 (12.5%) had 2-3 episodes. All exhibited complete spontaneous healing on subsequent endoscopies. CONCLUSIONS In this large-scale endoscopic surveillance study of IL-10 KO mice, 40% of mice did not develop endoscopic left-sided colitis. Furthermore, IL-10 KO mice did not exhibit persistent colitis and universally exhibited complete spontaneous healing without treatment. The natural history of colitis in IL-10 KO mice may not be comparable with that of IBD in humans and requires careful consideration.
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Affiliation(s)
- Seung Young Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
| | - Jae Ho Park
- Division of Gastroenterology, Department of Internal Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Gabriela Leite
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mark Pimentel
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
| | - Ali Rezaie
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA.
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10
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Ardura MI, Kim SC. Infectious Complications of Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:687-697. [DOI: 10.1007/978-3-031-14744-9_49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Shin SY, Park S, Moon JM, Kim K, Kim JW, Chun J, Lee TH, Choi CH. Compositional Changes in the Gut Microbiota of Responders and Non-responders to Probiotic Treatment Among Patients With Diarrhea-predominant Irritable Bowel Syndrome: A Post Hoc Analysis of a Randomized Clinical Trial. J Neurogastroenterol Motil 2022; 28:642-654. [PMID: 36250371 PMCID: PMC9577570 DOI: 10.5056/jnm21202] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/08/2022] [Accepted: 02/14/2022] [Indexed: 11/21/2022] Open
Abstract
Background/Aims We aim to evaluate the differences in the microbiome of responders and non-responders, as well as predict the response to probiotic therapy, based on fecal microbiome data in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Methods A multi-strain probiotics that contains Lactobacillus acidophilus (KCTC 11906BP), Lactobacillus plantarum (KCTC11867BP), Lactobacillus rhamnosus (KCTC 11868BP), Bifidobacterium breve (KCTC 11858BP), Bifidobacterium lactis (KCTC 11903BP), Bifidobacterium longum (KCTC 11860BP), and Streptococcus thermophilus (KCTC 11870BP) were used. Patients were categorized into probiotic and placebo groups, and fecal samples were collected from all patients before and at the end of 8 weeks of treatment. The probiotic group was further divided into responders and non-responders. Responders were defined as patients who experienced adequate relief of overall irritable bowel syndrome symptoms after probiotic therapy. Fecal microbiota were investigated using Illumina MiSeq and analyzed using the EzBioCloud 16S database and microbiome pipeline (https://www.EZbiocloud.net). Results There was no significant difference in the alpha and beta diversity between the responder and non-responder groups. The abundances of the phylum Proteobacteria and genus Bacteroides significantly decreased after probiotic treatment. Bifidobacterium bifidum, Pediococcus acidilactici, and Enterococcus faecium showed a significantly higher abundance in the probiotic group after treatment compared to the placebo group. Enterococcus faecalis and Lactococcus lactis were identified as biomarkers of non-response to probiotics. The abundance of Fusicatenibacter saccharivorans significantly increased in the responders after treatment. Conclusions Probiotic treatment changes some composition of fecal bacteria in patients with IBS-D. E. faecalis and L. lactis may be prediction biomarkers for non-response to probiotics. Increased abundance of F. sccharivorans is correlated to symptom improvement by probiotics in patients with IBS-D.
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Affiliation(s)
- Seung Yong Shin
- Chung-Ang University College of Medicine, Department of Internal Medicine, Seoul, Korea
| | - Sein Park
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.,Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea
| | - Jung Min Moon
- Chung-Ang University College of Medicine, Department of Internal Medicine, Seoul, Korea
| | - Kisung Kim
- Chung-Ang University College of Medicine, Department of Internal Medicine, Seoul, Korea
| | - Jeong Wook Kim
- Chung-Ang University College of Medicine, Department of Internal Medicine, Seoul, Korea
| | - Jongsik Chun
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.,Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.,School of Biological Sciences, Seoul National University, Seoul, Korea
| | - Tae Hee Lee
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Chang Hwan Choi
- Chung-Ang University College of Medicine, Department of Internal Medicine, Seoul, Korea
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12
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Metwaly A, Reitmeier S, Haller D. Microbiome risk profiles as biomarkers for inflammatory and metabolic disorders. Nat Rev Gastroenterol Hepatol 2022; 19:383-397. [PMID: 35190727 DOI: 10.1038/s41575-022-00581-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 12/12/2022]
Abstract
The intestine harbours a complex array of microorganisms collectively known as the gut microbiota. The past two decades have witnessed increasing interest in studying the gut microbiota in health and disease, largely driven by rapid innovation in high-throughput multi-omics technologies. As a result, microbial dysbiosis has been linked to many human pathologies, including type 2 diabetes mellitus and inflammatory bowel disease. Integrated analyses of multi-omics data, including metagenomics and metabolomics along with measurements of host response and cataloguing of bacterial isolates, have identified many bacteria and bacterial products that are correlated with disease. Nevertheless, insight into the mechanisms through which microbes affect intestinal health requires going beyond correlation to causation. Current understanding of the contribution of the gut microbiota to disease causality remains limited, largely owing to the heterogeneity of microbial community structures, interindividual differences in disease evolution and incomplete understanding of the mechanisms that integrate microbiota-derived signals into host signalling pathways. In this Review, we provide a broad insight into the microbiome signatures linked to inflammatory and metabolic disorders, discuss outstanding challenges in this field and propose applications of multi-omics technologies that could lead to an improved mechanistic understanding of microorganism-host interactions.
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Affiliation(s)
- Amira Metwaly
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany
| | - Sandra Reitmeier
- ZIEL Institute for Food & Health, Technical University of Munich, Freising, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technical University of Munich, Freising, Germany. .,ZIEL Institute for Food & Health, Technical University of Munich, Freising, Germany.
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13
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Liu ZZ, Sun JH, Wang WJ. Gut microbiota in gastrointestinal diseases during pregnancy. World J Clin Cases 2022; 10:2976-2989. [PMID: 35647135 PMCID: PMC9082698 DOI: 10.12998/wjcc.v10.i10.2976] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota (GM) is a micro-ecosystem composed of all microorganisms in the human intestine. The interaction between GM and the host plays an important role in maintaining normal physiological functions in the host. Dysbiosis of the GM may cause various diseases. GM has been demonstrated to be associated with human health and disease, and changes during individual development and disease. Pregnancy is a complicated physiological process. Hormones, the immune system, metabolism, and GM undergo drastic changes during pregnancy. Gastrointestinal diseases during pregnancy, such as hepatitis, intrahepatic cholestasis of pregnancy, and pre-eclampsia, can affect both maternal and fetal health. The dysregulation of GM during pregnancy may lead to a variety of diseases, including gastrointestinal diseases. Herein, we review recent research articles on GM in pregnancy-related gastrointestinal diseases, discuss the interaction of the GM with the host under normal physiological conditions, gastrointestinal diseases, and pregnancy-specific disorders. As more attention is paid to reproductive health, the pathogenic mechanism of GM in gastrointestinal diseases during pregnancy will be further studied to provide a theoretical basis for the use of probiotics to treat these diseases.
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Affiliation(s)
- Zhong-Zhen Liu
- BGI-Shenzhen, Shenzhen 518083, Guangdong Province, China
| | - Jing-Hua Sun
- BGI-Shenzhen, Shenzhen 518083, Guangdong Province, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wen-Jing Wang
- BGI-Shenzhen, Shenzhen 518083, Guangdong Province, China
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14
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Long-read sequencing to interrogate strain-level variation among adherent-invasive Escherichia coli isolated from human intestinal tissue. PLoS One 2021; 16:e0259141. [PMID: 34710159 PMCID: PMC8553045 DOI: 10.1371/journal.pone.0259141] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/13/2021] [Indexed: 01/19/2023] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) is a pathovar linked to inflammatory bowel diseases (IBD), especially Crohn’s disease, and colorectal cancer. AIEC are genetically diverse, and in the absence of a universal molecular signature, are defined by in vitro functional attributes. The relative ability of difference AIEC strains to colonize, persist, and induce inflammation in an IBD-susceptible host is unresolved. To evaluate strain-level variation among tissue-associated E. coli in the intestines, we develop a long-read sequencing approach to identify AIEC by strain that excludes host DNA. We use this approach to distinguish genetically similar strains and assess their fitness in colonizing the intestine. Here we have assembled complete genomes using long-read nanopore sequencing for a model AIEC strain, NC101, and seven strains isolated from the intestinal mucosa of Crohn’s disease and non-Crohn’s tissues. We show these strains can colonize the intestine of IBD susceptible mice and induce inflammatory cytokines from cultured macrophages. We demonstrate that these strains can be quantified and distinguished in the presence of 99.5% mammalian DNA and from within a fecal population. Analysis of global genomic structure and specific sequence variation within the ribosomal RNA operon provides a framework for efficiently tracking strain-level variation of closely-related E. coli and likely other commensal/pathogenic bacteria impacting intestinal inflammation in experimental settings and IBD patients.
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15
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Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, Yu J, Cao H. Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther 2021; 12:463. [PMID: 34407875 PMCID: PMC8375136 DOI: 10.1186/s13287-021-02533-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS Stem cell transplantation is a valuable supplementary therapy for CD.
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Affiliation(s)
- Ruo Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Pan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
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16
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Fan TJ, Goeser L, Lu K, Faith JJ, Hansen JJ. Enterococcus faecalis Glucosamine Metabolism Exacerbates Experimental Colitis. Cell Mol Gastroenterol Hepatol 2021; 12:1373-1389. [PMID: 34246809 PMCID: PMC8479252 DOI: 10.1016/j.jcmgh.2021.06.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are caused in part by aberrant immune responses to resident intestinal bacteria. Certain dietary components, including carbohydrates, are associated with IBDs and alter intestinal bacterial composition. However, the effects of luminal carbohydrates on the composition and colitogenic potential of intestinal bacteria are incompletely understood. We hypothesize that carbohydrate metabolism by resident proinflammatory intestinal bacteria enhances their growth and worsens intestinal inflammation. METHODS We colonized germ-free, wild-type, and colitis-susceptible interleukin-10 knockout mice (Il10-/-) with a consortium of resident intestinal bacterial strains and quantified colon inflammation using blinded histologic scoring and spontaneous secretion of IL12/23p40 by colon explants. We measured luminal bacterial composition using real-time 16S polymerase chain reaction, bacterial gene expression using RNA sequencing and real-time polymerase chain reaction, and luminal glucosamine levels using gas chromatography-mass spectrometry. RESULTS We show that a consortium of 8 bacterial strains induces severe colitis in Il10-/- mice and up-regulates genes associated with carbohydrate metabolism during colitis. Specifically, Enterococcus faecalis strain OG1RF is proinflammatory and strongly up-regulates OG1RF_11616-11610, an operon that encodes genes of a previously undescribed phosphotransferase system that we show imports glucosamine. Experimental colitis is associated with increased levels of luminal glucosamine and OG1RF_11616 causes worse colitis, not by increasing E faecalis numbers, but rather by mechanisms that require the presence of complex microbiota. CONCLUSIONS Further studies of luminal carbohydrate levels and bacterial carbohydrate metabolism during intestinal inflammation will improve our understanding of the pathogenesis of IBDs and may lead to the development of novel therapies for these diseases.
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Affiliation(s)
- Ting-Jia Fan
- Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina; Department of Microbiology and Immunology, Chapel Hill, North Carolina
| | - Laura Goeser
- Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina
| | - Kun Lu
- Department of Environmental Sciences and Engineering, Chapel Hill, North Carolina
| | - Jeremiah J Faith
- The Precision Immunology Institute, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jonathan J Hansen
- Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina; Department of Microbiology and Immunology, Chapel Hill, North Carolina; Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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17
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Bhat MI, Sowmya K, Kapila S, Kapila R. Potential Probiotic Lactobacillus rhamnosus (MTCC-5897) Inhibits Escherichia coli Impaired Intestinal Barrier Function by Modulating the Host Tight Junction Gene Response. Probiotics Antimicrob Proteins 2021; 12:1149-1160. [PMID: 31732863 DOI: 10.1007/s12602-019-09608-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Probiotic as a preventive medicine is emerging as an indispensable tool in addressing the foodborne infections or gastrointestinal disorders. The present study was sought to determine the in vitro prophylactic potential of probiotic Lactobacillus rhamnosus (LR: MTCC-5897) against Escherichia coli (ATCC 14948) induced impairment in intestinal barrier function using Caco-2 cells. Intestinal cells exposed to E. coli demonstrated significantly higher phenol red flux (p < 0.05) and concomitantly decreased TEER (0.69 ± 0.01) in contrast to control or L. rhamnosus (109 cfu/mL)-treated cells. However, E. coli-induced barrier hyperpermeability was restored to significant extents (p < 0.01) when E. coli were excluded, competed or displaced by probiotic LR. Similarly, exposure of Caco-2 cells to E. coli reduced the mRNA expression of key tight junction genes, viz. Zo-1, Claudin-1, Occludin and Cingulin which however were restored significantly (p < 0.05) with L. rhamnosus treatment during exclusion or competition than displacement assays. The protective behaviour of probiotic LR against E. coli can also be observed in immunofluorescent and electron micrograph where intact cellular morphology along with preserved distribution and localisation of key integrity proteins can be found in LR-treated cells in contrast to distorted and disorganised distribution observed with E. coli exposure. In conclusion, L. rhamnosus inhibited and re-established E. coli-impaired intestinal barrier function by improving the expression and distribution of key junction protein and hence could serve an essential food additive to address the various health complications especially those associated with gastrointestinal tract.
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Affiliation(s)
- Mohd Iqbal Bhat
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Kandukuri Sowmya
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Suman Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India
| | - Rajeev Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, Haryana, 132001, India.
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18
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Franzin M, Stefančič K, Lucafò M, Decorti G, Stocco G. Microbiota and Drug Response in Inflammatory Bowel Disease. Pathogens 2021; 10:211. [PMID: 33669168 PMCID: PMC7919657 DOI: 10.3390/pathogens10020211] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
A mutualistic relationship between the composition, function and activity of the gut microbiota (GM) and the host exists, and the alteration of GM, sometimes referred as dysbiosis, is involved in various immune-mediated diseases, including inflammatory bowel disease (IBD). Accumulating evidence suggests that the GM is able to influence the efficacy of the pharmacological therapy of IBD and to predict whether individuals will respond to treatment. Additionally, the drugs used to treat IBD can modualate the microbial composition. The review aims to investigate the impact of the GM on the pharmacological therapy of IBD and vice versa. The GM resulted in an increase or decrease in therapeutic responses to treatment, but also to biotransform drugs to toxic metabolites. In particular, the baseline GM composition can help to predict if patients will respond to the IBD treatment with biologic drugs. On the other hand, drugs can affect the GM by incrementing or reducing its diversity and richness. Therefore, the relationship between the GM and drugs used in the treatment of IBD can be either beneficial or disadvantageous.
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Affiliation(s)
- Martina Franzin
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Katja Stefančič
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy; (K.S.); (G.S.)
| | - Marianna Lucafò
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy;
| | - Giuliana Decorti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy;
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy;
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy; (K.S.); (G.S.)
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19
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Gut microbiome analysis as a predictive marker for the gastric cancer patients. Appl Microbiol Biotechnol 2021; 105:803-814. [PMID: 33404833 DOI: 10.1007/s00253-020-11043-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 11/24/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
Gut microbiota have been implicated in the development of cancer. Colorectal and gastric cancers, the major gastrointestinal tract cancers, are closely connected with the gut microbiome. Nevertheless, the characteristics of gut microbiota composition that correlate with gastric cancer are unclear. In this study, we investigated gut microbiota alterations during the progression of gastric cancer to identify the most relevant taxa associated with gastric cancer and evaluated the potential of the microbiome as an indicator for the diagnosis of gastric cancer. Compared with the healthy group, gut microbiota composition and diversity shifted in patients with gastric cancer. Different bacteria were used to design a random forest model, which provided an area under the curve value of 0.91. Verification samples achieved a true positive rate of 0.83 in gastric cancer. Principal component analysis showed that gastritis shares some microbiome characteristics of gastric cancer. Chemotherapy reduced the elevated bacteria levels in gastric cancer by more than half. More importantly, we found that the genera Lactobacillus and Megasphaera were associated with gastric cancer.Key Points• Gut microbiota has high sensitivity and specificity in distinguishing patients with gastric cancer from healthy individuals, indicating that gut microbiota is a potential noninvasive tool for the diagnosis of gastric cancer.• Gastritis shares some microbiota features with gastric cancer, and chemotherapy reduces the microbial abundance and diversity in gastric cancer patients.• Two bacterial taxa, namely, Lactobacillus and Megasphaera, are predictive markers for gastric cancer.
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20
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Scarpellini E, Fagoonee S, Rinninella E, Rasetti C, Aquila I, Larussa T, Ricci P, Luzza F, Abenavoli L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:2488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. METHODS We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. RESULTS The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. CONCLUSIONS Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
- Department of Biomedical Sciences, KU Leuven, Gasthuisberg University Hospital, TARGID, 3000 Leuven, Belgium
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, 10121 Turin, Italy;
| | - Emanuele Rinninella
- Nephrology and Urology Department, Gastroenterology, Endocrinology, Fondazione Policlinico A, Clinical Nutrition Unit, Gemelli IRCCS, 00168 Rome, Italy;
- Institute of Medical Pathology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Carlo Rasetti
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
| | - Isabella Aquila
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Tiziana Larussa
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Pietrantonio Ricci
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
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21
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Charlet R, Bortolus C, Sendid B, Jawhara S. Bacteroides thetaiotaomicron and Lactobacillus johnsonii modulate intestinal inflammation and eliminate fungi via enzymatic hydrolysis of the fungal cell wall. Sci Rep 2020; 10:11510. [PMID: 32661259 PMCID: PMC7359362 DOI: 10.1038/s41598-020-68214-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Alterations to the gut microbiota can cause an amplification of the inflammatory response to intestinal pathogens. We assessed the effect of Bacteroides thetaiotaomicron and Lactobacillus johnsonii on the elimination of Candida species and whether restoration of these two anaerobic bacteria could attenuate the development of colitis in mice. In this study, L. johnsonii and B. thetaiotaomicron interacted directly with Candida species and induced a degradation of the fungal cell wall, mediated via chitinase-like and mannosidase-like activities, which promoted the inhibition of Candida species growth. In the DSS-induced colitis model, oral administration of L. johnsonii and B. thetaiotaomicron to mice reduced the overgrowth of Escherichia coli, Enterococcus faecalis and Candida glabrata populations and resulted in a significant reduction in inflammatory parameters. L. johnsonii and B. thetaiotaomicron decreased pro-inflammatory mediators and enhanced the anti-inflammatory cytokine response with high TLR9 expression and chitinase-like protein-1 activation, which promoted the elimination of C. glabrata from the gut. Overall, these findings provide evidence that L. johnsonii and B. thetaiotaomicron decrease the development of colitis mediated by TLR9 and promote the elimination of C. glabrata from the gut via chitinase-like and mannosidase-like activities.
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Affiliation(s)
- Rogatien Charlet
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, INSERM U1285, 59000, Lille, France.,University of Lille, 1 place Verdun, 59000, Lille, France.,CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, 59000, Lille, France
| | - Clovis Bortolus
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, INSERM U1285, 59000, Lille, France.,University of Lille, 1 place Verdun, 59000, Lille, France.,CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, 59000, Lille, France
| | - Boualem Sendid
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, INSERM U1285, 59000, Lille, France.,University of Lille, 1 place Verdun, 59000, Lille, France.,CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, 59000, Lille, France
| | - Samir Jawhara
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, INSERM U1285, 59000, Lille, France. .,University of Lille, 1 place Verdun, 59000, Lille, France. .,CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, 59000, Lille, France.
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22
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Jawhara S. Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients? Int J Mol Sci 2020; 21:E2272. [PMID: 32218340 PMCID: PMC7178250 DOI: 10.3390/ijms21072272] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/23/2020] [Accepted: 03/23/2020] [Indexed: 02/06/2023] Open
Abstract
The emergence of the novel coronavirus in Wuhan, China, which causes severe respiratory tract infections in humans (COVID-19), has become a global health concern. Most coronaviruses infect animals but can evolve into strains that cross the species barrier and infect humans. At the present, there is no single specific vaccine or efficient antiviral therapy against COVID-19. Recently, we showed that intravenous immunoglobulin (IVIg) treatment reduces inflammation of intestinal epithelial cells and eliminates overgrowth of the opportunistic human fungal pathogen Candida albicans in the murine gut. Immunotherapy with IVIg could be employed to neutralize COVID-19. However, the efficacy of IVIg would be better if the immune IgG antibodies were collected from patients who have recovered from COVID-19 in the same city, or the surrounding area, in order to increase the chance of neutralizing the virus. These immune IgG antibodies will be specific against COVID-19 by boosting the immune response in newly infected patients. Different procedures may be used to remove or inactivate any possible pathogens from the plasma of recovered coronavirus patient derived immune IgG, including solvent/detergent, 60 °C heat-treatment, and nanofiltration. Overall, immunotherapy with immune IgG antibodies combined with antiviral drugs may be an alternative treatment against COVID-19 until stronger options such as vaccines are available.
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Affiliation(s)
- Samir Jawhara
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, INSERM U1285, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
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23
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Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients? Int J Mol Sci 2020. [PMID: 32218340 DOI: 10.3390/ijms21072272.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The emergence of the novel coronavirus in Wuhan, China, which causes severe respiratory tract infections in humans (COVID-19), has become a global health concern. Most coronaviruses infect animals but can evolve into strains that cross the species barrier and infect humans. At the present, there is no single specific vaccine or efficient antiviral therapy against COVID-19. Recently, we showed that intravenous immunoglobulin (IVIg) treatment reduces inflammation of intestinal epithelial cells and eliminates overgrowth of the opportunistic human fungal pathogen Candida albicans in the murine gut. Immunotherapy with IVIg could be employed to neutralize COVID-19. However, the efficacy of IVIg would be better if the immune IgG antibodies were collected from patients who have recovered from COVID-19 in the same city, or the surrounding area, in order to increase the chance of neutralizing the virus. These immune IgG antibodies will be specific against COVID-19 by boosting the immune response in newly infected patients. Different procedures may be used to remove or inactivate any possible pathogens from the plasma of recovered coronavirus patient derived immune IgG, including solvent/detergent, 60 °C heat-treatment, and nanofiltration. Overall, immunotherapy with immune IgG antibodies combined with antiviral drugs may be an alternative treatment against COVID-19 until stronger options such as vaccines are available.
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24
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Alhinai EA, Walton GE, Commane DM. The Role of the Gut Microbiota in Colorectal Cancer Causation. Int J Mol Sci 2019; 20:ijms20215295. [PMID: 31653078 PMCID: PMC6862640 DOI: 10.3390/ijms20215295] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/18/2019] [Accepted: 10/23/2019] [Indexed: 12/16/2022] Open
Abstract
Here, we reviewed emerging evidence on the role of the microbial community in colorectal carcinogenesis. A healthy gut microbiota promotes intestinal homeostasis and can exert anti-cancer effects; however, this microbiota also produces a variety of metabolites that are genotoxic and which can negatively influence epithelial cell behaviour. Disturbances in the normal microbial balance, known as dysbiosis, are frequently observed in colorectal cancer (CRC) patients. Microbial species linked to CRC include certain strains of Bacteroides fragilis, Escherichia coli, Streptococcus gallolyticus, Enterococcus faecalis and Fusobacterium nucleatum, amongst others. Whether these microbes are merely passive dwellers exploiting the tumour environment, or rather, active protagonists in the carcinogenic process is the subject of much research. The incidence of chemically-induced tumours in mice models varies, depending upon the presence or absence of these microorganisms, thus strongly suggesting influences on disease causation. Putative mechanistic explanations differentially link these strains to DNA damage, inflammation, aberrant cell behaviour and immune suppression. In the future, modulating the composition and metabolic activity of this microbial community may have a role in prevention and therapy.
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Affiliation(s)
- Eiman A Alhinai
- Dietetics Department, Al Nahdha Hospital, Ministry of Health, Muscat, PO Box 937, Ruwi, Muscat PC 112, Oman.
| | - Gemma E Walton
- Department of Food and Nutritional Sciences, University of Reading, Reading RG6 6UA, UK.
| | - Daniel M Commane
- Department of Applied and Health Sciences, University of Northumbria, Newcastle Upon Tyne NE1 8ST, UK.
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25
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Yersiniabactin-Producing Adherent/Invasive Escherichia coli Promotes Inflammation-Associated Fibrosis in Gnotobiotic Il10-/- Mice. Infect Immun 2019; 87:IAI.00587-19. [PMID: 31481410 PMCID: PMC6803345 DOI: 10.1128/iai.00587-19] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 08/22/2019] [Indexed: 12/16/2022] Open
Abstract
Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohn’s disease (CD). Mechanisms that favor fibrosis are not well understood, and therapeutic strategies are limited. Here we demonstrate that colitis-susceptible Il10-deficient mice develop inflammation-associated fibrosis when monoassociated with adherent/invasive Escherichia coli (AIEC) that harbors the yersiniabactin (Ybt) pathogenicity island. Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohn’s disease (CD). Mechanisms that favor fibrosis are not well understood, and therapeutic strategies are limited. Here we demonstrate that colitis-susceptible Il10-deficient mice develop inflammation-associated fibrosis when monoassociated with adherent/invasive Escherichia coli (AIEC) that harbors the yersiniabactin (Ybt) pathogenicity island. Inactivation of Ybt siderophore production in AIEC nearly abrogated fibrosis development in inflamed mice. In contrast, inactivation of Ybt import through its cognate receptor FyuA enhanced fibrosis severity. This corresponded with increased colonic expression of profibrogenic genes prior to the development of histological disease, therefore suggesting causality. fyuA-deficient AIEC also exhibited greater localization within subepithelial tissues and fibrotic lesions that was dependent on Ybt biosynthesis and corresponded with increased fibroblast activation in vitro. Together, these findings suggest that Ybt establishes a profibrotic environment in the host in the absence of binding to its cognate receptor and indicate a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis.
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26
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The commensal Escherichia coli CEC15 reinforces intestinal defences in gnotobiotic mice and is protective in a chronic colitis mouse model. Sci Rep 2019; 9:11431. [PMID: 31391483 PMCID: PMC6685975 DOI: 10.1038/s41598-019-47611-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 07/10/2019] [Indexed: 02/06/2023] Open
Abstract
Escherichia coli is a regular inhabitant of the gut microbiota throughout life. However, its role in gut health is controversial. Here, we investigated the relationship between the commensal E. coli strain CEC15 (CEC), which we previously isolated, and the intestine in homeostatic and disease-prone settings. The impact of CEC was compared to that of the probiotic E. coli Nissle 1917 (Nissle) strain. The expression of ileal and colonic genes that play a key role in intestinal homeostasis was higher in CEC- and Nissle-mono-associated wild-type mice than in germfree mice. This included genes involved in the turnover of reactive oxygen species, antimicrobial peptide synthesis, and immune responses. The impact of CEC and Nissle on such gene expression was stronger in a disease-prone setting, i.e. in gnotobiotic IL10-deficient mice. In a chronic colitis model, CEC more strongly decreased signs of colitis severity (myeloperoxidase activity and CD3+ immune-cell infiltration) than Nissle. Thus, our study shows that CEC and Nissle contribute to increased expression of genes involved in the maintenance of gut homeostasis in homeostatic and inflammatory settings. We show that these E. coli strains, in particular CEC, can have a beneficial effect in a chronic colitis mouse model.
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27
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Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages. Infect Immun 2019; 87:IAI.00080-19. [PMID: 31036600 DOI: 10.1128/iai.00080-19] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/21/2019] [Indexed: 02/07/2023] Open
Abstract
Enterococcus faecalis strains are resident intestinal bacteria associated with invasive infections, inflammatory bowel diseases, and colon cancer. Although factors promoting E. faecalis colonization of intestines are not fully known, one implicated pathway is a phosphotransferase system (PTS) in E. faecalis strain OG1RF that phosphorylates gluconate and contains the genes OG1RF_12399 to OG1RF_12402 (OG1RF_12399-12402). We hypothesize that this PTS permits growth in gluconate, facilitates E. faecalis intestinal colonization, and exacerbates colitis. We generated E. faecalis strains containing deletions/point mutations in this PTS and measured bacterial growth and PTS gene expression in minimal medium supplemented with selected carbohydrates. We show that E. faecalis upregulates OG1RF_12399 transcription specifically in the presence of gluconate and that E. faecalis strains lacking, or harboring a single point mutation in, OG1RF_12399-12402 are unable to grow in minimal medium containing gluconate. We colonized germfree wild-type and colitis-prone interleukin-10-deficient mice with defined bacterial consortia containing the E. faecalis strains and measured inflammation and bacterial abundance in the colon. We infected macrophage and intestinal epithelial cell lines with the E. faecalis strains and measured intracellular bacterial survival and proinflammatory cytokine secretion. The presence of OG1RF_12399-12402 is not required for E. faecalis colonization of the mouse intestine but is associated with an accelerated onset of experimental colitis in interleukin-10-deficient mice, altered bacterial composition in the colon, enhanced E. faecalis survival within macrophages, and increased proinflammatory cytokine secretion by colon tissue and macrophages. Further studies of bacterial carbohydrate metabolism in general, and E. faecalis PTS-gluconate in particular, during inflammation may identify new mechanisms of disease pathogenesis.
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28
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Lengfelder I, Sava IG, Hansen JJ, Kleigrewe K, Herzog J, Neuhaus K, Hofmann T, Sartor RB, Haller D. Complex Bacterial Consortia Reprogram the Colitogenic Activity of Enterococcus faecalis in a Gnotobiotic Mouse Model of Chronic, Immune-Mediated Colitis. Front Immunol 2019; 10:1420. [PMID: 31281321 PMCID: PMC6596359 DOI: 10.3389/fimmu.2019.01420] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/05/2019] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are associated with compositional and functional changes of the intestinal microbiota, but specific contributions of individual bacteria to chronic intestinal inflammation remain unclear. Enterococcus faecalis is a resident member of the human intestinal core microbiota that has been linked to the pathogenesis of IBD and induces chronic colitis in susceptible monoassociated IL-10-deficient (IL-10−/−) mice. In this study, we characterized the colitogenic activity of E. faecalis as part of a simplified human microbial consortium based on seven enteric bacterial strains (SIHUMI). RNA sequencing analysis of E. faecalis isolated from monoassociated wild type and IL-10−/− mice identified 408 genes including 14 genes of the ethanolamine utilization (eut) locus that were significantly up-regulated in response to inflammation. Despite considerable up-regulation of eut genes, deletion of ethanolamine utilization (ΔeutVW) had no impact on E. faecalis colitogenic activity in monoassociated IL-10−/− mice. However, replacement of the E. faecalis wild type bacteria by a ΔeutVW mutant in SIHUMI-colonized IL-10−/− mice resulted in exacerbated colitis, suggesting protective functions of E. faecalis ethanolamine utilization in complex bacterial communities. To better understand E. faecalis gene response in the presence of other microbes, we purified wild type E. faecalis cells from the colon content of SIHUMI-colonized wild type and IL-10−/− mice using immuno-magnetic separation and performed RNA sequencing. Transcriptional profiling revealed that the bacterial environment reprograms E. faecalis gene expression in response to inflammation, with the majority of differentially expressed genes not being shared between monocolonized and SIHUMI conditions. While in E. faecalis monoassociation a general bacterial stress response could be observed, expression of E. faecalis genes in SIHUMI-colonized mice was characterized by up-regulation of genes involved in growth and replication. Interestingly, in mice colonized with SIHUMI lacking E. faecalis enhanced inflammation was observed in comparison to SIHUMI-colonized mice, supporting the hypothesis that E. faecalis ethanolamine metabolism protects against colitis in complex consortia. In conclusion, this study demonstrates that complex bacterial consortia interactions reprogram the gene expression profile and colitogenic activity of the opportunistic pathogen E. faecalis toward a protective function.
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Affiliation(s)
- Isabella Lengfelder
- Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Irina G Sava
- Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Jonathan J Hansen
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, United States
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass Spectrometry, Technische Universität München, Freising, Germany
| | - Jeremy Herzog
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, United States
| | - Klaus Neuhaus
- ZIEL - Institute for Food & Health, Technische Universität München, Freising, Germany.,ZIEL Core Facility Microbiome, Technische Universität München, Freising, Germany
| | - Thomas Hofmann
- Bavarian Center for Biomolecular Mass Spectrometry, Technische Universität München, Freising, Germany.,ZIEL - Institute for Food & Health, Technische Universität München, Freising, Germany
| | - R Balfour Sartor
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, United States
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany.,ZIEL - Institute for Food & Health, Technische Universität München, Freising, Germany
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29
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Escherichia coli K12: An evolving opportunistic commensal gut microbe distorts barrier integrity in human intestinal cells. Microb Pathog 2019; 133:103545. [PMID: 31112772 DOI: 10.1016/j.micpath.2019.103545] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 01/07/2023]
Abstract
Commensal enteric microbes under specific conditions viz. immunocompromised system, altered microbiota or uncompetitive niche induce their otherwise dormant pathogenic phenotype to distort host cellular functioning. Here we investigate how under in vitro environment established by using Caco-2 cells, commensal gut microbe E. coli K12 (ATCC 14849) disrupt intestinal epithelial barrier function. Caco-2 cells exposed to E. coli showed the time dependent significant (P < 0.01) decrease in transepithelial electrical resistance (TEER) and concomitantly increased phenol red flux across cell monolayer in contrast to non infected control cells. E. coli infected intestinal cells were observed with suppressed (p < 0.05) mRNA levels of ZO-1, Claudin-1, Occludin and Cingulin-1 in contrast to significantly (p < 0.05) higher PIgR and hbd-2 mRNA fold changes. Immunofluorescent and electron micrographs revealed the disrupted distribution and localisation of specific tight junction proteins (Zo-1 and Claudin-1) and actin filament in E. coli infected Caco-2 cells that ultimately resulted in deformed cellular morphology. Taken together, E. coli K12 under compromised in vitro milieu disrupted the intestinal barrier functions by decreasing the expression of important tight junction genes along with the altered distribution of associated proteins that increased the intestinal permeability as reflected by phenol red flux and TEER values.
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30
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Low END, Mokhtar NM, Wong Z, Raja Ali RA. Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways. J Crohns Colitis 2019; 13:755-763. [PMID: 30954025 PMCID: PMC6535502 DOI: 10.1093/ecco-jcc/jjz002] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Patients with ulcerative colitis [UC] with long disease duration have a higher risk of developing colitis-associated cancer [CAC] compared with patients with short-duration UC. The aim of this study was to identify transcriptomic differences associated with the duration of UC disease. METHODS We conducted transcriptome profiling on 32 colonic biopsies [11 long-duration UC, ≥20 years; and 21 short-duration UC, ≤5 years] using Affymetrix Human Transcriptome Array 2.0. Differentially expressed genes [fold change > 1.5, p < 0.05] and alternative splicing events [splicing index > 1.5, p < 0.05] were determined using the Transcriptome Analysis Console. KOBAS 3.0 and DAVID 6.8 were used for KEGG and GO analysis. Selected genes from microarray analysis were validated using qPCR. RESULTS There were 640 differentially expressed genes between both groups. The top ten upregulated genes were HMGCS2, UGT2A3 isoforms, B4GALNT2, MEP1B, GUCA2B, ADH1C, OTOP2, SLC9A3, and LYPD8; the top ten downregulated genes were PI3, DUOX2, VNN1, SLC6A14, GREM1, MMP1, CXCL1, TNIP3, TFF1, and LCN2. Among the 123 altered KEGG pathways, the most significant were metabolic pathways; fatty acid degradation; valine, leucine, and isoleucine degradation; the peroxisome proliferator-activated receptor signalling pathway; and bile secretion, which were previously linked with CAC. Analysis showed that 3560 genes exhibited differential alternative splicing between long- and short-duration UC. Among them, 374 were differentially expressed, underscoring the intrinsic relationship between altered gene expression and alternative splicing. CONCLUSIONS Long-duration UC patients have altered gene expressions, pathways, and alternative splicing events as compared with short-duration UC patients, and these could be further validated to improve our understanding of the pathogenesis of CAC.
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Affiliation(s)
- Eden Ngah Den Low
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Zhiqin Wong
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia,Corresponding author: Professor Dr Raja Affendi Raja Ali, MD, FRCP, Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: 603-9145-6094; Fax: 603-9145-6679;
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31
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Schmitz JM, Tonkonogy SL, Dogan B, Leblond A, Whitehead KJ, Kim SC, Simpson KW, Sartor RB. Murine Adherent and Invasive E. coli Induces Chronic Inflammation and Immune Responses in the Small and Large Intestines of Monoassociated IL-10-/- Mice Independent of Long Polar Fimbriae Adhesin A. Inflamm Bowel Dis 2019; 25:875-885. [PMID: 30576451 PMCID: PMC6458545 DOI: 10.1093/ibd/izy386] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Adherent and invasive Escherichia coli (AIEC) is preferentially associated with ileal Crohn's disease (CD). The role of AIEC in the development of inflammation and its regional tropism is unresolved. The presence of long polar fimbriae (LPF) in 71% of ileal CD AIEC suggests a role for LPF in the tropism and virulence of AIEC. The aim of our study is to determine if AIEC, with or without LpfA, induces intestinal inflammation in monoassociated IL-10-/- mice. METHODS We compared murine AIEC strains NC101 (phylogroup B2, LpfA-) and CUMT8 (phylogroup B1, LpfA+), and isogenic mutant CUMT8 lacking lpfA154, with a non-AIEC (E. coli K12), evaluating histologic inflammation, bacterial colonization, mucosal adherence and invasion, and immune activation. RESULTS IL-10-/- mice monoassociated with AIEC (either CUMT8, CUMT8:ΔlpfA, or NC101) but not K12 developed diffuse small intestinal and colonic inflammation. There was no difference in the magnitude and distribution of inflammation in mice colonized with CUMT8:ΔlpfA compared with wild-type CUMT8. Bacterial colonization was similar for all E. coli strains. Fluorescence in situ hybridization revealed mucosal adherence and tissue invasion by AIEC but not K12. Production of the cytokines IL-12/23 p40 by the intestinal tissue and IFN-γ and IL-17 by CD4 T cells correlated with inflammation. CONCLUSIONS IL-10-/- mice monoassociated with murine AIEC irrespective of LpfA expression developed chronic inflammation accompanied by IL-12/23 p40 production in the small and large intestines and IFN-γ/IL-17 production by CD4 T cells that model the interplay between enteric pathosymbionts, host susceptibility, and enhanced immune responses in people with IBD.
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MESH Headings
- Animals
- Bacterial Adhesion
- Escherichia coli/immunology
- Escherichia coli Infections/immunology
- Escherichia coli Infections/metabolism
- Escherichia coli Infections/microbiology
- Escherichia coli Infections/pathology
- Escherichia coli Proteins/metabolism
- Fimbriae Proteins/metabolism
- Fimbriae, Bacterial/immunology
- Fimbriae, Bacterial/pathology
- Inflammation/etiology
- Inflammation/metabolism
- Inflammation/pathology
- Interleukin-10/physiology
- Intestine, Large/immunology
- Intestine, Large/metabolism
- Intestine, Large/microbiology
- Intestine, Large/pathology
- Intestine, Small/immunology
- Intestine, Small/metabolism
- Intestine, Small/microbiology
- Intestine, Small/pathology
- Mice
- Mice, Knockout
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Affiliation(s)
- Julia M Schmitz
- Center for Gastrointestinal Biology and Disease, University of North Carolina and North Carolina State University, Chapel Hill and Raleigh, North Carolina
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Susan L Tonkonogy
- Center for Gastrointestinal Biology and Disease, University of North Carolina and North Carolina State University, Chapel Hill and Raleigh, North Carolina
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
| | - Belgin Dogan
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Anna Leblond
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
| | - Kristi J Whitehead
- Center for Gastrointestinal Biology and Disease, University of North Carolina and North Carolina State University, Chapel Hill and Raleigh, North Carolina
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Sandra C Kim
- Center for Gastrointestinal Biology and Disease, University of North Carolina and North Carolina State University, Chapel Hill and Raleigh, North Carolina
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kenneth W Simpson
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina and North Carolina State University, Chapel Hill and Raleigh, North Carolina
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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32
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Charlet R, Sendid B, Kaveri SV, Poulain D, Bayry J, Jawhara S. Intravenous Immunoglobulin Therapy Eliminates Candida albicans and Maintains Intestinal Homeostasis in a Murine Model of Dextran Sulfate Sodium-Induced Colitis. Int J Mol Sci 2019; 20:ijms20061473. [PMID: 30909599 PMCID: PMC6471409 DOI: 10.3390/ijms20061473] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 12/21/2022] Open
Abstract
Intravenous immunoglobulin (IVIg) therapy has diverse anti-inflammatory and immunomodulatory effects and has been employed successfully in autoimmune and inflammatory diseases. The role of IVIg therapy in the modulation of intestinal inflammation and fungal elimination has not been yet investigated. We studied IVIg therapy in a murine model of dextran sulfate sodium (DSS)-induced colitis. Mice received a single oral inoculum of Candidaalbicans and were exposed to DSS treatment for 2 weeks to induce colitis. All mice received daily IVIg therapy starting on day 1 for 7 days. IVIg therapy not only prevented a loss of body weight caused by the development of colitis but also reduced the severity of intestinal inflammation, as determined by clinical and histological scores. IVIg treatment significantly reduced the Escherichiacoli,Enterococcusfaecalis, and C.albicans populations in mice. The beneficial effects of IVIg were associated with the suppression of inflammatory cytokine interleukin (IL)-6 and enhancement of IL-10 in the gut. IVIg therapy also led to an increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), while toll-like receptor 4 (TLR-4) expression was reduced. IVIg treatment reduces intestinal inflammation in mice and eliminates C.albicans overgrowth from the gut in association with down-regulation of pro-inflammatory mediators combined with up-regulation of anti-inflammatory cytokines.
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Affiliation(s)
- Rogatien Charlet
- Inserm, U995/Team2, Université Lille, 1 place Verdun, F-59000 Lille, France.
- University Lille2, U995-LIRIC, Lille Inflammation Research International Centre, F-59000 Lille, France.
- CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France.
| | - Boualem Sendid
- Inserm, U995/Team2, Université Lille, 1 place Verdun, F-59000 Lille, France.
- University Lille2, U995-LIRIC, Lille Inflammation Research International Centre, F-59000 Lille, France.
- CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France.
| | - Srini V Kaveri
- Inserm Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immuno-intervention Thérapeutique, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
| | - Daniel Poulain
- Inserm, U995/Team2, Université Lille, 1 place Verdun, F-59000 Lille, France.
- University Lille2, U995-LIRIC, Lille Inflammation Research International Centre, F-59000 Lille, France.
- CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France.
| | - Jagadeesh Bayry
- Inserm Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immuno-intervention Thérapeutique, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
| | - Samir Jawhara
- Inserm, U995/Team2, Université Lille, 1 place Verdun, F-59000 Lille, France.
- University Lille2, U995-LIRIC, Lille Inflammation Research International Centre, F-59000 Lille, France.
- CHU Lille, Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France.
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Charlet R, Bortolus C, Barbet M, Sendid B, Jawhara S. A decrease in anaerobic bacteria promotes Candida glabrata overgrowth while β-glucan treatment restores the gut microbiota and attenuates colitis. Gut Pathog 2018; 10:50. [PMID: 30524506 PMCID: PMC6276212 DOI: 10.1186/s13099-018-0277-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/29/2018] [Indexed: 01/30/2023] Open
Abstract
Background The intestinal microbiota plays a crucial role in the maintenance of gut homeostasis. Changes in crosstalk between the intestinal epithelial cells, immune cells and the microbiota are critically involved in the development of inflammatory bowel disease. In the experimental mouse model, the development of colitis induced by dextran sulfate sodium (DSS) promotes overgrowth of the opportunistic yeast pathogen Candida glabrata. Conversely, fungal colonization aggravates inflammatory parameters. In the present study, we explored the effect of C. glabrata colonization on the diversity of the gut microbiota in a DSS-induced colitis model, and determined the impact of soluble β-glucans on C. glabrata-host interactions. Results Mice were administered a single inoculum of C. glabrata and were exposed to DSS treatment for 2 weeks in order to induce acute colitis. For β-glucan treatment, mice were administered with soluble β-glucans purified from C. glabrata (3 mg per mouse), orally and daily, for 5 days, starting on day 1. The number of C. glabrata colonies and changes in microbiota diversity were assessed in freshly collected stool samples from each tagged mouse, using traditional culture methods based on agar plates. An increase in Escherichia coli and Enterococcus faecalis populations and a reduction in Lactobacillus johnsonii and Bacteroides thetaiotaomicron were observed during colitis development. This decrease in L. johnsonii was significantly accentuated by C. glabrata overgrowth. Oral administration of β-glucans to mice decreased the overgrowth of aerobic bacteria and IL-1β expression while L. johnsonii and B. thetaiotaomicron populations increased significantly. β-glucan treatment increased IL-10 production via PPARγ sensing, promoting the attenuation of colitis and C. glabrata elimination. Conclusions This study shows that the colonic inflammation alters the microbial balance, while β-glucan treatment increases the anaerobic bacteria and promotes colitis attenuation and C. glabrata elimination.
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Affiliation(s)
- Rogatien Charlet
- 1U995/Team2, INSERM, 59000 Lille, France.,2LIRIC-INSERM U995/2, Lille Inflammation Research International Center, University Lille, 1 Place Verdun, 59000 Lille, France.,3Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Clovis Bortolus
- 1U995/Team2, INSERM, 59000 Lille, France.,2LIRIC-INSERM U995/2, Lille Inflammation Research International Center, University Lille, 1 Place Verdun, 59000 Lille, France.,3Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Melissandre Barbet
- 1U995/Team2, INSERM, 59000 Lille, France.,2LIRIC-INSERM U995/2, Lille Inflammation Research International Center, University Lille, 1 Place Verdun, 59000 Lille, France.,3Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Boualem Sendid
- 1U995/Team2, INSERM, 59000 Lille, France.,2LIRIC-INSERM U995/2, Lille Inflammation Research International Center, University Lille, 1 Place Verdun, 59000 Lille, France.,3Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
| | - Samir Jawhara
- 1U995/Team2, INSERM, 59000 Lille, France.,2LIRIC-INSERM U995/2, Lille Inflammation Research International Center, University Lille, 1 Place Verdun, 59000 Lille, France.,3Service de Parasitologie Mycologie, Pôle de Biologie Pathologie Génétique, CHU Lille, 59000 Lille, France
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Yu LCH. Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: exploring a common ground hypothesis. J Biomed Sci 2018; 25:79. [PMID: 30413188 PMCID: PMC6234774 DOI: 10.1186/s12929-018-0483-8] [Citation(s) in RCA: 271] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 10/29/2018] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial disease which arises as a result of the interaction of genetic, environmental, barrier and microbial factors leading to chronic inflammation in the intestine. Patients with IBD had a higher risk of developing colorectal carcinoma (CRC), of which the subset was classified as colitis-associated cancers. Genetic polymorphism of innate immune receptors had long been considered a major risk factor for IBD, and the mutations were also recently observed in CRC. Altered microbial composition (termed microbiota dybiosis) and dysfunctional gut barrier manifested by epithelial hyperpermeability and high amount of mucosa-associated bacteria were observed in IBD and CRC patients. The findings suggested that aberrant immune responses to penetrating commensal microbes may play key roles in fueling disease progression. Accumulative evidence demonstrated that mucosa-associated bacteria harbored colitogenic and protumoral properties in experimental models, supporting an active role of bacteria as pathobionts (commensal-derived opportunistic pathogens). Nevertheless, the host factors involved in bacterial dysbiosis and conversion mechanisms from lumen-dwelling commensals to mucosal pathobionts remain unclear. Based on the observation of gut leakiness in patients and the evidence of epithelial hyperpermeability prior to the onset of mucosal histopathology in colitic animals, it was postulated that the epithelial barrier dysfunction associated with mucosal enrichment of specific bacterial strains may predispose the shift to disease-associated microbiota. The speculation of leaky gut as an initiating factor for microbiota dysbiosis that eventually led to pathological consequences was proposed as the "common ground hypothesis", which will be highlighted in this review. Overall, the understanding of the core interplay between gut microbiota and epithelial barriers at early subclinical phases will shed light to novel therapeutic strategies to manage chronic inflammatory disorders and colitis-associated cancers.
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Affiliation(s)
- Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Suite 1020, #1 Jen-Ai Rd. Sec. 1, Taipei, 100, Taiwan, Republic of China.
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Ring C, Klopfleisch R, Dahlke K, Basic M, Bleich A, Blaut M. Akkermansia muciniphila strain ATCC BAA-835 does not promote short-term intestinal inflammation in gnotobiotic interleukin-10-deficient mice. Gut Microbes 2018; 10:188-203. [PMID: 30252588 PMCID: PMC6546315 DOI: 10.1080/19490976.2018.1511663] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Akkermansia muciniphila is a common member of the intestinal microbiota of healthy human individuals. Its abundance is negatively associated with inflammatory bowel disease and metabolic disorders and the oral administration of A. muciniphila improves the symptoms of metabolic disease in mice. Therefore, A. muciniphila is a promising candidate for the treatment of type-2 diabetes and obesity. However, some studies using animal models of intestinal inflammation reported that A. muciniphila may exacerbate gut inflammation. Because of these contradictory reports the present study aimed to clarify the role of A. muciniphila in the development of intestinal inflammation and the conditions promoting it. For this purpose, the short-term colitogenic potential of A. muciniphila strain ATCC BAA-835 was investigated in colitis-prone, gnotobiotic IL-10-deficient (Il10-/-) mice. Il10-/- mice mono-associated with A. muciniphila showed no signs of intestinal inflammation based on body-weight change, histopathological scoring and inflammatory markers. Additional association of the mice with the colitogenic Escherichia coli strain NC101 led to cecal but not colonic inflammation. However, the severity of the inflammation did not exceed that observed in mice mono-associated with E. coli NC101. Il10-/- mice colonized with a simplified human intestinal microbiota showed increased histopathology, but no increase in inflammatory markers. Furthermore, co-colonization with A. muciniphila did not modify histopathology. The turnover of intestinal mucus was similar in all groups despite the mucus-degrading property of A. muciniphila. Overall, the data do not support a short-term pro-inflammatory effect of A. muciniphila strain ATCC BAA-835 in the Il10-/- mouse model for inflammatory bowel disease.
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Affiliation(s)
- Christiane Ring
- Department Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany,CONTACT Christiane Ring Department Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, Nuthetal 14558, Germany
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universitaet Berlin, Berlin, Germany
| | - Katja Dahlke
- Department Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - André Bleich
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Michael Blaut
- Department Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
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Casey KM, Johnson AL, Hunrath MN, Fraser JK, McCowan NC, Wasson K, Doty RA, Griffey SM, Imai DM. Proliferative Typhlocolitis With Multinucleated Giant Cells: A Nonspecific Enteropathy in Immunodeficient Sentinel Mice. Vet Pathol 2018; 56:157-168. [PMID: 30222063 DOI: 10.1177/0300985818798106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Beginning in 2015, athymic nude sentinel mice from conventional, medium-, and high-security facilities presented to the Comparative Pathology Laboratory (CPL) with weight loss, diarrhea, and/or rectal prolapse. Regardless of whether clinical signs were present or absent, the gross observation of ceco-colonic thickening corresponded histologically to pleocellular typhlocolitis with mucosal hyperplasia and lamina proprial multinucleated cells. A subset of affected sentinels exhibited granulomatous serositis and hepatosplenic necrosis with multinucleated cells. Initial suspicion of mouse hepatitis virus infection was excluded by polymerase chain reaction, electron microscopy, and serology. Multinucleated giant cells were confirmed as macrophages by positive immunoreactivity to Mac-3 and Iba-1 and negative immunoreactivity to pancytokeratin. From conventional and medium-security facilities, Helicobacter species were identified in 40 of 143 (27.9%) mice, with H. hepaticus accounting for 72.5% of identified Helicobacter species. Other agents included opportunistic bacterial infection (41/145, 28.3%), murine norovirus (16/106, 15.1%), and pinworms (2/146, 1.4%). From high-security facilities, only Enterobacter cloacae was identified (2/13, 15.4%), and no evidence of Helicobacter sp., murine norovirus, or pinworms was present. No potentially infectious disease agent(s) was identified in 71 of 146 (48.6%) affected nude sentinels from conventional and medium-security facilities and 11 of 13 (84.6%) affected nude sentinels from high-security facilities. No statistically significant differences in histologic lesion scores were identified between Helicobacter-positive and Helicobacter-negative mice. Thus, proliferative typhlocolitis with multinucleated giant cells was considered a nonspecific histologic pattern associated with a variety of primary and opportunistic pathogens in athymic nude mice.
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Affiliation(s)
- Kerriann M Casey
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA.,2 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Amanda L Johnson
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Melea N Hunrath
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Jenelle K Fraser
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Nicole C McCowan
- 3 Campus Veterinary Services, University of California, Davis, CA, USA
| | - Katherine Wasson
- 4 Office of Research and Economic Development, University of California, Merced, CA, USA
| | | | - Stephen M Griffey
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
| | - Denise M Imai
- 1 Comparative Pathology Laboratory, University of California, Davis, CA, USA
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37
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Affiliation(s)
- Serre-Yu Wong
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, United States of America
- Department of Medicine, Henry D. Janowitz Division of Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
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38
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Remodeling of the Candida glabrata cell wall in the gastrointestinal tract affects the gut microbiota and the immune response. Sci Rep 2018; 8:3316. [PMID: 29463799 PMCID: PMC5820338 DOI: 10.1038/s41598-018-21422-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 02/02/2018] [Indexed: 12/17/2022] Open
Abstract
The gastrointestinal (GI) microbiota acts a natural barrier to the proliferation of opportunistic pathogens. Candida glabrata is an opportunistic yeast pathogen that has adapted to colonize all segments of the human GI tract. We observed an increase in Escherichia coli, Enterococcus faecalis, and Bacteroides vulgatus populations, and a decrease in Lactobacillus johnsonii, Bacteroides thetaiotaomicron, and Bifidobacterium animalis in mice with DSS-induced colitis. This reduction was more pronounced for L. johnsonii during C. glabrata overgrowth. In addition, C. glabrata overgrowth increased mouse mortality and inflammatory parameters, and modulated the expression of intestinal receptors and signaling pathways. The C. glabrata cell wall underwent various changes during the course of C. glabrata colonization, and showed a significant increase in chitin. C. glabrata deficient in chitin synthase-3 induced fewer inflammatory parameters than the parental strain during intestinal inflammation. Oral administration of chitin attenuated the impact of colitis, and reduced the number of aerobic bacteria and C. glabrata overgrowth, while chitinase-3-like protein-1 increased. This study provides evidence that inflammation of the gut alters the microbial balance and leads to C. glabrata cell wall remodeling through an increase in chitin, which is involved in promoting persistence of C. glabrata in the gut.
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Haberman Y, BenShoshan M, Di Segni A, Dexheimer PJ, Braun T, Weiss B, Walters TD, Baldassano RN, Noe JD, Markowitz J, Rosh J, Heyman MB, Griffiths AM, Crandall WV, Mack DR, Baker SS, Kellermayer R, Patel A, Otley A, Steiner SJ, Gulati AS, Guthery SL, LeLeiko N, Moulton D, Kirschner BS, Snapper S, Avivi C, Barshack I, Oliva-Hemker M, Cohen SA, Keljo DJ, Ziring D, Anikster Y, Aronow B, Hyams JS, Kugathasan S, Denson LA. Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease. Inflamm Bowel Dis 2018; 24:346-360. [PMID: 29361088 PMCID: PMC6231367 DOI: 10.1093/ibd/izx013] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Long noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA. METHODS Using RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes. RESULTS We characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury. CONCLUSIONS We systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.
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Affiliation(s)
- Yael Haberman
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio,Sheba Medical Center, Israel,Address correspondence to: Yael Haberman, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, MLC 2010, 3333 Burnet Avenue, Cincinnati, OH 45229 ()
| | | | | | | | | | - Batia Weiss
- Sheba Medical Center, Israel,Tel Aviv University, Israel
| | - Thomas D Walters
- Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | | | - Joshua D Noe
- Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Joel Rosh
- Goryeb Children’s Hospital/Atlantic Health, Morristown, New Jersey
| | - Melvin B Heyman
- University of California, San Francisco, San Francisco, California
| | - Anne M Griffiths
- Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | | | - David R Mack
- Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
| | | | | | - Ashish Patel
- UT Southwestern Medical Center at Dallas, Dallas, Texas
| | | | | | - Ajay S Gulati
- University of North Carolina, Chapel Hill, North Carolina
| | | | | | | | | | | | | | - Iris Barshack
- Sheba Medical Center, Israel,Tel Aviv University, Israel
| | | | - Stanley A Cohen
- Children’s Center for Digestive Healthcare, Atlanta, Georgia
| | - David J Keljo
- Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Yair Anikster
- Sheba Medical Center, Israel,Tel Aviv University, Israel
| | - Bruce Aronow
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Jeffrey S Hyams
- Connecticut Children’s Medical Center, Hartford, Connecticut
| | | | - Lee A Denson
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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Li N, Shi RH. Updated review on immune factors in pathogenesis of Crohn's disease. World J Gastroenterol 2018; 24:15-22. [PMID: 29358878 PMCID: PMC5757119 DOI: 10.3748/wjg.v24.i1.15] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Although the incidence of Crohn's disease (CD) in China is not as high as that in European and American countries, there has been a clear increasing trend in recent years. Little is known about its pathogenesis, cause of deferment, and the range of complications associated with the disease. Local and international scholars have presented many hypotheses about CD pathogenesis based on experimental and clinical studies, including genetic susceptibility, immune function defects, intestinal microflora disorders, delayed hypersensitivity, and food antigen stimulation. However, the specific mechanism leading to this immune imbalance, which causes persistent intestinal mucosal damage, and the source of the inflammatory cascade reaction are still unclear. So far, the results of research studies differ locally and internationally. This paper presents the most current research on immune factors in the pathogenesis of CD.
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Affiliation(s)
- Na Li
- Department of Gastroenterology, Zhongda Hospital, Affiliated Hospital of Southeast University, Nanjing 210009, Jiangsu Province, China
- Clinical Medical School of Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Rui-Hua Shi
- Department of Gastroenterology, Zhongda Hospital, Affiliated Hospital of Southeast University, Nanjing 210009, Jiangsu Province, China
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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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Sartor RB, Wu GD. Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology 2017; 152:327-339.e4. [PMID: 27769810 PMCID: PMC5511756 DOI: 10.1053/j.gastro.2016.10.012] [Citation(s) in RCA: 597] [Impact Index Per Article: 74.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 02/08/2023]
Abstract
Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.
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Affiliation(s)
- R Balfour Sartor
- Departments of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
| | - Gary D Wu
- Division of Gastroenterology, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
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43
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Ardura MI, Kim SC. Infectious Complications of Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2017:605-614. [DOI: 10.1007/978-3-319-49215-5_49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mottawea W, Chiang CK, Mühlbauer M, Starr AE, Butcher J, Abujamel T, Deeke SA, Brandel A, Zhou H, Shokralla S, Hajibabaei M, Singleton R, Benchimol EI, Jobin C, Mack DR, Figeys D, Stintzi A. Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease. Nat Commun 2016; 7:13419. [PMID: 27876802 PMCID: PMC5122959 DOI: 10.1038/ncomms13419] [Citation(s) in RCA: 298] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 09/27/2016] [Indexed: 02/07/2023] Open
Abstract
Intestinal microbial dysbiosis is associated with Crohn's disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. In this report, we use systems-level approaches to study the interactions between the gut microbiota and host in new-onset paediatric patients to evaluate causality and mechanisms of disease. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. In particular, mitochondrial proteins implicated in H2S detoxification are downregulated, while the relative abundance of H2S microbial producers is increased. Network correlation analysis reveals that Atopobium parvulum controls the central hub of H2S producers. A. parvulum induces pancolitis in colitis-susceptible interleukin-10-deficient mice and this phenotype requires the presence of the intestinal microbiota. Administrating the H2S scavenger bismuth mitigates A. parvulum-induced colitis in vivo. This study reveals that host–microbiota interactions are disturbed in CD and thus provides mechanistic insights into CD pathogenesis. Crohn's disease is associated with altered intestinal microbiota. Here, the authors show that the microbe Atopobium parvulum is associated with Crohn's disease patients, triggers colitis in a mouse model, and that scavenging microbe-induced hydrogen sulfide improved symptoms in mice.
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Affiliation(s)
- Walid Mottawea
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Cheng-Kang Chiang
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Marcus Mühlbauer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida 32611, USA
| | - Amanda E Starr
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - James Butcher
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Turki Abujamel
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Shelley A Deeke
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Annette Brandel
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Hu Zhou
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Shadi Shokralla
- Biodiversity Institute of Ontario, Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1
| | - Mehrdad Hajibabaei
- Biodiversity Institute of Ontario, Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1
| | - Ruth Singleton
- Children's Hospital of Eastern Ontario (CHEO) Inflammatory Bowel Disease Centre and CHEO Research Institute, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8L1
| | - Eric I Benchimol
- Children's Hospital of Eastern Ontario (CHEO) Inflammatory Bowel Disease Centre and CHEO Research Institute, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.,Department of Pediatrics, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Christian Jobin
- Department of Medicine, Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida 32611, USA
| | - David R Mack
- Children's Hospital of Eastern Ontario (CHEO) Inflammatory Bowel Disease Centre and CHEO Research Institute, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.,Department of Pediatrics, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Daniel Figeys
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Department of Chemistry and Biomolecular Sciences, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
| | - Alain Stintzi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.,Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
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45
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Hörmannsperger G, Schaubeck M, Haller D. Intestinal Microbiota in Animal Models of Inflammatory Diseases. ILAR J 2016; 56:179-91. [PMID: 26323628 DOI: 10.1093/ilar/ilv019] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The intestinal microbiota has long been known to play an important role in the maintenance of health. In addition, alterations of the intestinal microbiota have recently been associated with a range of immune-mediated and metabolic disorders. Characterizing the composition and functionality of the intestinal microbiota, unravelling relevant microbe-host interactions, and identifying disease-relevant microbes are therefore currently of major interest in scientific and medical communities. Experimental animal models for the respective diseases of interest are pivotal in order to address functional questions on microbe-host interaction and to clarify the clinical relevance of microbiome alterations associated with disease initiation and development. This review presents an overview of the outcomes of highly sophisticated experimental studies on microbe-host interaction in animal models of inflammatory diseases, with a focus on inflammatory bowel disease (IBD). We will address the advantages and drawbacks of analyzing microbe-host interaction in complex colonized animal models compared with gnotobiotic animal models using monoassociation, simplified microbial consortia (SMC), or microbial humanization.
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Affiliation(s)
- G Hörmannsperger
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
| | - M Schaubeck
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
| | - D Haller
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
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46
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Wang T, Pan D, Zhou Z, You Y, Jiang C, Zhao X, Lin X. Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut. PLoS Pathog 2016; 12:e1005662. [PMID: 27280399 PMCID: PMC4900642 DOI: 10.1371/journal.ppat.1005662] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 05/06/2016] [Indexed: 12/28/2022] Open
Abstract
Interactions between commensal fungi and gut immune system are critical for establishing colonic homeostasis. Here we found that mice deficient in Dectin-3 (Clec4d-/-), a C-type lectin receptor that senses fungal infection, were more susceptible to dextran sodium sulfate (DSS)-induced colitis compared with wild-type mice. The specific fungal burden of Candida (C.) tropicalis was markedly increased in the gut after DSS treatment in Clec4d-/- mice, and supplementation with C. tropicalis aggravated colitis only in Clec4d-/- mice, but not in wild-type controls. Mechanistically, Dectin-3 deficiency impairs phagocytic and fungicidal abilities of macrophages, and C. tropicalis-induced NF-κB activation and cytokine production. The conditioned media derived from Dectin-3-deficient macrophages were defective in promoting tissue repairing in colonic epithelial cells. Finally, anti-fungal therapy was effective in treating colitis in Clec4d-/- mice. These studies identified the role of Dectin-3 and its functional interaction with commensal fungi in intestinal immune system and regulation of colonic homeostasis. C-type lectin receptors (CLRs) comprise a diverse family of soluble and trans-membrane proteins that function as pattern recognition receptors (PRRs). Dectin-3 (also known as MCL/CLECSF8/Clec4d), a myeloid cell-specific CLR family member, could recognize bacterial and fungal components and induce intracellular signaling pathways that regulate the immune response. Although investigators have explored the role of Dectin-3 in systemic immunity, its function in the gastrointestinal immune system is not clear. Using a dextran sodium sulfate (DSS)-induced colitis mice model, we show here Dectin-3-deficient mice were more susceptible to DSS-induced colitis compared with wild-type mice. The specific fungal burden of a commensal fungi C. tropicalis was markedly increased in the gut after DSS treatment in Dectin-3-deficient mice, and antifungal therapy could effectively protect these mice from colitis. Taken together, we demonstrate the important function of Dectin-3 and its functional interaction with commensal fungi in intestinal immune responses and regulation of colonic homeostasis.
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Affiliation(s)
- Tingting Wang
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
| | - Deng Pan
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas, Graduate School of Biomedical Sciences, Houston, Texas, United States of America
| | - Zhicheng Zhou
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas, Graduate School of Biomedical Sciences, Houston, Texas, United States of America
| | - Yun You
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Changying Jiang
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Xueqiang Zhao
- Institute for Immunology, Tsinghua University School of Medicine, Beijing, China
| | - Xin Lin
- Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas, Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Institute for Immunology, Tsinghua University School of Medicine, Beijing, China
- * E-mail:
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The Distribution of SIgA and IgG Antibody-Secreting Cells in the Small Intestine of Bactrian Camels (Camelus bactrianus) of Different Ages. PLoS One 2016; 11:e0156635. [PMID: 27249417 PMCID: PMC4889134 DOI: 10.1371/journal.pone.0156635] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022] Open
Abstract
Secretory immunoglobulin A (SIgA) and immunoglobulin G (IgG) antibody-secreting cells (ASCs) are two important cell types in the mucosal immune system. This study aimed to explore the distribution of these ASC populations in the small intestine of Bactrian camels of different ages. Twenty-four Alashan Bactrian camels were divided into the following four age groups: young (1–2 years), pubertal (3–5 years), middle-aged (6–16 years) and old (17–20 years). SIgA and IgG ASCs in the intestinal mucosa lamina propria (LP) were observed and analyzed using immunohistochemcal techniques. The results from all age groups show that both SIgA and IgG ASCs were diffusely distributed in the intestinal LP, and some cells aggregated around the crypts. Moreover, the densities of the two ASC populations gradually increased from the duodenum to the jejunum and then decreased in the ileum. Meanwhile, there were more SIgA ASCs than IgG ASCs in the duodenum, jejunum, and ileum, and these differences were significant in the young and pubertal groups (P<0.05). In addition, the SIgA and IgG ASC densities increased from the young to the pubertal period, peaked at puberty, and then gradually decreased with age. The results demonstrate that the SIgA and IgG ASC distributions help to form two immunoglobulin barriers in the intestinal mucosa to provide full protection, helping to maintain homeostasis. These findings also underscore the importance of researching the development and degeneration of intestinal mucosal immunity in Bactrian camels.
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Nagao-Kitamoto H, Kitamoto S, Kuffa P, Kamada N. Pathogenic role of the gut microbiota in gastrointestinal diseases. Intest Res 2016; 14:127-38. [PMID: 27175113 PMCID: PMC4863046 DOI: 10.5217/ir.2016.14.2.127] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 02/29/2016] [Accepted: 02/29/2016] [Indexed: 12/22/2022] Open
Abstract
The gastrointestinal (GI) tract is colonized by a dense community of commensal microorganisms referred to as the gut microbiota. The gut microbiota and the host have co-evolved, and they engage in a myriad of immunogenic and metabolic interactions. The gut microbiota contributes to the maintenance of host health. However, when healthy microbial structure is perturbed, a condition termed dysbiosis, the altered gut microbiota can trigger the development of various GI diseases including inflammatory bowel disease, colon cancer, celiac disease, and irritable bowel syndrome. There is a growing body of evidence suggesting that multiple intrinsic and extrinsic factors, such as genetic variations, diet, stress, and medication, can dramatically affect the balance of the gut microbiota. Therefore, these factors regulate the development and progression of GI diseases by inducing dysbiosis. Herein, we will review the recent advances in the field, focusing on the mechanisms through which intrinsic and extrinsic factors induce dysbiosis and the role a dysbiotic microbiota plays in the pathogenesis of GI diseases.
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Affiliation(s)
- Hiroko Nagao-Kitamoto
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Sho Kitamoto
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Peter Kuffa
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
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49
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The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection. Microbiol Spectr 2016; 3. [PMID: 26185088 DOI: 10.1128/microbiolspec.mbp-0008-2014] [Citation(s) in RCA: 148] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The healthy human intestine is colonized by as many as 1014 bacteria belonging to more than 500 different species forming a microbial ecosystem of unsurpassed diversity, termed the microbiota. The microbiota's various bacterial members engage in a physiological network of cooperation and competition within several layers of complexity. Within the last 10 years, technological progress in the field of next-generation sequencing technologies has tremendously advanced our understanding of the wide variety of physiological and pathological processes that are influenced by the commensal microbiota (1, 2). An increasing number of human disease conditions, such as inflammatory bowel diseases (IBD), type 2 diabetes, obesity, allergies and colorectal cancer are linked with altered microbiota composition (3). Moreover, a clearer picture is emerging of the composition of the human microbiota in healthy individuals, its variability over time and between different persons and how the microbiota is shaped by environmental factors (i.e., diet) and the host's genetic background (4). A general feature of a normal, healthy gut microbiota can generate conditions in the gut that disfavor colonization of enteric pathogens. This is termed colonization-resistance (CR). Upon disturbance of the microbiota, CR can be transiently disrupted, and pathogens can gain the opportunity to grow to high levels. This disruption can be caused by exposure to antibiotics (5, 6), changes in diet (7, 8), application of probiotics and drugs (9), and a variety of diseases (3). Breakdown of CR can boost colonization by intrinsic pathogens or increase susceptibility to infections (10). One consequence of pathogen expansion is the triggering of inflammatory host responses and pathogen-mediated disease. Interestingly, human enteric pathogens are part of a small group of bacterial families that belong to the Proteobacteria: the Enterobacteriaceae (E. coli, Yersinia spp., Salmonella spp., Shigella spp.), the Vibrionaceae (Vibrio cholerae) and the Campylobacteriaceae (Campylobacter spp.). In general, members of these families (be it commensals or pathogens) only constitute a minority of the intestinal microbiota. However, proteobacterial "blooms" are a characteristic trait of an abnormal microbiota such as in the course of antibiotic therapy, dietary changes or inflammation (11). It has become clear that the gut microbiota not only plays a major role in priming and regulating mucosal and systemic immunity, but that the immune system also contributes to host control over microbiota composition. These two ways of mutual communication between the microbiota and the immune system were coined as "outside-in" and "inside-out," respectively (12). The significance of those interactions for human health is particularly evident in Crohn's disease (CD) and Ulcerative Colitis (UC). The symptoms of these recurrent, chronic types of gut inflammation are caused by an excessive immune response against one's own commensal microbiota (13). It is assumed that deregulated immune responses can be caused by a genetic predisposition, leading to, for example, the impairment of intestinal barrier function or disruption of mucosal T-cell homeostasis. In CD or UC patients, an abnormally composed microbiota, referred to as "dysbiosis," is commonly observed (discussed later). This is often characterized by an increased relative abundance of facultative anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time, depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia. So far, it is unclear whether dysbiosis is a cause or a consequence of inflammatory bowel disease (IBD). In fact, both scenarios are equally conceivable. Recent work suggests that inflammatory immune responses in the gut (both IBD and pathogen-induced) can alter the gut luminal milieu in a way that favors dysbiosis (14). In this chapter, I present a survey on our current state of understanding of the characteristics and mechanisms underlying gut inflammation-associated dysbiosis. The role of dysbiosis in enteric infections and human IBD is discussed. In addition, I will focus on competition of enteric pathogens and the gut microbiota in the inflamed gut and the role of dysbiotic microbiota alterations (e.g., "Enterobacterial blooms" (11)) for the evolution of pathogenicity.
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50
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Bang B, Lichtenberger LM. Methods of Inducing Inflammatory Bowel Disease in Mice. ACTA ACUST UNITED AC 2016; 72:5.58.1-5.58.42. [PMID: 26995548 DOI: 10.1002/0471141755.ph0558s72] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of the disease, identifying new targets for therapeutic intervention, and testing novel therapeutics. This unit provides detailed protocols for five widely used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, the CD4(+) CD45RB(hi) SCID transfer colitis model, and the IL-10(-/-) colitis model. © 2016 by John Wiley & Sons, Inc.
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Affiliation(s)
- Byoungwook Bang
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.,Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas
| | - Lenard M Lichtenberger
- Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas
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