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1.
Proc Natl Acad Sci U S A ; 117(35): 21536-21545, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32817490

ABSTRACT

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.


Subject(s)
Fecal Microbiota Transplantation , Inflammatory Bowel Diseases/microbiology , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Animals , Colitis/prevention & control , Colon/microbiology , Crohn Disease/metabolism , Crohn Disease/microbiology , Cytokines/immunology , Disease Models, Animal , Feces/microbiology , Female , Gastrointestinal Microbiome/immunology , Humans , Inflammatory Bowel Diseases/immunology , Male , Mice , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/microbiology , Th17 Cells/microbiology
2.
Cell Host Microbe ; 27(3): 467-475.e6, 2020 Mar 11.
Article in English | MEDLINE | ID: mdl-32075742

ABSTRACT

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.


Subject(s)
Bacteroides/classification , Feces , Gastrointestinal Microbiome , Immunoglobulin A/immunology , Intestine, Large/immunology , Animals , B-Lymphocytes/immunology , Bacteroides/immunology , CD4-Positive T-Lymphocytes/immunology , Germ-Free Life , Humans , Intestine, Large/microbiology , Mice , Mice, Inbred C57BL
3.
Inflamm Bowel Dis ; 25(6): 969-979, 2019 05 04.
Article in English | MEDLINE | ID: mdl-30852592

ABSTRACT

BACKGROUND: Recurrent and severe Clostridium difficile infections (CDI) are treated with fecal microbiota transplant (FMT). Uncertainty exists regarding FMT effectiveness for CDI with underlying inflammatory bowel disease (IBD) and regarding its effects on disease activity and effectiveness in transferring the donor microbiota to patients with and without IBD. METHODS: Subjects with and without IBD who underwent FMT for recurrent or severe CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) frequency of IBD flare after FMT; (3) microbiota engraftment after FMT; (and 4) predictors of CDI recurrence. RESULTS: One hundred thirty-four patients, 46 with IBD, were treated with FMT. Follow-up was available in 83 and 118 patients at 6 and 2 months, respectively. There was no difference in recurrence in patients with and without IBD at 6 months (38.7% vs 36.5%; P > 0.99) and 2 months (22.5% vs 17.9%; P = 0.63). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. Pre-FMT microbiota was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment, with no difference in engraftment based on CDI recurrence or IBD endoscopic severity at FMT. CONCLUSIONS: Inflammatory bowel disease did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiota was not predictive of recurrence, and microbial engraftment was impacted in those requiring IBD treatment escalation, though not by CDI recurrence or IBD disease severity.


Subject(s)
Bacteria/classification , Clostridioides difficile/physiology , Clostridium Infections/therapy , Fecal Microbiota Transplantation/methods , Inflammatory Bowel Diseases/complications , Adult , Clostridium Infections/complications , Clostridium Infections/microbiology , Female , Follow-Up Studies , Humans , Inflammatory Bowel Diseases/microbiology , Longitudinal Studies , Male , Middle Aged , Recurrence , Retrospective Studies , Treatment Outcome
4.
Immunity ; 50(1): 212-224.e4, 2019 01 15.
Article in English | MEDLINE | ID: mdl-30650377

ABSTRACT

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1-/- mice. The proportions of Th17 and RORγt+ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1-/- colitis model. Thus, an impact on intestinal Th17 and RORγt+ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.


Subject(s)
Colitis/microbiology , Gastrointestinal Microbiome/genetics , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/microbiology , RNA, Ribosomal, 16S/genetics , T-Lymphocytes, Regulatory/immunology , Th17 Cells/metabolism , Animals , Cell Differentiation , Colitis/chemically induced , Colitis/immunology , Disease Models, Animal , Disease Progression , Homeostasis , Humans , Mice , Mice, Inbred C57BL , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
5.
Elife ; 82019 01 22.
Article in English | MEDLINE | ID: mdl-30666957

ABSTRACT

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn's disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Subject(s)
Clostridium Infections/microbiology , Crohn Disease/microbiology , Fecal Microbiota Transplantation , Gastrointestinal Microbiome , Adiposity , Adult , Aged , Aged, 80 and over , Animals , Clostridioides difficile , Female , Homeostasis , Humans , Ileum/microbiology , Immune System , Inflammatory Bowel Diseases , Male , Mice , Mice, Inbred C57BL , Microbiota , Middle Aged , Mucous Membrane/microbiology , Phenotype , RNA, Ribosomal, 16S/metabolism , Species Specificity , Young Adult
6.
Gastroenterology ; 154(4): 1037-1046.e2, 2018 03.
Article in English | MEDLINE | ID: mdl-29174952

ABSTRACT

BACKGROUND & AIMS: It is not clear how the complex interactions between diet and the intestinal microbiota affect development of mucosal inflammation or inflammatory bowel disease. We investigated interactions between dietary ingredients, nutrients, and the microbiota in specific pathogen-free (SPF) and germ-free (GF) mice given more than 40 unique diets; we quantified individual and synergistic effects of dietary macronutrients and the microbiota on intestinal health and development of colitis. METHODS: C56BL/6J SPF and GF mice were placed on custom diets containing different concentrations and sources of protein, fat, digestible carbohydrates, and indigestible carbohydrates (fiber). After 1 week, SPF and GF mice were given dextran sulfate sodium (DSS) to induce colitis. Disease severity was determined based on the percent weight change from baseline, and modeled as a function of the concentration of each macronutrient in the diet. In unchallenged mice, we measured intestinal permeability by feeding mice labeled dextran and measuring levels in blood. Feces were collected and microbiota were analyzed by 16S rDNA sequencing. We collected colons from mice and performed transcriptome analyses. RESULTS: Fecal microbiota varied with diet; the concentration of protein and fiber had the strongest effect on colitis development. Among 9 fiber sources tested, psyllium, pectin, and cellulose fiber reduced the severity of colitis in SPF mice, whereas methylcellulose increased severity. Increasing dietary protein increased the density of the fecal microbiota and the severity of colitis in SPF mice, but not in GF mice or mice given antibiotics. Psyllium fiber reduced the severity of colitis through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary casein protein and psyllium fiber in parallel accounted for most variation in gut microbial density and intestinal permeability in unchallenged mice, as well as the severity of DSS-induced colitis; changes in 1 ingredient could be offset by changes in another. CONCLUSIONS: In an analysis of the effects of different dietary components and the gut microbiota on mice with and without DSS-induced colitis, we found complex mixtures of nutrients affect intestinal permeability, gut microbial density, and development of intestinal inflammation.


Subject(s)
Bacteria/growth & development , Colitis/microbiology , Colon/microbiology , Diet , Gastrointestinal Microbiome , Animal Feed , Animals , Bacteria/classification , Bacteria/isolation & purification , Caseins/administration & dosage , Colitis/metabolism , Colitis/physiopathology , Colitis/prevention & control , Colon/metabolism , Colon/physiopathology , Dextran Sulfate , Diet/adverse effects , Dietary Fiber/administration & dosage , Dietary Proteins/administration & dosage , Disease Models, Animal , Feces/microbiology , Female , Homeodomain Proteins/genetics , Male , Mice, Inbred C57BL , Mice, Knockout , Nutritional Status , Nutritive Value , Permeability , Psyllium/administration & dosage , Severity of Illness Index , Time Factors
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