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  • Defined microbiota transplant restores Th17/RORγt+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas. Proceedings of the National Academy of Sciences of the United States of America Britton, G. J., Contijoch, E. J., Spindler, M. P., Aggarwala, V., Dogan, B., Bongers, G., San Mateo, L., Baltus, A., Das, A., Gevers, D., Borody, T. J., Kaakoush, N. O., Kamm, M. A., Mitchell, H., Paramsothy, S., Clemente, J. C., Colombel, J. F., Simpson, K. W., Dubinsky, M. C., Grinspan, A., Faith, J. J. 2020; 117 (35): 21536-21545

    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.

    View details for DOI 10.1073/pnas.1922189117

    View details for PubMedID 32817490

    View details for PubMedCentralID PMC7474624

  • Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation CELL HOST & MICROBE Yang, C., Mogno, I., Contijoch, E. J., Borgerding, J. N., Aggarwala, V., Li, Z., Siu, S., Grasset, E. K., Helmus, D. S., Dubinsky, M. C., Mehandru, S., Cerutti, A., Faith, J. J. 2020; 27 (3): 467-+

    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.

    View details for DOI 10.1016/j.chom.2020.01.016

    View details for Web of Science ID 000519891100028

    View details for PubMedID 32075742

    View details for PubMedCentralID PMC7213796

  • Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium Difficile in Patients With and Without Inflammatory Bowel Disease INFLAMMATORY BOWEL DISEASES Hirten, R. P., Grinspan, A., Fu, S., Luo, Y., Suarez-Farinas, M., Rowland, J., Contijoch, E. J., Mogno, I., Yang, N., Luong, T., Labrias, P. R., Peter, I., Cho, J. H., Sands, B. E., Colombel, J., Faith, J. J., Clemente, J. C. 2019; 25 (6): 969-979

    Abstract

    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.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.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.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.

    View details for DOI 10.1093/ibd/izy398

    View details for Web of Science ID 000472801000013

    View details for PubMedID 30852592

    View details for PubMedCentralID PMC6499938

  • Gut microbiota density influences host physiology and is shaped by host and microbial factors ELIFE Contijoch, E. J., Britton, G. J., Yang, C., Mogno, I., Li, Z., Ng, R., Llewellyn, S. R., Hira, S., Johnson, C., Rabinowitz, K. M., Barkan, R., Dotan, I., Hirten, R. P., Fu, S., Luo, Y., Yang, N., Luong, T., Labrias, P. R., Lira, S., Peter, I., Grinspan, A., Clemente, J. C., Kosoy, R., Kim-Schulze, S., Qin, X., Castillo, A., Hurley, A., Atreja, A., Rogers, J., Fasihuddin, F., Saliaj, M., Nolan, A., Reyes-Mercedes, P., Rodriguez, C., Aly, S., Santa-Cruz, K., Peters, L., Suarez-Farinas, M., Huang, R., Hao, K., Zhu, J., Zhang, B., Losic, B., Irizar, H., Song, W., Di Narzo, A., Wang, W., Cohen, B. L., DiMaio, C., Greenwald, D., Itzkowitz, S., Lucas, A., Marion, J., Maser, E., Ungaro, R., Naymagon, S., Novak, J., Shah, B., Ullman, T., Rubin, P., George, J., Legnani, P., Telesco, S. E., Friedman, J. R., Brodmerkel, C., Plevy, S., Cho, J. H., Colombel, J., Schadt, E. E., Argmann, C., Dubinsky, M., Kasarskis, A., Sands, B., Faith, J. J. 2019; 8

    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.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).

    View details for DOI 10.7554/eLife.40553

    View details for Web of Science ID 000456237300001

    View details for PubMedID 30666957

    View details for PubMedCentralID PMC6342524

  • Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and ROR gamma t(+) Regulatory T Cells and Exacerbate Colitis in Mice IMMUNITY Britton, G. J., Contijoch, E. J., Mogno, I., Vennaro, O. H., Llewellyn, S. R., Ng, R., Li, Z., Mortha, A., Merad, M., Das, A., Gevers, D., McGovern, D. B., Singh, N., Braun, J., Jacobs, J. P., Clemente, J. C., Grinspan, A., Sands, B. E., Colombel, J., Dubinsky, M. C., Faith, J. J. 2019; 50 (1): 212-+

    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.

    View details for DOI 10.1016/j.immuni.2018.12.015

    View details for Web of Science ID 000455661600021

    View details for PubMedID 30650377

    View details for PubMedCentralID PMC6512335

  • Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice GASTROENTEROLOGY Llewellyn, S. R., Britton, G. J., Contijoch, E. J., Vennaro, O. H., Mortha, A., Colombel, J., Grinspan, A., Clemente, J. C., Merad, M., Faith, J. J. 2018; 154 (4): 1037-+

    Abstract

    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.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.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.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.

    View details for DOI 10.1053/j.gastro.2017.11.030

    View details for Web of Science ID 000427453300043

    View details for PubMedID 29174952

    View details for PubMedCentralID PMC5847454

  • DUAL OXIDASE (DUOX) 2 IS INCREASED IN INTESTINAL INFLAMMATION AND MEDIATES CHANGES IN MUCUS COMPOSITION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES (IBD) Rabinowitz, K. M., Cohen-Kedar, S., Chait, K., Contijoch, E. J., Pasmanik-Chor, M., Faith, J., Shen-Orr, S., Dotan, I. W B SAUNDERS CO-ELSEVIER INC. 2017: S964

    View details for DOI 10.1016/S0016-5085(17)33271-7

    View details for Web of Science ID 000403140304030

  • Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression NATURE Sandler, N. G., Bosinger, S. E., Estes, J. D., Zhu, R. R., Tharp, G. K., Boritz, E., Levin, D., Wijeyesinghe, S., Makamdop, K., del Prete, G. Q., Hill, B. J., Timmer, J., Reiss, E., Yarden, G., Darko, S., Contijoch, E., Todd, J., Silvestri, G., Nason, M., Norgren, R. B., Keele, B. F., Rao, S., Langer, J. A., Lifson, J. D., Schreiber, G., Douek, D. C. 2014; 511 (7511): 601-+

    Abstract

    Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.

    View details for DOI 10.1038/nature13554

    View details for Web of Science ID 000339566300037

    View details for PubMedID 25043006

    View details for PubMedCentralID PMC4418221