Biology subjects

Colombel, J.-F.

Publications and source records attributed to Colombel, J.-F..

5 recordsLinked to original sources

bioRxiv2018

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-4{beta}7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. 4{beta}7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-4{beta}7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-4{beta}7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-4{beta}7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-4{beta}7 therapy in HIV-1 infection.\n\nOne Sentence SummaryAnti-4{beta}7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

immunology↗

bioRxiv2018

Inflammatory bowel disease microbiotas alter gut CD4 T-cell homeostasis and drive colitis in mice

To examine the functional contribution of Inflammatory Bowel Disease (IBD) microbes to immune homeostasis and colitis, we colonized unchallenged and colitis-susceptible germ-free mice with over twenty human intestinal microbiotas from healthy and IBD donors. Compared to healthy microbiotas, IBD microbiotas led to expanded ROR{gamma}t+Th17 cells and reduced ROR{gamma}t+Treg in the gut of unchallenged gnotobiotic mice and increased disease severity in colitis-susceptible mice. The proportions of ROR{gamma}t+Th17 and ROR{gamma}t+Treg induced by each microbiota were highly predictive of the human disease status and strongly correlated with disease severity in colitis-susceptible mice colonized with the same human microbiotas. The transmittable functional potential of IBD microbes suggests a mechanism for a microbial contribution to IBD pathogenesis and a potential route for its treatment and prevention.

immunology↗

bioRxiv2018

Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium difficile Patients With and Without IBD

Background & AimsRecurrent and refractory Clostridium difficile infections (CDI) are effectively treated with fecal microbiota transplant (FMT). Uncertainty exists regarding the effectiveness of FMT for CDI with underlying inflammatory bowel disease (IBD), its effects on disease activity and its effectiveness transferring the donor microbiome to patients with and without IBD. This study aims to determine FMTs effectiveness in subjects with and without IBD, its impact on IBD activity, the level of microbiome engraftment, and predictors of CDI recurrence.\n\nMethodsSubjects with and without IBD who underwent FMT for recurrent or refractory 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) Microbiome engraftment after FMT; (4) Predictors of CDI recurrence.\n\nResultsOverall, 134 patients, 46 with IBD, were treated with FMT. There was no difference in recurrence in patients with and without IBD at 2 months (22.5% vs 17.9%; p=0.63) and 6 months (38.7% vs 36.5%; p>0.99). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. The pre-FMT microbiome was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment. There was no difference in engraftment based on IBD endoscopic severity at FMT.\n\nConclusionsIBD did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiome was not predictive of recurrence, and microbial engraftment was dependent on IBD treatment escalation but not on underlying disease severity.

microbiology↗

bioRxiv2018

Diet Modifies Colonic Microbiota and CD4+ T cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo, we generated a mouse model in which IL-23 was conditionally expressed by CX3CR1+ myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4+ T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag-/- mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4+ T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

immunology↗

bioRxiv2017

Deciphering the combinatorial influence of diet and the microbiota on experimental colitis

Background & AimsThe complex interactions between diet and the microbiota that influence mucosal inflammation and inflammatory bowel disease are poorly understood. Experimental colitis models provide the opportunity to control and systematically perturb diet and the microbiota in parallel to quantify the contributions between multiple dietary ingredients and the microbiota on host physiology and colitis.\n\nMethodsTo examine the interplay of diet and the gut microbiota on host health and colitis, we fed over 40 different diets with varied macronutrient sources and concentrations to specific pathogen free or germ free mice either in the context of healthy, unchallenged animals or colitis models (dextran sodium sulfate (DSS) and T cell transfer).\n\nResultsDiet influenced physiology in both health and colitis across all models, with the concentration of protein and psyllium fiber having the most profound effects. Increasing dietary protein elevated gut microbial density and worsened DSS colitis severity. Depleting gut microbial density by using germ-free animals or antibiotics negated the effect of a high protein diet. Psyllium fiber influenced host physiology and attenuated colitis severity through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary protein and psyllium fiber in parallel explain most variation in gut microbial density, intestinal permeability, and DSS colitis severity, and changes in one ingredient can be offset by changes in the other.\n\nConclusionsOur results demonstrate the importance of examining complex mixtures of nutrients to understand the role of diet in intestinal inflammation.

microbiology↗