Biology subjects

Dubinsky, M. C.

Publications and source records attributed to Dubinsky, M. C..

6 recordsLinked to original sources

bioRxiv2025

Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein

We examine disease-specific and cross-disease functions of the human gut microbiome by colonizing germ-free mice, at risk for inflammatory arthritis, colitis, or neuroinflammation, with over 100 human fecal microbiomes from subjects with rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohns disease, or colorectal cancer. We find common inflammatory phenotypes driven by microbiomes from individuals with intestinal inflammation or inflammatory arthritis, as well as distinct functions specific to microbiomes from multiple sclerosis patients. Inflammatory disease in mice colonized with human microbiomes correlated with systemic inflammation, measured by C-reactive protein, in the human donors. These cross-disease patterns of human microbiome pathogenicity mirror features of the inflammatory diseases, including therapeutic targets and the presence or absence of systemic inflammation, suggesting shared and disease-specific mechanisms by which the microbiome is shaped and drives pathogenic inflammatory responses.

immunology↗

bioRxiv2022

Gut microbiota bacterial strain richness is species specific and limits therapeutic engraftment

Despite the fundamental role of strain variation in gut microbiota function, the number of unique strains of a species that can stably colonize the human gut is still unknown. In this work, we determine the strain richness of common gut species using thousands of sequenced bacterial isolates and metagenomes. We find that strain richness varies across species, is transferable by fecal microbiota transplantation, and is low in the gut compared to other environments. Therapeutic administration of supraphysiologic numbers of strains per species only temporarily increases recipient strain richness, which subsequently converges back to the population average. These results suggest that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and provide a theoretical framework for strain engraftment and replacement in fecal microbiota transplantation and defined live biotherapeutic products.

microbiology↗

bioRxiv2020

Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease

The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication within enterocytes. Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation and IBD treatment. A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. Additionally, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.

immunology↗

bioRxiv2019

Defined microbiota transplant restores Th17/RORtγ+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

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, where clinical trials of fecal microbiota transplant 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 and a deficit in the tolerogenic ROR{gamma}t+ Treg cell subset. Transplanting healthy donor-derived microbiota into mice colonized with human IBD microbiotas lead to induction of ROR{gamma}t+ 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 Crohns 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, correlated with a reduction in Th17 cells.

immunology↗

bioRxiv2019

Strain-level differences in gut microbiome composition determine fecal IgA levels and are modifiable by gut microbiota manipulation

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. By accessing the IgA-inducing capacity of a diverse set of human gut microbial strains, we identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied biomodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through both T-cell-dependent and T-cell-independent B cell-activation pathways. 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. Thus, microbial strain specificity is essential for the optimal induction of high-IgA responses in the gut. 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.

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↗