A commensal Clostridium species protects against inflammation by modulating ILC3s Chin Yee Tan1,2, Neeraj K. Surana1,2,3 1Department of Molecular Genetics and Microbiology; 2Department of Pediatrics; 3Department of Immunology, Duke University School of Medicine The microbiome is intricately linked to human health and, when dysregulated, can cause disease. Recently, it has been shown that specific members of the intestinal microbiota regulate immunity, a finding that offers an approach for treating autoimmune disease through microbiome engineering. In previously published work, we identified Clostridium immunis, a new human-derived commensal bacterium that protects mice against colitis. To understand the host immunological response to C. immunis, we performed comprehensive flow cytometric analysis of the colonic immune system of C. immunis-treated mice, as well as cytokine analysis of mouse colonic tissue cultured ex vivo with C. immunis. Interestingly, we observed that the number of group 3 innate lymphoid cells (ILC3s), as well as ILC3-produced cytokines were significantly decreased with C. immunis treatment. ILC3s are a rare but critical tissue-resident cell population known to have protective roles in certain enteric infections, but also exert pathogenic effects in autoimmune disease. We studied if C. immunis is able to modulate the outcomes of diseases known to be attenuated or exacerbated by ILC3s—Citrobacter rodentium infection and a murine model of multiple sclerosis (MS), respectively. Accordingly, C. immunis administration led to worse disease in Citrobacter rodentium infection, but conversely was protective in the MS model. Lastly, we investigated if C. immunis was also able to modulate the human immune system. Indeed, co-culturing colonic biopsies from patients with inflammatory bowel disease with C. immunis led to a decrease in inflammatory cytokines. Considered together, we have identified a commensal intestinal bacterium that exerts a potent immunomodulatory effect on inflammatory disease, likely through its effect on ILC3s.