Impact of the Microbiota on Intestinal Th17 Cells at Steady-State and in Autoimmune Disease

Abstract

The gut microbiota is critical in shaping many facets of the host immune system, including the induction of intestinal T helper (Th) 17 cells. Changes in microbiota compositions have been associated with a variety of inflammatory disorders, including type-1 diabetes (T1D) and inflammatory bowel disease (IBD). Th17 responses have also been implicated in these diseases. We therefore sought to elucidate the mechanisms underpinning the links among intestinal symbionts, Th17 cells, and autoimmune disease, by focusing first on the activity of Segmented Filamentous Bacteria (SFB), a murine symbiont that robustly induces intestinal Th17 populations and whose colonization was reported to correlate with protection from T1D in the nonobese diabetic (NOD) mouse. Our studies revealed an unexpected diversity in SFB populations across different animal facilities and illuminated the roles of SAA3, a member of the serum amyloid A family of proteins, and intestinal macrophages in the induction of gut Th17 cells by SFB. We then sought to find human symbionts functionally analogous to SFB in eliciting intestinal Th17 cells, and identified several bacterial species, in particular Bifidobacterium adolescentis, that could, alone, engender Th17 cells in the murine intestine. B. adolescentis and SFB exhibited overlapping but also distinct activities, suggesting multiple routes to gut Th17 induction. Importantly, B. adolescentis exacerbated chemically induced colitis and autoimmune arthritis, and was found to be altered in abundance in the microbiotas of IBD patients, arguing for its pathological relevance. Our results help to inform the search for therapeutic targets in diseases associated with Th17 responses and mucosal dysfunction.