Microbiota-derived butyrate limits the autoimmune response by promoting follicular regulatory T cells

Abstract

Abstract Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA is associated with the expansion of Prevotellaceae and the under representation of the Clostridiumcluster XIVa, including Lachnospiraceae, which are major butyrate producers in the gut, although the pathological relevance has remained obscure. Here, we report that microbiota fermentation product butyrate controls the development of autoimmune arthritis in the host. We found that systemic autoantigen immunization causes hyperplasia of gut-associated lymphoid tissues by amplifying the germinal center (GC) reaction. Butyrate mitigated these pathological events by increasing Bcl-6+CXCR5+CD25−Foxp3+ follicular regulatory T (TFR) cells. Butyrate directly induced the differentiation of functional TFR cells by enhancing histone acetylation in TFR cell marker genes. The adoptive transfer of butyrate-induced TFR cells prevented autoimmune arthritis in mice. Notably, TFR cells induced by butyrate suppressed the development of autoreactive follicular helper T (TFH) and GCB cells and their migration from GALT into articulation-draining lymph nodes (DLNs). Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells which suppress the GC reaction and autoantibody production in the systemic lymphoid tissue, eventually ameliorating autoimmune arthritis. Our findings provide mechanistic insights into the link between the gut microbiota and RA risk.