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

Background: 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 (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T-FR) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T-FR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T-FR cell differentiation remains unknown. Methods: We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5(+)Bcl-6(+)Foxp3(+) T-FR (iT(FR)) cell culture system and examined whether butyrate promotes the differentiation of iT(FR) cells. Findings: Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T-FR cell differentiation. Butyrate directly induced the differentiation of functional T-FR cells in vitro by enhancing histone acetylation in T-FR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T-FR-cell marker genes. The adoptive transfer of the butyrate-treated iT(FR) cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation: Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T-FR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)