B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids

Short-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fibers fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that these SCFAs directly impact B cells to modulate in a dose-dependent fashion AID and Blimp1 expression, class-switch DNA recombination, somatic hypermutation and plasma cell differentiation, thereby impairing, through B cell-intrinsic activity, local (intestinal) and systemic T-dependent and T-independent antibody responses. In human and mouse B cells, butyrate and propionate upregulate select miRNAs that target Aicda and Prdm1 mRNA-3’UTRs through epigenetic inhibition of histone deacetylation of the respective miRNA host genes. Further, they modulate B cell Aicda and Prdm1 by acting as HDAC inhibitors, not as energy substrate or through GPR-engagement signaling. Finally, butyrate and propionate epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in lupus MRL/Faslpr/lpr and NZB/WF1 mice. Analysis of the mRNA and micrRNA expression profiles in human B cells stimulated with CD154 plus IL-4 and IL-21 in the presence of nil or short-chain fatty acid butyrate