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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140111 | GEO | 2020/01/13

REPOSITORIES: GEO

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Project description:Background: Acetate, propionate, and butyrate are the main short-chain fatty acids (SCFA) produced in the colon as a result of microbial fermentation of dietary fibers. An increasing amount of evidence suggests that these SCFA have major health benefits. The composition of the microbiota is altered by dietary fat, and this is believed to impact SCFA production. Currently it is unknown whether host gene expression responses to SCFA are modulated by fat content of the diet. The aim of this study was to compare the changes in colonic gene expression profiles after acetate, propionate and butyrate infusions between a low fat and high fat diet. Methods: Male C57BL/6J mice were fed semi-synthetic low fat (10 energy%) or high fat (45 E%) diets starting 2 weeks before the SCFA treatment period. During treatment, mice received a rectal infusion of either an acetate, propionate, butyrate, or a saline (control) solution for 6 consecutive days, after which colon was subjected to gene expression profiling. Unsupervised visualization of the dataset was performed using Independent Principal Component Analysis. For each SCFA, similarities of its effects on a low fat and a high fat diet were assessed using Rank-Rank Hypergeometric Overlap. In addition, differentially expressed genes were identified, and gene set enrichment analysis was performed to determine functional implications of the regulated genes. Results: Taking into account the complete dataset, we observed that more variation in gene expression profiles was explained by fat content of the diet than by SCFA treatment. Gene expression responses to acetate and butyrate were similar on the low fat versus high fat diet, but were opposite for propionate. Functionally the expression changes reflected differential modulation of several metabolic processes; genes involved in oxidative phosphorylation, lipid catabolism, lipoprotein metabolism and cholesterol transport were suppressed by acetate and butyrate treatment, whereas propionate treatment resulted in changes in fatty acid and sterol biosynthesis, and in amino acid and carbohydrate metabolism. Conclusions: We demonstrated that dietary fat content impacts the colonic gene expression response to propionate, and to a lesser extent to acetate and butyrate. The study demonstrates that knowledge on diet composition is essential when studying effects of SCFAs on metabolism.

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

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