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

Helia N. Sanchez, Justin B. Moroney, Huoqun Gan, Tian Shen, John L. Im, Tianbao Li, Julia R. Taylor, Hong Zan () and Paolo Casali ()
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Helia N. Sanchez: University of Texas Long School of Medicine, UT Health Science Center
Justin B. Moroney: University of Texas Long School of Medicine, UT Health Science Center
Huoqun Gan: University of Texas Long School of Medicine, UT Health Science Center
Tian Shen: University of Texas Long School of Medicine, UT Health Science Center
John L. Im: University of Texas Long School of Medicine, UT Health Science Center
Tianbao Li: University of Texas Long School of Medicine, UT Health Science Center
Julia R. Taylor: University of Texas Long School of Medicine, UT Health Science Center
Hong Zan: University of Texas Long School of Medicine, UT Health Science Center
Paolo Casali: University of Texas Long School of Medicine, UT Health Science Center

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Short-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination (CSR), while decreasing at higher doses over a broad physiological range, AID and Blimp1 expression, CSR, somatic hypermutation and plasma cell differentiation. In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by upregulating select miRNAs that target Aicda and Prdm1 mRNA-3′UTRs through inhibition of histone deacetylation (HDAC) of those miRNA host genes. By acting as HDAC inhibitors, not as energy substrates or through GPR-engagement signaling in these B cell-intrinsic processes, these SCFAs impair intestinal and systemic T-dependent and T-independent antibody responses. Their epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in mouse lupus models.

Date: 2020
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DOI: 10.1038/s41467-019-13603-6

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