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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AICDA (Activation-Induced Cytidine Deaminase)
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Animals
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Antibodies / genetics*
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Antibodies / immunology
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Antibodies / metabolism
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Autoantibodies / genetics
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Autoantibodies / immunology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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Butyrates / pharmacology
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Cytidine Deaminase / antagonists & inhibitors
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Cytidine Deaminase / genetics
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Cytidine Deaminase / immunology
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Cytidine Deaminase / metabolism
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Dietary Fiber
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Epigenesis, Genetic / drug effects*
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Fatty Acids, Volatile / isolation & purification
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Fatty Acids, Volatile / pharmacokinetics
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Fatty Acids, Volatile / pharmacology*
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Female
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Gastrointestinal Microbiome / drug effects
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Gastrointestinal Microbiome / genetics
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Gastrointestinal Microbiome / immunology*
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Histone Deacetylase Inhibitors / immunology
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Lupus Erythematosus, Systemic / drug therapy
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Lupus Erythematosus, Systemic / immunology
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Positive Regulatory Domain I-Binding Factor 1 / antagonists & inhibitors
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Positive Regulatory Domain I-Binding Factor 1 / genetics
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Positive Regulatory Domain I-Binding Factor 1 / immunology
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Positive Regulatory Domain I-Binding Factor 1 / metabolism
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Propionates / pharmacology
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Tissue Distribution
Substances
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Antibodies
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Autoantibodies
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Butyrates
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Dietary Fiber
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Fatty Acids, Volatile
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Histone Deacetylase Inhibitors
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Prdm1 protein, mouse
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Propionates
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Positive Regulatory Domain I-Binding Factor 1
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AICDA (Activation-Induced Cytidine Deaminase)
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Cytidine Deaminase