Gut Microbial Metabolites Fuel Host Antibody Responses

Abstract

SUMMARY Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.

Regulation of humoral immunity by gut microbial products

“…24 In low SCFA conditions due to low DF consumption, serum antibody and mucosal IgA levels are significantly decreased. 23,25 Germinal center responses in PPs are suppressed in low SCFA conditions but SCFA administration restored antibody production in mice fed a DF-free diet (Fig. 1).…”

“…Recently, we reported that SCFAs support plasma B cell differentiation. 23 SCFA deficiency occurs when DF levels in diet are low or when the microbiota are suppressed by antibiotics or altered due to dysbiosis. In GF mice, the SCFA levels in the colon are decreased to about one percent of normal levels.…”

“…SCFAs increase cellular levels of acetyl-CoA and energy (e.g., ATP) and lipid biogenesis to drive plasma B cell differentiation. 23 SCFAs are efficient histone deacetylase (HDAC) inhibitors, and this function boosts the expression of genes such as Xbp-1, Aicda and Prdm1, involved in plasma B cell differentiation. Activation of the mTOR pathway increases glycolysis in B cells.…”

“…25,27 Interestingly, it is not just intestinal IgA but also systemic IgG responses that are supported by SCFAs. 23 We will discuss the roles of non-B cells in mediating the regulatory effects of the gut microbiota on B cells responses in the next section. (Fig.…”

The antihyperlipidemic effects of fullerenol nanoparticles via adjusting the gut microbiota in vivo

“…4b). Since the furan-and pyran-like structures of fullerenol NPs appeared similar to those of the polysaccharides in dietary fiber, which is the main nutrient for SCFAs-producing gut bacteria [33], we hypothesize that Fol1 and Fol113 NPs might function like dietary polysaccharides to promote SCFAs-producing bacteria survival.…”