Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity

Wenjing Yang,Leiqi Xu,Xiangsheng Huang,Fan Pan,Sara M Dann,Jia Zhou,Yingzi Cong,Jiaren Sun,Tianming Yu,Craig L Maynard,Wenbo Zhang,Zhanju Liu,Nagendra Singh,Yao Lu,Suxia Yao,Anthony J Bilotta

doi:10.1038/s41467-020-18262-6

Abstract

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.

Highlights

Innate lymphoid cells (ILCs) and CD4+ T cells produce Interleukin 22 (IL-22), which is critical for intestinal immunity
We demonstrate that short-chain fatty acids (SCFAs) promote IL-22 production in CD4+ T cells and ILCs through histone deacetylase (HDAC) inhibition and G-protein receptor 41 (GPR41), but not GPR43 and GPR109a
Emerging evidence indicates that interaction between microbiota and IL-22 is central at barrier sites in the regulation of intestinal homeostasis

Summary

Result

SCFAs promote IL-22 in CD4+ T cells and ILCs in vitro. SCFAs have been shown to promote regulatory T cell (Treg) development as well as CD4+ T cell IL-10 production[20,26,28]. Butyrate did not affect IL-23p19 expression in LP DCs (Supplementary Fig. 5b) Taken all together, these data indicate that SCFAs promote IL-22 production in CD4+ T cells and ILCs in vivo. Treatment with GPR41-specific agonist, AR420626, promoted CD4+ T cell IL-22 expression at both mRNA and protein levels under Th1 (Fig. 3a–c) and Th17 (Supplementary Fig. 8i–j) conditions, indicating that GPR41, but not GPR43 and GPR109a, mediates butyrate induction of IL-22 in CD4+ T cells. Butyrate promotion of AhR and HIF1α expression in CD4+ T cells under Th1 conditions was verified at both RNA and protein levels by qRT-PCR (Fig. 4b, c) and western blot (Fig. 4d, e). We obtained similar results for the roles of Stat[3] and mTOR in butyrate-induced IL-22 production and expression of HIF1α and AhR in CD4+ T cells cultured under Th17 conditions (Supplementary Fig. 12g–l). These results demonstrated that butyrate protects the intestines from inflammation induced by both enteric infection and intestinal injury through the upregulation of IL-22 production

85 Day: 0 1 2 3 4 5 6 7 8 9 10

Discussion

Findings

Methods