Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis.

Shuting Wen,Senhui Weng,Runyuan Zhao,Zhuotai Zhong,Fengbin Liu,Long He,Hong Mi

doi:10.3389/fimmu.2021.741934

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

Highlights

Inflammatory bowel disease (IBD) is a chronic and relapsing form of intestinal inflammation that includes Crohn’s disease (CD) and ulcerative colitis (UC) [1]
Stigmasterol increased the expression of IL-10 and TGF-b but downregulated the expression of interleukin 17A (IL-17A) (Figure 2I). These findings strongly suggested that stigmasterol promotes The percentages of CD4+Foxp3+ (Treg) cell development and inhibits the T helper 17 (Th17) cell response in dextran sodium sulfate (DSS)-induced colitis mice
The results suggested that butyrate promotes the metabolic transition of glycolysis to oxidative phosphorylation (OXPHOS) by activating peroxisome proliferator-activated receptor gamma (PPARg), thereby inducing T-cell differentiation into Treg cells but not Th17 cells

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic and relapsing form of intestinal inflammation that includes Crohn’s disease (CD) and ulcerative colitis (UC) [1]. The immune response of the intestinal mucosa is associated with IBD, and an imbalance of regulatory T (Treg) cells and T helper 17 (Th17) cells can contribute to IBD pathogenesis. Tregs have immunosuppressive properties that can be present in the intestinal mucosa. Tregs are crucial to maintain immune homeostasis and can protect the host from an overactive immune response and tissue damage [5]. In addition to inhibiting inflammation, Tregs can regulate processes such as metabolic homeostasis and tissue repair [6]. Regulating the Treg/Th17 balance can improve the intestinal inflammatory microenvironment and intestinal immune balance reconstitution [8]

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