Gut microbiota-derived inosine from dietary barley leaf supplementation attenuates colitis through PPAR\u03b3 signaling activation

Daotong Li,Meiling Tian,Fang Chen,Junfu Ji,Yu Feng,Xiaosong Hu

doi:10.1186/s40168-021-01028-7

Abstract

BackgroundUlcerative colitis is a type of chronic inflammatory bowel disease closely associated with gut microbiota dysbiosis and intestinal homeostasis dysregulation. Barley leaf (BL) has a long history of use in Traditional Chinese Medicine with potential health-promoting effects on intestinal functions. However, its mechanism of action is not yet clear. Here, we explore the potential modulating roles of gut microbial metabolites of BL to protect against colitis and elucidate the underlying molecular mechanisms.ResultsUsing 16S rRNA gene-based microbiota analysis, we first found that dietary supplementation of BL ameliorated dextran sulfate sodium (DSS)-induced gut microbiota dysbiosis. The mechanisms by which BL protected against DSS-induced colitis were resulted from improved intestinal mucosal barrier functions via the activation of peroxisome proliferator-activated receptor (PPAR)γ signaling. In addition, metabolomic profiling analysis showed that the gut microbiota modulated BL-induced metabolic reprograming in the colonic tissues particularly by the enhancement of glycolysis process. Notably, dietary BL supplementation resulted in the enrichment of microbiota-derived purine metabolite inosine, which could activate PPARγ signaling in human colon epithelial cells. Furthermore, exogenous treatment of inosine reproduced similar protective effects as BL to protect against DSS-induced colitis through improving adenosine 2A receptor (A2AR)/PPARγ-dependent mucosal barrier functions.ConclusionsOverall, our findings suggest that the gut microbiota-inosine-A2AR/PPARγ axis plays an important role in the maintenance of intestinal homeostasis, which may represent a novel approach for colitis prevention via manipulation of the gut microbial purine metabolite.7KxheC7u6V5hPgskc1_WuPVideo

Highlights

Ulcerative colitis is a type of chronic inflammatory bowel disease closely associated with gut microbiota dysbiosis and intestinal homeostasis dysregulation
(See figure on previous page.) Fig. 1 Barley leaf (BL) attenuates dextran sulfate sodium (DSS)-induced colitis and gut microbiota dysbiosis. a–i Mice were fed with a standard chow diet (CD) or an isocaloric BL-supplemented diet for two weeks
Colitis was induced by administering 2.5% DSS dissolved in drinking water for 7 days. a Study design of in vivo mouse experiment. b Percentage body weight change, c diseases activity scores, d colon lengths, and e intestinal permeability of the CD- and BL-fed mice with or without DSS treatment (n = 10–12). f Weighted UniFrac Principal coordinate analysis (PCoA) plot of the gut microbiota composition at the operational taxonomic unit (OTU) level from different mouse groups (n = 10). g Alpha diversity analysis of gut bacterial richness (Chao1 index) and diversity (Shannon index) from different mouse groups (n = 10). h Taxonomic distributions of gut bacterial composition at the phylum level (n = 10). i Taxonomic distributions of gut bacterial composition at the family level (n = 10)

Summary

Introduction

Ulcerative colitis is a type of chronic inflammatory bowel disease closely associated with gut microbiota dysbiosis and intestinal homeostasis dysregulation. Ulcerative colitis is characterized by the presence of discontinuous lesions that mainly affect the mucosal layer in the cecum and colon [2]. It is highly prevalent in the developed countries, recent studies have shown that it is becoming more frequent in developing countries and this disease has emerged as a worldwide public health challenge [3, 4]. Patients with ulcerative colitis display decreased expression of peroxisome proliferatoractivated receptor (PPAR)γ in the colonic epithelium, which may be an important factor for the cause of intestinal dysfunction and chronic inflammation [6]. There is an unmet need for developing new therapeutic strategies for the prevention and treatment of colitis

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