Gut Microbiota-Derived Inosine From Dietary Barley Leaf Supplementation Attenuates Colitis Through PPARγ Signaling Activation

Abstract

Background Ulcerative 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. Results Using 16S rRNA gene-based microbiota analysis, we first found that dietary supplementation of BL ameliorated dextran sulphate 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 enrichment of microbiota-derived purine metabolite inosine, which could activate PPARγ signaling in human colon epithelial cells. Furthermore, exogenous treatment of inosine reproduced the similar protective effects as BL to protect against DSS-induced colitis through improving adenosine 2A receptor (A2AR)/PPARγ-dependent mucosal barrier functions. Conclusions Overall, 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.

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“…It could activate PPARγ pathway to increase the expression of MUC-2 so that enhance the intestine barrier function. 51 Besides, both inosine and xanthosine were involved in the purine metabolism pathway. The previous study has confirmed that intestinal barrier dysfunction was correlated with purine metabolism, and related metabolites uric acid were upregulated in the DSS group.…”

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“…After another 3 h, blood was collected and centrifuged at 1000 g for 15 min. Serum was obtained, and the fluorescence intensity was measured at 485 nm (excitation wavelength) and 535 nm (emission wavelength) …”

“…Serum was obtained, and the fluorescence intensity was measured at 485 nm (excitation wavelength) and 535 nm (emission wavelength). 15 2.9. Determination of Short-Chain Fatty Acids (SCFAs) in Colonic Contents.…”