MicroRNAs are small non-coding RNAs regulating gene expression at the post-transcriptional level. The regulation of microRNA expression in the gut intestine is gradually recognized as one of the crucial contributors of intestinal homeostasis and overall health. Recent studies indicated that both the microRNAs endogenous in the gut intestine and exogenous from diets could play influential roles in modulating microbial colonization and intestinal immunity. In this review, we discuss the biological functions of microRNAs in regulating intestinal homeostasis by modulating intestinal immune responses and gut microbiota. We particularly focus on addressing the microRNA-dependent communication and interactions among microRNA, gut microbiota, and intestinal immune system. Besides, we also summarize the roles of diet-derived microRNAs in host-microbiome homeostasis and their benefits on intestinal health. A better understanding of the relationships among intestinal disorders, microRNAs, and other factors influencing intestinal health can facilitate the application of microRNA-based therapeutics for gastrointestinal diseases.

Gastrointestinal dysfunction is a common symptom of acute mountain sickness (AMS). The gut microbiota and γδ T cells play critical roles in intestinal disease. However, the mechanistic link between the microbiota and γδ T cells in hypoxia-induced intestinal injury remains unclear. Here, we show that hypoxia-induced intestinal damage was significantly alleviated after microbiota depletion with antibiotics. Hypoxia modulated gut microbiota composition by promoting antimicrobial peptides angiogenin-4 secretions. The abundance of Clostridium in the gut of mice after hypoxia significantly decreased, while the abundance of Desulfovibrio significantly increased. Furthermore, Desulfovibrio-derived phosphatidylethanolamine and phosphatidylcholine promoted γδ T cell activation. In CD1d-deficient mice, the levels of intraepithelial IL-17A and γδ T cells and intestinal damage were significantly decreased compared with those in wild-type mice under hypoxia. Mechanistically, phospholipid metabolites from Desulfovibrio are presented by intestinal epithelial CD1d to induce the proliferation of IL-17A-producing γδ T cells, which aggravates intestinal injury. Gut microbiota-derived metabolites promote hypoxia-induced intestinal injury via CD1d-dependent γδ T cells, suggesting that phospholipid metabolites and γδ T cells can be targets for AMS therapy.