Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function

Kelly C J, Zheng L, Campbell E L, et al. Cell host & microbe, 2015, 17(5): 662-671.

Speaker: Yang Fei(費暘)                                                  Time: 13:00~14:00, Oct. 28, 2015

Commentator: I-Hsiu Huang, Ph.D(黃一修 老師)     Place: Room 601

Abstract:

Trillions of microbes inhabit the human intestine, forming a complex ecological community that influences normal physiology and susceptibility to disease through its collective metabolic activities and host interactions. These microbes ferment within the intestinal lumen and produce short-chain fatty acids (SCFAs) to benefit the host. Among these SCFAs, butyrate plays an important role in maintaining colonic homeostasis and providing energy for intestinal epithelial cells. On the other hand, the physiologically low O₂ conditions in the intestinal lumen not only enable microbiota-derived SCFAs production but also place unusual metabolic demands on the colonic epithelium. Nevertheless, the colonic epithelium is uniquely adapted to this “physiologic hypoxia” environment that has been shown to maintain intestinal barrier function via the hypoxia-inducible factor (HIF), which is the major cellular transcription factor targeting to various genes for maintaining tissue barrier and microbial defense in low O₂ environments. In this study, the authors further explored whether the epithelial metabolism of SCFAs is a primary determinant of ‘‘physiologic hypoxia’’ in the mucosa. They first demonstrated that the microbial-derived butyrate promoted localized O₂ depletion to the extent that HIF is stabilized and transcriptionally active. They then destroyed the physiologic hypoxia by using broad-spectrum antibiotics to examine the impact of butyrate concentration on HIF production in colon. They also showed that the germ-free mice had diminished “physiologic hypoxia” and decreased HIF, and butyrate rescued hypoxia and colonic barrier function in a HIF-dependent manner. In conclusion, the microbiota-derived SCFAs can enhance the intestinal barrier function by stabilizing HIF.

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