Editors' ChoiceHost-Microbe Interactions

Butyrate benefits the intestinal barrier

Sci. Signal.  26 May 2015:
Vol. 8, Issue 378, pp. ec135
DOI: 10.1126/scisignal.aac6198

Intestinal microbiota influence host immunity, metabolism, physiology, and nutrition. By fermenting dietary fiber, intestinal microbes produce short-chain fatty acids (SCFAs), which are an important source of energy for intestinal epithelial cells. Kelly et al. report that SCFAs are also important for maintaining the stability of hypoxia-inducible factor (HIF), a transcription factor that promotes intestinal epithelial barrier function, antimicrobial defense, and mucus production. Compared with other tissues, the colonic epithelium exists in a relatively hypoxic environment because it is located between the O2-poor gut lumen and the O2-rich lamina propria. Addition of the SCFAs butyrate, acetate, or propionate to the medium stimulated O2 consumption by cultured human epithelial adenocarcinoma Caco2 cells. The presence of butyrate, the major SCFA utilized by intestinal epithelial cells, stabilized the HIF subunit HIF-1α in Caco2 cells, as indicated by increases in the nuclear accumulation of HIF-1α and expression of a HIF-responsive reporter and endogenous HIF target genes. Oral administration of broad-spectrum antibiotics eliminated SCFA-producing bacteria and depleted butyrate, acetate, and propionate from the colons of mice. The authors visualized hypoxia in colon samples from mice that had been intraperitoneally injected with the O2-sensitive dye pimonidazole (PMDZ), which is retained in hypoxic tissues. Although PMDZ was present in a gradient from the lumen to the lamina propria in control mice, PMDZ was not retained in samples from antibiotic-treated mice. Antibiotic treatment also reduced the abundance of luciferase in the colons of mice carrying a ubiquitously expressed transgene encoding luciferase fused to the domain of HIF-1α that mediates degradation under O2-rich conditions. Oral administration of butyrate restored luciferase activity in antibiotic-treated animals. In Caco2 cell monolayers, butyrate promoted the integrity of the epithelial barrier in a manner dependent on HIF. These results imply that microbial-derived SCFAs may enhance O2 consumption by the colonic epithelium, thus promoting hypoxia and the stabilization of HIF. These findings may partially explain why loss of butyrate-producing gut microbes has been associated with colitis and inflammatory bowel disease.

C. J. Kelly, L. Zheng, E. L. Campbell, B. Saeedi, C. C. Scholz, A. J. Bayless, K. E. Wilson, L. E. Glover, D. J. Kominsky, A. Magnuson, T. L. Weir, S. F. Ehrentraut, C. Pickel, K. A. Kuhn, J. M. Lanis, V. Nguyen, C. T. Taylor, S. P. Colgan, Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015). [PubMed]