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

Abstract

SUMMARY Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the effects of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut.

Oxygen metabolism and barrier regulation in the intestinal mucosa

“…Butyrate-derived acetyl-CoA is made available for oxidative phosphorylation and becomes a prominent fuel for colonic epithelial cells (80). It was recently revealed by Kelly et al that butyrate increases epithelial O 2 consumption to the extent that cells sense metabolic hypoxia and HIF is stabilized (81). These same studies revealed that the lack of microbiota (using germ-free or antibiotic-treated mice) resulted in the depletion of butyrate and loss of HIF stabilization.…”

Impact of Dietary Fibers on Nutrient Management and Detoxification Organs: Gut, Liver, and Kidneys

“…SCFAs decrease intestinal pH, which can alter the gut microbiota by inhibiting the growth of pathogens and reduce the expression of microbial virulence genes (63). Recently, it was shown that epithelial cell lines metabolize the SCFA butyrate (and to a lesser extent propionate and acetate), resulting in oxygen reduction that leads to stabilization of the transcription factor, hypoxia-inducible factor 1a (Hif-1a) (64). In the intestine, this transcription factor has been implicated in gut barrier function by regulating inflammation (65) and apoptosis (66).…”

Function and Phylogeny of Bacterial Butyryl Coenzyme A:Acetate Transferases and Their Diversity in the Proximal Colon of Swine

“…As with other SCFAs, butyrate is consumed by the host as an energy source; however, unlike the other common SCFAs, such as propionate and acetate, butyrate is the preferred energy source for colonocytes (2) and is rapidly absorbed and used by the colonic epithelium. This rapid oxidation of butyrate reduces local oxygen concentrations, causing the epithelia to become hypoxic and thus limiting the growth of facultative aerobic pathogens, such as Salmonella species (3,4). In addition, butyrate alters host gene expression to promote immune tolerance to the colonic microbiota and to improve the barrier function of the colonic epithelium.…”