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

By Caleb J. Kelly, Leon Zheng, Eric L Campbell, B. Saeedi, Carsten C. Scholz, A. Bayless, Kelly E. Wilson, Louise E. Glove, Douglas J. Kominsky, Aaron M. Magnuson and 8 more. Cell Host and Microbe, 2015

1,494 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e050e695ee9a70874a8bce4814a04e75b4ade4ad

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Citations in the corpus

• Short-chain fatty acids: linking diet, the microbiome and immunity (2024, positive): “Moreover, SCFAs — particularly butyrate — stimulate IL-22 production by CD4 + T cells and innate lymphoid cells (ILCs) via upregulating expression of AHR and HIF, which both maintain intestinal homeostasis 91 .”
• Microbiota metabolite short chain fatty acids, GCPR, and inflammatory bowel diseases (2016, background): “A recent study has shown that SCFA were highly produced in low O2 condition and then regulated O2 metabolism in intestinal epithelial cells, and further maintained epithelial integrity and protected the barrier via increase HIF stabilization [58].”
• Colonocyte metabolism shapes the gut microbiota (2018, background): “Early insights into mechanisms that disrupt gut homeostasis were obtained by studying the effect of antibiotic treatment (40), which alters epithelial metabolism by depleting microbes that produce fermentation products, including the short-chain fatty acids butyrate, propionate, and acetate (12).”
• Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases (2019, background): “Importantly, butyrate induces the barrier function (measured by FITC-dextran flux) in T84 cells, but not in the absence of HIF-1β, demonstrating a crucial role for HIF1 in maintaining barrier integrity (76).”
• Factors affecting the composition of the gut microbiota, and its modulation (2019, background): “, 2010), modifying insulin resistance and affecting its secretion (Kelly et al., 2015), and affecting the behavioral and neurological functions of the host (Buffington et al.”
• Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid–Producing Microbiota in the Gut (2016, background): “epithelial metabolism and deplete intracellular O2, resulting in stabilization of the transcription factor HIF-1 and increasing epithelial barrier function (38).”
• SCFA: mechanisms and functional importance in the gut (2020, background): “By stabilising the transcription factor HIF, butyrate increases VO2 by IEC favouring the physiologic hypoxia in the colon(130).”
• Short‐chain fatty acids: microbial metabolites that alleviate stress‐induced brain–gut axis alterations (2018, background): “This was reversed by SCFA treatment, which is not surprising as SCFAs have previously been shown to restore intestinal permeability (Kelly et al. 2015; Tong et al. 2016; Simeoli et al. 2017).”
• Mechanisms of inflammation-driven bacterial dysbiosis in the gut (2016, positive): “Bacterial respiration of butyrate, a SCFA, was shown to render epithelial cells in the colon hypoxic.(71) In addition, a recent study illustrated that when butyrate-producing Clostridia are depleted by streptomycin treatment, epithelial oxygenation is elevated, leading to Enterobacteriaceae”
• The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “Among the established microbial functions known to be expressed by human gut microbiomes are catalytic pathways for the metabolism of complex carbohydrates that produce short chain fatty acids (SCFAs; Table 1), anti-inflammatory, anti-proliferative lipids that represent an essential energy source fo”
• The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “Butyrate also influences the epithelial O2 consumption, contributing to the stabilization of transcription factor hypoxia-inducible factor (HIF), which coordinates the gut barrier protection.(117) A proper gut barrier integrity is essential to avoid some pathogenic bacteria (e.”
• Regulation of the intestinal barrier by nutrients: The role of tight junctions (2020, background): “Kelly et al. (2015) demonstrated that butyrate stimulates the epithelial metabolism and depletes intracellular oxygen, resulting in the stabilization of the transcription factor HIF-1 and enhanced barrier integrity.”
• Short chain fatty acids in human gut and metabolic health. (2020, positive): “Intracellular oxidation of butyrate results in depletion of oxygen and stabilisation of HIF, which targets genes in the intestinal cells that are critical for microbial defence, barrier production and mucin production (Kelly et al. , 2015).”