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Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis, 2021, Hinrishsen et al

Discussion in 'Other health news and research' started by Andy, Nov 29, 2021.

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  1. Andy

    Andy Committee Member

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    [In mice].

    Highlights
    • Loss of epithelial HK2 protects against acute intestinal inflammation
    • Ablation of HK2 suppresses cell death and dysregulates mitochondrial function
    • The microbiome regulates HK2 expression via SCFAs targeting HDAC8
    • The SCFA butyrate ameliorates intestinal inflammation by downregulating HK2

    Summary

    Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highly expressed in gut epithelium, contributes to immune responses, and is upregulated during inflammation. We examined the microbial regulation of HK2 and its impact on inflammation using mice lacking HK2 in intestinal epithelial cells (Hk2ΔIEC). Hk2ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2ΔIEC mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cells revealed reduced mitochondrial respiration and epithelial cell death in the absence of HK2. The microbiota strongly regulated HK2 expression and activity. The microbially derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histone deacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not in HK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.

    Paywall, https://www.sciencedirect.com/science/article/abs/pii/S1550413121005325
     
    alktipping and hibiscuswahine like this.

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