Institute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
Department of Infectious Diseases and Microbiology, University of Lübeck, 23538 Lübeck, Germany.
Cell Metab. 2021 Dec 7;33(12):2355-2366.e8. doi: 10.1016/j.cmet.2021.11.004. Epub 2021 Nov 29.
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 (Hk2). Hk2 mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2 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 Hk2 mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.
己糖激酶（HK）催化糖酵解的第一步，限制其速度。HK2 在肠道上皮细胞中高度表达，有助于免疫反应，并在炎症期间上调。我们使用缺乏肠道上皮细胞中 HK2 的小鼠（Hk2）研究了微生物对 HK2 的调节及其对炎症的影响。Hk2 小鼠不易发生急性结肠炎。在结肠炎期间分析 Hk2 小鼠的上皮转录组，并使用 HK2 缺陷的肠类器官和 Caco-2 细胞，发现 HK2 缺失时线粒体呼吸和上皮细胞死亡减少。微生物强烈调节 HK2 的表达和活性。微生物衍生的短链脂肪酸（SCFA）丁酸盐通过组蛋白去乙酰化酶 8（HDAC8）抑制 HK2 的表达，并降低野生型但不降低 HK2 缺陷型 Caco-2 细胞中的线粒体呼吸。丁酸盐补充保护野生型但不保护 Hk2 小鼠免受结肠炎。我们的发现定义了丁酸盐如何促进肠道内稳态的机制，并提示靶向 HK2 抑制作为炎症的治疗途径。
