小柯机器人

近日，德国基尔大学Felix Sommer及其课题组发现，己糖激酶2的微生物调节与结肠炎中的线粒体代谢和细胞死亡有关。这一研究成果于2021年11月29日在线发表在国际学术期刊《细胞—代谢》上。

研究人员使用在肠道上皮细胞中缺乏己糖激酶（HK）2的小鼠（Hk2^ΔIEC）来研究了HK2的微生物调节及其对炎症的影响。Hk2^ΔIEC小鼠对急性结肠炎的敏感性较低。分析结肠炎期间Hk2^ΔIEC小鼠的上皮细胞转录组，并使用HK2缺陷的肠道器官和Caco-2细胞发现在没有HK2的情况下，线粒体呼吸减少，上皮细胞死亡。

微生物群强烈调节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）抑制了HK2的表达，减少了野生型细胞的线粒体呼吸，但在HK2缺陷的Caco-2细胞中没有。补充丁酸盐可以保护野生型但不是Hk2^ΔIEC小鼠免受结肠炎的影响。这些研究结果确定了丁酸盐如何促进肠道平衡的机制，并建议将HK2抑制作为治疗炎症的途径。

据了解，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，并在炎症期间被上调。

附：英文原文

Title: Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis

Author: Finn Hinrichsen, Jacob Hamm, Magdalena Westermann, Lena Schrder, Kensuke Shima, Neha Mishra, Alesia Walker, Nina Sommer, Kenneth Klischies, Daniela Prasse, Johannes Zimmermann, Sina Kaiser, Dora Bordoni, Antonella Fazio, Georgios Marinos, Georg Laue, Simon Imm, Valentina Tremaroli, Marijana Basic, Robert Hsler, Ruth A. Schmitz, Stefan Krautwald, Andrea Wolf, Brbel Stecher, Philippe Schmitt-Kopplin, Christoph Kaleta, Jan Rupp, Fredrik Bckhed, Philip Rosenstiel, Felix Sommer

Issue&Volume: 2021-11-29

Abstract: Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highlyexpressed in gut epithelium, contributes to immune responses, and is upregulated duringinflammation. We examined the microbial regulation of HK2 and its impact on inflammationusing mice lacking HK2 in intestinal epithelial cells (Hk2ΔIEC). Hk2ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptomefrom Hk2ΔIEC mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cellsrevealed reduced mitochondrial respiration and epithelial cell death in the absenceof HK2. The microbiota strongly regulated HK2 expression and activity. The microbiallyderived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histonedeacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not inHK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinalhomeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.

DOI: 10.1016/j.cmet.2021.11.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00532-5

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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