Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.

中文翻译：

---

结肠生酮是一种微生物调节过程，有助于产生血酮并预防小鼠结肠炎

生酮作用被认为主要发生在肝脏中，当葡萄糖的可用性/利用受损时，产生酮作为非肝组织的替代能源。3-羟基-3-甲基戊二酰辅酶A合酶-2 (HMGCS2) 介导该线粒体途径中的限速步骤。公开数据库显示，克罗恩病和溃疡性结肠炎的结肠组织中 HMGCS2 显着下调。这促使我们研究该通路在结肠中的表达和功能及其与小鼠结肠炎症的相关性。Hmgcs2 在盲肠和结肠中表达。由于 Hmgcs2 的整体缺失显示出显着的出生后死亡率，因此我们使用了仅限于肠道的酶缺失的条件性基因敲除小鼠。这些小鼠没有产后死亡。这些小鼠的空腹血酮较低，表明结肠生酮对循环酮的贡献。还有证据表明，肠道屏障被破坏，实验性结肠炎的易感性增加，与循环中 IL-6、IL-1β 和 TNF-α 水平升高相关。有趣的是，其中许多现象在雄性小鼠中最为明显。结肠中的 Hmgcs2 表达受到结肠微生物群的控制，无菌小鼠和抗生素处理的常规小鼠中的表达降低以及用盲肠内容物的水提取物处理后人结肠上皮细胞系中的表达增加证明了这一点。对对照小鼠和 Hmgcs2 缺失小鼠的结肠上皮细胞的转录组分析表明，结肠生酮在维持最佳线粒体功能、胆固醇稳态和细胞间紧密连接组织中发挥着重要作用。这些发现证明生酮在预防小鼠结肠炎症方面具有性别依赖性的必然作用。