The Inflammasome in the Regulation of Intestinal Glucose Homeostasis, Microbiota and Inflammation

摘要 人类炎症性肠病(IBD)由溃疡性结肠炎和克罗恩病组成，是一种 发达国家的主要健康问题。虽然确切的病因还没有明确定义，但基因 易感性、肠道微生物区系改变和西式饮食是IBD的危险因素。然而，这些因素是如何 它们在诱导和触发IBD方面协调一致，但人们对此知之甚少。我们最近证明了老鼠 炎性小体缺乏易患实验性结肠炎，这与肠道改变有关 微生物区系。炎症体是一个多蛋白复合体，参与caspase-1的裂解，而caspase-1 激活促炎细胞因子IL-1b和IL-18。我们的初步研究表明， 在结肠炎期间给予炎症体缺陷小鼠IL-18可降低结肠炎的易感性 与病原菌的减少有关，提示炎症小体/IL-18信号轴 在维持健康的微生物群落和肠道内环境稳定方面起着至关重要的作用。值得注意的是，IL-18- 缺乏和其他炎症体缺陷的小鼠容易发生肥胖和表现出葡萄糖缺陷 新陈代谢。我们一致地观察到血糖水平升高和葡萄糖表达减少。 炎症体缺陷小鼠肠道中的转运蛋白基因。值得注意的是，葡萄糖是 许多致病菌。因此，我们假设炎症小体维持肠道葡萄糖。 肠上皮细胞和炎症体中通过调节选择性葡萄糖转运体的动态平衡 功能障碍导致肠道内葡萄糖积聚，通过调节肠道微生物区系而引发结肠炎。这些 假说将通过解决两个具体目标来检验：目标1：确定饮食中葡萄糖的作用 在结肠炎发病机制中的作用，目的2：阐明炎症体在肠道葡萄糖稳态中的作用。 总之，这项研究将确立饮食中单糖葡萄糖在结肠炎发病机制中的作用，并揭示一种 维持肠道葡萄糖动态平衡的新免疫机制。从这项研究获得的数据 将指导IBD患者的饮食建议，并导致开发针对 炎性小体或其下游信号通路参与葡萄糖的运输。

ABSTRACT Human inflammatory bowel diseases (IBD), comprised of ulcerative colitis and Crohn’s disease, constitute a major health problem in developed countries. While precise etiology is not clearly defined, genetic predisposition, altered gut microbiota, and Western diet are risk factors for IBD. However, how these factors are coordinated in inducing and triggering IBD is poorly understood. We recently demonstrated that mice deficient in the inflammasome are susceptible to experimental colitis, which is associated with altered gut microbiota. The inflammasome is a multiprotein complex involved in the cleavage of caspase-1, which in turn activates proinflammatory cytokines IL-1b and IL-18. Our preliminary study demonstrated that the administration of IL-18 in inflammasome-deficient mice during colitis reduces colitis susceptibility which is associated with a reduction of pathogenic bacteria, suggesting that the inflammasome/IL-18 signaling axis plays a critical role in maintaining healthy microbial community and intestinal homeostasis. Notably, IL-18- deficient and other inflammasome defective mice are prone to develop obesity and exhibit defective glucose metabolism. Consistently, we observed an elevated level of glucose and reduced expression of a glucose transporter gene in inflammasome-deficient mouse guts. Notably, glucose is the primary energy source for many pathogenic bacteria. We, therefore, hypothesize that the inflammasome maintains intestinal glucose homeostasis via regulation of selective glucose transporters in intestinal epithelial cells, and inflammasome dysfunction leads to glucose accumulation in the gut triggering colitis via modulation of gut microbiota. These hypotheses will be tested through addressing two specific aims: Aim 1: to determine the role of dietary glucose in colitis pathogenesis, and Aim 2: to elucidate the role of the inflammasome in glucose homeostasis in the gut. Overall, this study will establish a role for dietary simple sugar glucose in colitis pathogenesis, and reveal a novel immune mechanism for maintaining glucose homeostasis in the gut. The data obtained from this study will guide diet recommendations for IBD patients and lead to developing novel IBD treatments targeting the inflammasome or its downstream signaling pathways involved in glucose transport.