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

摘要 人类炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，构成了一种肠道疾病。 发达国家的主要健康问题。虽然确切的病因尚未明确定义，但遗传 易感性、肠道微生物群改变和西方饮食是IBD的危险因素。然而，这些因素如何 在诱导和触发IBD中的协调作用知之甚少。我们最近证明了老鼠 缺乏炎性体的人易患实验性结肠炎，这与肠道改变有关。 微生物群炎性小体是一种多蛋白复合物，参与半胱天冬酶-1的切割， 激活促炎细胞因子IL-1b和IL-18。我们的初步研究表明， 在炎性小体缺陷小鼠中结肠炎期间给予IL-18降低结肠炎易感性， 与病原菌的减少相关，表明炎性小体/IL-18信号传导轴 在维持健康的微生物群落和肠道内稳态方面起着关键作用。值得注意的是，IL-18- 缺乏和其它炎性体缺陷小鼠易于发展成肥胖症并表现出葡萄糖缺陷 新陈代谢.因此，我们观察到葡萄糖水平升高和葡萄糖受体表达减少。 在炎性小体缺陷小鼠肠道中的转运基因。值得注意的是，葡萄糖是主要的能量来源， 许多致病菌。因此，我们假设炎性小体维持肠道葡萄糖 通过调节肠上皮细胞和炎性小体中的选择性葡萄糖转运蛋白实现体内平衡 功能障碍导致葡萄糖在肠道中积聚，通过调节肠道微生物群触发结肠炎。这些 假设将通过解决两个具体目标进行测试：目标1：确定膳食葡萄糖的作用 目的2：阐明炎性小体在肠道葡萄糖稳态中的作用。 总的来说，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 维持肠道葡萄糖稳态的新免疫机制。从这项研究中获得的数据 将指导IBD患者的饮食建议，并导致开发针对IBD患者的新型IBD治疗方法。 炎症小体或其下游信号通路参与葡萄糖转运。

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.