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

摘要

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.