Mechanisms underlying exacerbation of inflammatory bowel disease by diabetes

糖尿病导致炎症性肠病恶化的机制

• 批准号: 10597035
• 负责人: Kendra Leigh Francis-Stream
• 金额: $ 7.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597035
• 关键词: Acceleration; Acids; Address; Adult; Anti-Inflammatory Agents; Antidiabetic Drugs; Autopsy; Biochemical; Biological Assay; Blood Glucose; Body Weight decreased; Chronic; Clinical; Colitis; Colon; Complications of Diabetes Mellitus; Consumption; Crohn' s disease; Development; Dextrans; Diabetes Mellitus; Diet; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Dose; Epithelium; Exposure to; Extracellular Matrix; Feces; Fluorescein-5-isothiocyanate; Foundations; Functional disorder; Gastroenterology; Genetic; Genetic Models; Glucose; Goals; Hemorrhage; Hepatology; High Fat Diet; Histologic; Hospitalization; Hyperglycemia; Immune System Diseases; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knockout Mice; Link; Mass Spectrum Analysis; Measures; Medical; Medical Care Costs; Mesalamine; Metformin; Modeling; Modernization; Morbidity - disease rate; Mucins; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Oral; Outcome; Outcome Study; Pathogenicity; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Permeability; Population; Population Study; Prevalence; Process; Production; Proteins; Rectum; Research; Research Priority; Risk; Risk Factors; Rodent; Severities; Societies; Sodium; Sodium Dextran Sulfate; Stains; Streptozocin; Structure of beta Cell of islet; Symptoms; Testing; Tight Junctions; Time; Tissue Sample; Toxin; Translating; Treatment Protocols; Treatment outcome; Ulcerative Colitis; United States; University resources; Washington; Wild Type Mouse; Work; comorbidity; diabetes management; diabetic; diet-induced obesity; disorder risk; economic cost; effective therapy; glycemic control; gut inflammation; gut microbiome; improved; in vivo; infection risk; inhibitor; insight; interest; intestinal barrier; intestinal epithelium; intestinal injury; mortality; mouse model; multidisciplinary; novel; nutrition; obese patients; obesogenic; polysulfated glycosaminoglycan; pre-clinical; prevent; rectal; skills; symporter; traditional therapy; translational potential

Project Summary Type 2 diabetes (T2D) and inflammatory bowel disease (IBD) are among the most challenging and costly medical disorders of modern society. Both disease processes also share a common pathophysiology characterized by a chronic inflammatory state, altered gut microbiome, and dysfunctional intestinal barrier. Hyperglycemia is the primary cause of the many complications of diabetes, and recent studies have shown that hyperglycemia is capable of directly impairing intestinal barrier function independent of diet and obesity. Population-based studies have shown that patients with IBD also have an increased risk of T2D, which has important clinical consequences as comorbid T2D in patients with IBD is a predictor of poor disease-related outcomes, though the causative mechanisms remain unknown. In this proposal, we will investigate the novel hypothesis that diabetic hyperglycemia in the setting of diet-induced obesity (DIO) worsens IBD disease activity by increasing intestinal inflammation and associated barrier dysfunction. Specifically, we propose to characterize the effect of diabetic hyperglycemia on clinical and biochemical measures of intestinal inflammation and barrier function in murine models of IBD, and to determine the extent to which control of glycemia decreases intestinal inflammation and improves clinical outcomes in diabetic murine models of IBD. Diabetic-range hyperglycemia will be induced by administration of low-dose streptozotocin (STZ) in two independent models of IBD: 1) C57BL/6J wild-type (WT) mice treated with dextran sodium sulfate (DSS) and 2) Mdr1 knockout mice that spontaneously develop colitis, made obese by consumption of an obesogenic high-fat diet (HFD) or fed standard chow. The impact of hyperglycemia on intestinal barrier function and IBD pathology in the setting of DIO will be assessed using immunohistochemical staining, dextran-FITC permeability assays, and characterization of the components of the intestinal extracellular matrix. We will then investigate the translational potential of treating diabetic hyperglycemia to decrease IBD progression by administering a sodium-glucose cotransportor-2 (SGLT2) inhibitor to normalize glycemia in diabetic murine models of IBD. Lastly, SGLT2 inhibitors will be administered in combination with topical 5-aminosalysilic acids, which are standard first line therapy for mild-to-moderate ulcerative colitis but often fail to control more significant disease, to determine whether treating diabetic hyperglycemia improves the efficacy of introductory IBD therapies. The proposed project unites the clinical gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the considerable multi-disciplinary resources of the University of Washington Diabetes Institute to advance understanding of the mechanisms by which diabetic hyperglycemia influences intestinal inflammation, with the ultimate goal of understanding shared pathogenic mechanisms and identifying more effective treatments for both conditions.

项目摘要 2型糖尿病(T2D)和炎症性肠病(IBD)是最具挑战性和最昂贵的医疗疾病 现代社会的混乱。这两种疾病过程也有一个共同的病理生理过程，特征是 慢性炎症状态，肠道微生物群改变，肠道屏障功能障碍。高血糖是 糖尿病的许多并发症的主要原因，最近的研究表明，高血糖是 能够直接损害肠道屏障功能，不依赖于饮食和肥胖。基于人口的研究 已经表明，IBD患者患T2D的风险也增加，这具有重要的临床后果 IBD患者并发T2D是疾病相关预后不良的预测因子，尽管病因 机制仍不清楚。在这个提案中，我们将研究糖尿病的新假说 饮食诱导肥胖(DIO)环境中的高血糖通过增加肠道功能而加重IBD疾病活动 炎症和相关的屏障功能障碍。具体地说，我们建议表征糖尿病的影响 高血糖对小鼠肠道炎症和屏障功能的临床和生化指标的影响 IBD模型，并确定控制血糖在多大程度上减少肠道炎症和 改善糖尿病小鼠IBD模型的临床结果。糖尿病范围内的高血糖将由以下因素引起 小剂量链脲佐菌素在两种独立的IBD模型中的应用：1)C57BL/6J野生型(WT) 用葡聚糖硫酸钠(DSS)治疗的小鼠和2)自发发展为结肠炎的mdr1基因敲除小鼠， 通过食用导致肥胖的高脂肪饮食(HFD)或喂食标准食物而肥胖。网络的影响 在DIO环境下，高血糖对肠屏障功能和IBD病理的影响将通过 免疫组织化学染色、葡聚糖-FITC通透性测定和成分表征 肠道细胞外基质。然后我们将研究治疗糖尿病的翻译潜力 高血糖通过钠-葡萄糖共转运蛋白-2(SGLT2)抑制IBD进展 抑制糖尿病小鼠IBD模型的血糖正常化。最后，SGLT2抑制剂将在 联合外用5-氨基解唾酸，这是轻至中度的标准一线治疗方法 溃疡性结肠炎但往往不能控制较明显的疾病，以确定是否治疗糖尿病 高血糖可提高IBD介绍性治疗的疗效。拟议的项目将临床 申请人的胃肠病学、肝病和营养学的兴趣和研究技能，以及 华盛顿大学糖尿病研究所相当多的多学科资源将推进 了解糖尿病高血糖影响肠道炎症的机制 最终目标是了解共同的致病机制并找到更有效的治疗方法 条件。