Project 3: Gut microbiome -arsenic- diabetes interactions

项目 3：肠道微生物组-砷-糖尿病的相互作用

• 批准号: 10570876
• 负责人: Kun Lu
• 金额: $ 31.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570876
• 关键词: Address; Affect; Agonist; Animals; Arsenic; Attenuated; Bacteria; Bile Acids; Cholic Acids; Coupled; Data; Deoxycholic Acid; Diabetes Mellitus; Diabetes prevention; Diet; Disease; Exposure to; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genes; Germ-Free; Gluconeogenesis; Glucose; Health; Hepatic; Hepatocyte; Homeostasis; Human; Hydrolase; Impairment; In Vitro; Insulin; Intervention; Knock-out; Knowledge; Link; Lithocholic Acid; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Metagenomics; Methods; Molecular; Mus; Nature; North Carolina; Pathogenesis; Pathway interactions; Persons; Population; Public Health; Raspberries; Receptor Activation; Receptor Inhibition; Regulation; Regulator Genes; Research; Role; Shapes; Shotguns; Signal Recognition Particle; Signal Transduction; Signaling Molecule; Superfund; Symptoms; Techniques; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxic effect; Vision; Vulnerable Populations; adverse outcome; bile acid metabolism; bile salts; commensal bacteria; diabetes risk; dietary supplements; disorder prevention; dysbiosis; epidemiology study; exposed human population; glucose tolerance; gut bacteria; gut microbiome; gut microbiota; host microbiome; human disease; ileum; improved; in vivo Model; innovation; insulin signaling; knock-down; microbiome; microbiome alteration; microbiome research; microbiota transplantation; novel; programs; receptor

ABSTRACT: PROJECT 3 Exposure to inorganic arsenic (iAs) affects large human populations worldwide and leads to a number of human diseases, including diabetes. Project 3 addresses a fundamental gap in understanding mechanisms underlying iAs-induced diabetes – specifically the role of the gut microbiome. The association between iAs and diabetes has been established in numerous epidemiological studies. We and others have also demonstrated that iAs induces dysregulation of glucose and insulin metabolism in mice. The gut microbiome has a profound effect on human health through its key role in metabolic regulation, and emerges as a promising target for intervention and therapeutic treatment in human health. Accumulating evidence supports the role of the gut microbiome and Farnesoid X receptor (FXR) in the pathogenies and prevention of diabetes in both animals and humans. Our studies are among the first to demonstrate the functional interactions between iAs and the gut microbiome. Still, precisely how the iAs-altered gut microbiome affects diabetes risk remains to be determined. In particular, the molecular mechanisms underlying iAs-microbiome-host crosstalk are largely unknown. This represents a significant gap in iAs-microbiome research, which also impedes mechanism-based interventions to reduce arsenic-induced diabetes via targeting the gut microbiome and its metabolic functions. Our central hypothesis is that modulation of the gut microbiome will serve as a method for reduction of iAs-perturbed metabolic dysfunction/diabetes. Specifically, iAs-altered gut microbiome disrupts bile acids to inhibit FXR, which in turn alters gluconeogenesis and insulin signaling. Our robust preliminary data underscore the key role of microbiome- bile acid-FXR axis in iAs-induced diabetes, and highlight the potential to modulate iAs toxicity by targeting FXR via microbiome. To test this hypothesis, we will pursue three specific aims: Aim 1: Establish the functional link between altered gut microbiota and iAs-impaired bile acid metabolism; Aim 2: Determine the effects of inhibited FXR activation, driven by iAs-induced gut microbiome dysbiosis, on gluconeogenesis and insulin signaling; and Aim 3: Mediate iAs-induced diabetes via restoring FXR activation by gut microbiome manipulation. Our strong team (Drs. Lu, Sartor, Styblo and McDermott) has complimentary expertise in iAs toxicity, gut microbiome, iAs metabolism and iAs-induced diabetes. We use innovative techniques to characterize largely unknown contributions of gut microbiome-bile acid-FXR in iAs-induced diabetes and the project is in line with the theme of the UNC-SRP “Identifying novel methods to reduce iAs exposure and elucidating mechanisms underlying iAs- induced metabolic dysfunction with a vision for disease prevention.” The highly modifiable nature of the gut microbiome and in-depth mechanistic understanding of the role of microbiome in disease will allow us to develop new tangible approaches to reduce iAs-induced diabetes by targeting the gut microbiome and related signaling molecules.

摘要：项目3 暴露于无机砷（IAS）会影响全世界的大量人口，并导致许多人类 疾病，包括糖尿病。项目3解决了理解基本机制的根本差距 IAS诱导的糖尿病 - 特别是肠道微生物组的作用。 IAS与糖尿病之间的关联 在许多流行病学研究中已建立。我们和其他人也证明了IAS 诱导小鼠葡萄糖和胰岛素代谢的失调。肠道微生物组对 人类健康通过其在代谢法规中的关键作用，成为干预的承诺目标 和人类健康治疗。积累的证据支持肠道微生物组和 Farnesoid X受体（FXR）在动物和人类的糖尿病的病原体和预防中。我们的 研究是最早证明IAS与肠道微生物组之间功能相互作用的研究者。仍然， 确切地说，改变IAS的肠道微生物组如何影响糖尿病的风险尚待确定。特别是 IAS-微生物组主持串扰的分子机制在很大程度上未知。这代表 IAS-Microbiome研究的显着差距，这也阻碍了基于机制的干预措施 砷诱导的糖尿病是通过靶向肠道微生物组及其代谢功能的。我们的中心假设 是肠道微生物组的调节将作为减少IAS扰动代谢的方法 功能障碍/糖尿病。特别是改变IAS的肠道微生物组会破坏胆汁酸，以抑制FXR 改变糖异生和胰岛素信号传导。我们强大的初步数据强调了微生物组的关键作用 IAS诱导的糖尿病中的胆汁酸-FXR轴，并通过靶向FXR强调了调节IAS毒性的潜力 通过微生物组。为了检验这一假设，我们将追求三个具体目标：目标1：建立功能链接 在改变的肠道微生物群和IAS损伤的胆汁酸代谢之间；目标2：确定抑制的影响 FXR激活，由IAS诱导的肠道微生物组营养不良，糖异生和胰岛素信号传导驱动；和 AIM 3：通过通过肠道微生物组操纵恢复FXR激活来介导IAS诱导的糖尿病。我们的坚强 团队（Lu Dr.Lu，Sartor，Styblo和McDermott）在IAS毒性，肠道微生物组，IAS方面具有免费的专业知识 代谢和IAS诱导的糖尿病。我们使用创新的技术来表征很多未知的 IAS诱导的糖尿病中的肠道微生物组孔酸-FXR的贡献，该项目与主题一致 UNC-SRP的“识别新的方法来减少IAS暴露和阐明IAS的基础机制 诱导的代谢功能障碍具有预防疾病的愿景。”肠道的高度修改性质 微生物组和对微生物组在疾病中的作用的深入机理理解将使我们能够发展 通过靶向肠道微生物组和相关信号来降低IAS诱导的糖尿病的新新方法 分子。