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

基本信息

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
项目类别：
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

项目摘要

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 接触无机砷 (iAs) 会影响全世界大量人口，并导致许多人类健康问题。项目 3 解决了理解潜在机制方面的根本差距。 iAs 诱发的糖尿病——特别是肠道微生物组的作用 iAs 与糖尿病之间的关联。我们和其他人也已经在许多流行病学研究中证实了 iAs。引起小鼠葡萄糖和胰岛素代谢失调。肠道微生物组对小鼠具有深远的影响。通过其在代谢调节中的关键作用来影响人类健康，并成为有希望的干预目标越来越多的证据支持肠道微生物组的作用和法尼醇 X 受体 (FXR) 在动物和人类糖尿病的发病机制和预防中的作用。研究是最早证明 iAs 和肠道微生物组之间功能相互作用的研究之一。 iAs 改变的肠道微生物组到底如何影响糖尿病风险仍有待确定。 iAs-微生物组-宿主串扰的分子机制很大程度上是未知的。 iAs-微生物组研究存在巨大差距，这也阻碍了基于机制的干预措施，以减少我们的中心假设是通过针对肠道微生物组及其代谢功能而诱发糖尿病。肠道微生物组的调节将作为减少 iAs 扰动代谢的一种方法具体来说，iAs 改变的肠道微生物组会破坏胆汁酸以抑制 FXR，从而抑制 FXR。我们可靠的初步数据强调了微生物组的关键作用。胆汁酸-FXR 轴在 iAs 诱导的糖尿病中的作用，并强调通过靶向 FXR 调节 iAs 毒性的潜力为了检验这一假设，我们将追求三个具体目标：目标 1：建立功能联系。肠道微生物群改变与 iAs 胆汁酸代谢受损之间的关系目标 2：确定受抑制的影响；由 iAs 诱导的肠道微生物群失调驱动的 FXR 激活对糖异生和胰岛素信号传导的影响；目标 3：通过肠道微生物组恢复 FXR 激活来介导 iAs 诱发的糖尿病。团队（Lu 博士、Sartor、Styblo 和 McDermott）在 iAs 毒性、肠道微生物组、iAs 方面拥有互补的专业知识我们使用创新技术来表征很大程度上未知的疾病。肠道微生物组-胆汁酸-FXR 在 iAs 诱发的糖尿病中的贡献，该项目符合主题 UNC-SRP 的“确定减少 iAs 暴露的新方法并阐明 iAs 的潜在机制” 肠道的高度可改变性可以诱导代谢功能障碍。” 微生物组以及对微生物组在疾病中作用的深入机制了解将使我们能够开发通过针对肠道微生物组和相关信号传导来减少 iAs 诱发的糖尿病的新切实方法分子。