Project 3: Gut microbiome -arsenic- diabetes interactions

摘要：项目3 接触无机砷(IAS)影响着世界各地的大量人口，并导致许多人类 疾病，包括糖尿病。项目3解决了在理解潜在机制方面的一个根本差距 IAS诱导的糖尿病--特别是肠道微生物组的作用。胰岛素样生长因子与糖尿病的关系 已经在众多的流行病学研究中得到了证实。我们和其他人也证明了IAS 导致小鼠葡萄糖和胰岛素代谢紊乱。肠道微生物群对 人类健康通过其在代谢调节中的关键作用，并成为一个有希望的干预目标 和治疗对人类健康的影响。越来越多的证据支持肠道微生物群和 法尼类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。我们的 研究是最早证明IAS和肠道微生物组之间的功能相互作用的研究之一。不过， IAS改变的肠道微生物群如何影响糖尿病风险仍有待确定。尤其是， IAS-微生物-宿主串扰的分子机制在很大程度上是未知的。这表示一个 IAS-微生物组研究方面的重大差距，这也阻碍了基于机制的干预措施 以肠道微生物组及其代谢功能为靶点的砷致糖尿病。我们的中心假设 肠道微生物组的调节将作为减少IAS干扰的代谢的一种方法 功能障碍/糖尿病。具体地说，IAS改变的肠道微生物群破坏胆汁酸以抑制FXR，进而抑制FXR 改变糖异生和胰岛素信号转导。我们强劲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，并强调了通过靶向FXR来调节IAS毒性的可能性 通过微生物组。为了验证这一假设，我们将追求三个具体目标：目标1：建立功能联系 肠道微生物区系改变和IAS胆汁酸代谢受损之间的关系；目的2：确定抑制的影响 在IAS诱导的肠道微生物群失调的驱动下，FXR激活对糖异生和胰岛素信号转导；以及 目的3：通过肠道微生物组操作恢复FXR的激活，从而介导IAS诱导的糖尿病。我们的强者 团队(Lu博士、Sartor博士、Styblo博士和McDermott博士)在IAS毒性、肠道微生物组、IAS方面拥有丰富的专业知识 代谢和IAS诱导的糖尿病。我们使用创新的技术来刻画大部分未知的 肠道微生物组-胆汁酸-FXR在IAS诱导的糖尿病中的贡献，该项目符合主题 《联合国气候变化框架公约》--《确定减少国际会计准则暴露的新方法和阐明国际会计准则背后的机制》-- 导致代谢功能障碍，并着眼于疾病预防。肠道的高度可变化性 微生物组和深入了解微生物组在疾病中的作用将使我们能够发展 通过靶向肠道微生物组和相关信号来减少IAS诱导的糖尿病的新的有形方法 分子。

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.