"A microbiome-dependent bile acid metabolite improves type 2 diabetes."

“微生物组依赖性胆汁酸代谢物可改善 2 型糖尿病。”

• 批准号: 10543112
• 负责人: Eric Garland Sheu
• 金额: $ 66.58万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-08 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543112
• 关键词: Ablation; Agonist; Animals; Antidiabetic Drugs; Bacteria; Bariatrics; Bile Acids; Biochemical; Body Composition; Body Weight decreased; Cholic Acids; Chronic; Circulation; Diabetic mouse; Disease remission; Distal; Dose; Enzymes; Feces; Foundations; GPBAR1 gene; Gastrectomy; Germ-Free; Glucose; Goals; Grant; Hepatic; Hepatocyte; Human; In Vitro; Individual; Intestines; Knockout Mice; L Cells; Laboratories; Lead; Ligands; Lithocholic Acid; Liver; Long-Term Effects; Mediating; Metabolic; Metabolism; Molecular; Mus; NMR Spectroscopy; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Operative Surgical Procedures; Operon; Oral; Pathway interactions; Patients; Portal vein structure; Production; Property; Public Health; Research; Resolution; Role; Signal Pathway; Signal Transduction; Suggestion; Sulfate; Testing; Therapeutic; Translations; Vitamin D3 Receptor; Weight; Work; bariatric surgery; diet-induced obesity; effective therapy; feeding; glucagon-like peptide 1; glucose metabolism; glucose tolerance; improved; in vivo; incretin hormone; insulin secretion; insulin sensitivity; insulin tolerance; knock-down; liver ablation; metabolic phenotype; microbial; microbial products; microbiome; novel; obesity treatment; operation; peripheral blood; receptor; receptor expression; reconstitution; response; side effect; small hairpin RNA; small molecule; vector

Project Summary/Abstract The molecular mechanisms that explain the potent anti-diabetic effects of bariatric surgery remain elusive. The rapid nature of type 2 diabetes mellitus (T2D) remission after surgery have led to the suggestion that unidentified small molecules are responsible. For sleeve gastrectomy (SG), the most common bariatric operation performed today, knockout mouse studies have shown that bile acid receptors are critical for surgery’s metabolic benefits. The key ligand(s) that are changed post-SG to engage these bile acid receptors is unknown. Work from our laboratory has identified a bile acid metabolite, cholic acid 7-sulfate (CA7S), that is induced in the intestine by SG. We have found that CA7S is a potent TGR5 agonist that improves glucose handling in diabetic mice, and the production of CA7S occurs in the liver by sulfation of cholic acid in response to the gut microbial product, lithocholic acid (LCA), that signals via the hepatic vitamin D receptor (VDR). Our long-term goal is to understand and replicate less invasively the anti-diabetic mechanisms of bariatric surgery. The overall objective of this application is to define the anti-diabetic properties of CA7S, the microbiome-dependent mechanisms of CA7S production, and CA7S contribution to T2D remission following SG. Our central hypothesis is that CA7S is produced in response to gut microbial metabolites and improves T2D following SG via intestinal TGR5 activation. We will test this hypothesis in the following specific aims. In Aim 1, we will determine the effects of long-term CA7S administration on insulin sensitivity, glucose tolerance, and weight in diet induced obese (DIO) mice and TGR5 deficient mice to understand the global metabolic effects of CA7S and sustained intestinal TGR5 activation. In Aim 2, we will determine how the microbiome induces CA7S production by (1) quantifying LCA- producing Clostridia bacterial species and expression of LCA-producing enzymes post-SG in mice and humans, and (2) generating DIO mice with and without intestinal LCA and assessing their metabolic phenotype and response to SG. In Aim 3, we will determine the role of CA7S in T2D improvement post-SG. We will perform SG in VDR deficient mice, which lack endogenous CA7S, or in mice with knockdown of SULT2A1, the key enzyme responsible for CA7S production. We will reconstitute CA7S by exogenous replacement in CA7S deficient animals to determine the contribution of CA7S to surgical improvements in glucose metabolism. This work will characterize the effects of a natural, gut-restricted TGR5 agonist, CA7S, on T2D and lay the foundation for its translation as a therapeutic. By characterizing specific metabolite-receptor interactions within the intestine, portal vein, and liver, we will define a novel, microbiome-dependent, gut-liver signaling pathway that explains improvement in glucose metabolism after SG. This work will significantly advance our molecular understanding of the causal mechanisms of bariatric surgery and identify multiple novel targets for the treatment of T2D.

项目总结/摘要 解释减肥手术有效抗糖尿病作用的分子机制仍然难以捉摸。的 手术后2型糖尿病（T2 D）缓解的快速性质导致了以下建议： 小分子是罪魁祸首。对于袖状胃切除术（SG），最常见的减肥手术 今天，基因敲除小鼠的研究表明，胆汁酸受体对手术的代谢益处至关重要。 SG后发生变化以接合这些胆汁酸受体的关键配体尚不清楚。从我们的工作 一个实验室已经确定了一种胆汁酸代谢物，胆酸7-硫酸盐（CA 7S），它是由肠道内的 SG.我们发现CA 7S是一种有效的TGR 5激动剂，可改善糖尿病小鼠的葡萄糖处理， 在肝脏中通过响应于肠道微生物产物的胆酸硫酸化产生CA 7S， 石胆酸（LCA），通过肝脏维生素D受体（VDR）发出信号。我们的长期目标是了解 并以较少的侵入性复制减肥手术的抗糖尿病机制。本报告的总体目标 应用是定义CA 7S的抗糖尿病特性，CA 7S的微生物组依赖性机制， 生产和CA 7S对SG后T2 D缓解的贡献。我们的中心假设是CA 7S是 在响应于肠道微生物代谢物产生的，并通过肠道TGR 5活化改善SG后的T2 D。 我们将在以下具体目标中检验这一假设。在目标1中，我们将确定长期 CA 7S给药对饮食诱导的肥胖（DIO）小鼠中胰岛素敏感性、葡萄糖耐量和体重的影响， TGR 5缺陷小鼠，以了解CA 7S和持续肠TGR 5的整体代谢作用 activation.在目标2中，我们将通过以下方式确定微生物组如何诱导CA 7S产生：（1）定量LCA-1。 产生梭菌属细菌物种和在小鼠和人中SG后表达LCA产生酶， 和（2）产生具有和不具有肠LCA的DIO小鼠，并评估它们的代谢表型， 回复SG。在目标3中，我们将确定CA 7S在SG后T2 D改善中的作用。我们将执行 VDR缺陷小鼠（缺乏内源性CA 7S）或SULT 2A 1敲除小鼠中的SG是关键 负责CA 7S生产的酶。我们将通过外源性替代CA 7S来重建CA 7S 缺陷动物，以确定CA 7S对葡萄糖代谢的手术改善的贡献。这 这项工作将描述一种天然的肠道限制性TGR 5激动剂CA 7S对T2 D的影响，并为研究T2 D奠定基础。 因为它被翻译成了一种治疗剂通过表征肠内特定的代谢物-受体相互作用， 门静脉和肝脏，我们将定义一种新的，微生物组依赖的，肠道-肝脏信号通路， SG后葡萄糖代谢改善。这项工作将大大推进我们对分子的理解 肥胖手术的因果机制，并确定多个新的目标，用于治疗T2 D。