"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.

项目摘要/摘要 解释减肥手术潜在抗糖尿病作用的分子机制仍然难以捉摸。 手术后2型糖尿病（T2D）缓解的快速性质导致了未识别的建议 小分子是负责的。对于袖子止淋巴结术（SG），执行的最常见的减肥手术 如今，小鼠研究表明，胆汁酸受体对于手术的代谢益处至关重要。 SG后改变以吸引这些胆汁酸受体的关键配体尚不清楚。我们的工作 实验室已经鉴定出胆汁酸代谢物，胆酸7-硫酸盐（CA7S），该硫酸盐（CA7S）在肠中诱导 SG。我们发现CA7S是一种潜在的TGR5激动剂，可改善糖尿病小鼠的葡萄糖处理，并且 Ca7s的产生是通过胆汁酸的肠胃硫酸对肠道微生物产物的硫酸的产生。 岩性酸（LCA），通过肝维生素D受体（VDR）发出信号。我们的长期目标是了解 并降低了减肥手术的抗糖尿病机制。总体目标 应用是定义CA7的抗糖尿病特性，CA7S的微生物组依赖机制 生产和CA7在SG之后对T2D缓解的贡献。我们的中心假设是CA7是 响应肠道微生物代谢物而产生的，并通过肠道TGR5激活改善了T2D。 我们将在以下特定目标中检验这一假设。在AIM 1中，我们将确定长期的影响 饮食诱导肥胖（DIO）小鼠的胰岛素敏感性，葡萄糖耐受性和体重的CA7S给药 TGR5不足的小鼠了解CA7和持续肠道TGR5的全球代谢作用 激活。在AIM 2中，我们将确定微生物组如何通过（1）量化LCA-诱导CA7S的产生 在小鼠和人类中产生梭状芽胞杆菌种类和产生LCA的酶的表达， （2）产生有无肠LCA的DIO小鼠，并评估其代谢表型和 对SG的反应。在AIM 3中，我们将确定CA7在T2D改进后SG中的作用。我们将表演 缺乏内源性CA7的VDR缺陷小鼠或sult2a1敲低的小鼠中的SG（钥匙） 负责CA7S生产的酶。我们将通过CA7中的外源替换来重建CA7 不足的动物以确定CA7对葡萄糖代谢的手术改善的贡献。这 工作将表征天然，肠道限制的TGR5激动剂，CA7S对T2D的影响，并奠定基础 因为它翻译为治疗性。通过表征肠内特定的代谢产物 - 受体相互作用， 门静脉和肝脏，我们将定义一种新颖的微生物组依赖性的肠肝信号通路，该途径解释了 SG后葡萄糖代谢的改善。这项工作将大大提高我们的分子理解 减肥手术的因果机制，并确定了T2D治疗的多个新靶标。