"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: 10327309
• 负责人: Eric Garland Sheu
• 金额: $ 66.53万
• 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/10327309
• 关键词: Agonist; Animals; Antidiabetic Drugs; Bacteria; Bariatrics; Bile Acids; Biochemical; Blood Circulation; Body Composition; Body Weight decreased; Cholic Acids; Chronic; Conflict (Psychology); 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; metabolic phenotype; microbial; 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 减肥手术强大的抗糖尿病效果的分子机制仍然不清楚。这个 2型糖尿病(T2D)手术后迅速缓解的性质导致了不明原因的建议 小分子对此负有责任。对于袖状胃切除术，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新陈代谢益处至关重要。 SG术后与胆汁酸受体结合的关键配体(S)尚不清楚。从我们的工作 实验室已经确定了一种胆汁酸代谢物7-硫酸胆酸(CA7S)，它在肠道中由 SG.我们发现CA7S是一种有效的TGR5激动剂，可以改善糖尿病小鼠的葡萄糖处理能力，并且 在肝脏中，CA7S的产生是通过胆酸的硫酸反应肠道微生物产物而发生的。 石胆酸(LCA)，通过肝脏维生素D受体(VDR)传递信号。我们的长期目标是了解 并且更少侵入性地复制减肥手术的抗糖尿病机制。这样做的总体目标是 应用是确定CA7S的抗糖尿病特性，CA7S的微生物组依赖机制 生产，以及CA7S对SG后T2D缓解的贡献。我们的中心假设是CA7S是 对肠道微生物代谢产物作出反应，并通过肠道TGR5激活改善SG后的T2D。 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 CA7S对饮食诱导肥胖(DIO)小鼠胰岛素敏感性、糖耐量和体重的影响 TGR5基因缺陷小鼠了解CA7S和持续肠道TGR5对整体代谢的影响 激活。在目标2中，我们将通过(1)量化LCA-2来确定微生物如何诱导CA7S的产生。 芽孢杆菌在小鼠和人体内的产生菌种及其产生酶的表达， (2)建立有肠道LCA和无肠道LCA的DIO小鼠，并对其代谢表型和 对SG的回应。在目标3中，我们将确定CA7S在SG术后T2D改善中的作用。我们将表演 缺乏内源性CA7S的VDR缺陷小鼠或关键基因SULT2A1被敲除的小鼠的SG 负责CA7S产生的酶。我们将通过在CA7S中进行外源替换来重建CA7S 以确定CA7S对外科手术改善葡萄糖代谢的贡献。这 工作将描述一种天然的、肠道受限的TGR5激动剂CA7S对T2D的影响，并奠定基础 因为它的翻译是一种治疗。通过描述肠道内特定代谢物-受体的相互作用， 门静脉和肝脏，我们将定义一种新的、依赖于微生物组的肠道-肝脏信号通路，以解释 术后糖代谢改善。这项工作将极大地促进我们对分子的理解 研究减肥手术的致病机制，并确定治疗T2D的多个新靶点。