The Role of Bile Salt Hydrolase in Glucose Metabolism

胆盐水解酶在葡萄糖代谢中的作用

• 批准号: 10365160
• 负责人: Amir Zarrinpar
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365160
• 关键词: Address; Adult; Affect; Agonist; Back; Bacteria; Bile Acids; Blindness; Blood Glucose; Cholesterol Homeostasis; Data; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Fats; Dietary intake; Disease; Ecology; Energy Metabolism; Engineering; Environment; Enzymes; Escherichia coli; General Population; Genes; Gluconeogenesis; Glucose; Goals; Health; Hepatic; High Fat Diet; Homeostasis; Hormones; Hydrolase; Immune response; Insulin; Intake; Kidney Failure; Knock-in; Knockout Mice; Link; Lower Extremity; Mediating; Metabolic; Metabolic Biotransformation; Metabolic syndrome; Metabolism; Metagenomics; Mission; Modeling; Modification; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Outcome; Outcome Study; Performance; Physiological; Physiology; Play; Population; Prevalence; Production; Research; Research Personnel; Ribosomal RNA; Role; Serum; Signal Pathway; Signal Transduction; Source; Testing; Transcript; United States Department of Veterans Affairs; Veterans; Wild Type Mouse; absorption; antagonist; bile salts; blood glucose regulation; diet-induced obesity; glucose metabolism; glucose tolerance; glycogenesis; gut microbiome; gut microbiota; hepatic gluconeogenesis; improved; innovation; insulin sensitivity; interest; limb amputation; metabolic abnormality assessment; microbial; microbiome; microbiome research; microorganism; mortality; muricholic acid; new therapeutic target; novel strategies; receptor; research and development; response; tool; transcriptome sequencing; translational impact; vector

PROJECT SUMMARY/ABSTRACT Currently, 34.2 million US adults, or approximately 10.3% of the total population, have diabetes. The prevalence of diabetes is two-fold higher among Veterans (20.5%) and it is the leading cause of kidney failure, lower-limb amputations, and adult-onset blindness both in Veterans and the general population. Over the last two decades, multiple metabolic studies have demonstrated that bile acids play an unexpected but important role in glucose homeostasis and metabolic syndrome. Correlational 16S and metagenomic studies suggest that gut microflora can affect host glucose homeostasis through modification of bile acids. The overall goal of this proposal is to determine the mechanisms by which the gut microflora affect host glucose homeostasis. To have a better functional understanding of this relationship, investigators need to assess the role of specific bacterial bile acid biotransformations and investigate their effects on the gut luminal ecology, the flux of metabolites and nutrients, and ultimately, physiology in conventionally-raised (as opposed to microbiome-depleted) hosts. Thus, there is a critical need for a tool that will facilitate knocking-in of specific bacterial functions into the gut microbiome and investigate their effects on the host glucose metabolism and insulin sensitivity. The investigators demonstrate an innovative strategy that addresses this need using engineered native bacteria. This novel approach allows quick and effective knocking-in of a beneficial function into the gut microbiome. The function is sustained, potentially for perpetuity, in conventionally-raised hosts with a single treatment and without the need for microbiome depletion. To date, the investigators have demonstrated that tractable native bacteria can be engineered to modify bile acids ex vivo, reintroduced to the host, engraft the entire gut, deliver an intended beneficial function, alter luminal and serum metabolites as intended, affect host metabolism, and even reverse disease. These functions affect host physiology and potentially alleviate disease. Using this new approach, the investigators will pursue the overall goal by addressing the central hypothesis that gut microbiome affects host insulin sensitivity through bile acid deconjugation and that these functions can be used to treat type 2 diabetes. In the next four years, the investigators will pursue the proposal's central hypothesis with three specific aims. The first aim will determine if bacterial bile acid deconjugation affects ileal and hepatic glucoregulatory transcripts in conventionally-raised C57Bl6 mice. Ultimately this aim will determine the relationship between bacterial bile acid modification and host bile acid signaling, gluconeogenesis, and incretin production. The second aim will determine if the glucoregulatory effects of microbial bile acid deconjugation are mediated by the farnesoid X receptor (FXR), a major bile acid receptor. This will be done using engineered native bacteria with and without BSH in FXR knockout mice. In the end, this aim will determine the importance of the role of FXR in mediating the metabolic effects of gut microbiome. The third aim will determine how diet affects the bacterial bile acid deconjugation influence on the host metabolic homeostasis, using both the diet-induced obesity model (which uses a high-fat diet) and ob/ob mice (which uses normal chow diet). Because bile acid signaling is heavily influenced by diet, this aim will further elucidate the relationship between bacterial bile acid modifications, nutrient intake, and host glucoregulatory response. The expected outcome of these studies is a better understanding of a) how the gut microbiome affects host glucose regulation and b) whether the gut microbiome can be manipulated to improve insulin sensitivity. The outcome will have a positive translational impact because it will lead to novel therapeutic targets to T2D using the signaling pathways and functions employed by the gut microbiome.

项目概要/摘要 目前，3420 万美国成年人（约占总人口的 10.3%）患有糖尿病。这 退伍军人中糖尿病的患病率是其两倍（20.5%），它是肾衰竭的主要原因， 退伍军人和普通人群的下肢截肢和成人失明。过去的 二十年来，多项代谢研究表明胆汁酸发挥着意想不到但重要的作用 在葡萄糖稳态和代谢综合征中的作用。相关 16S 和宏基因组研究表明 肠道菌群可以通过胆汁酸的修饰影响宿主葡萄糖稳态。本次活动的总体目标 该提案的目的是确定肠道微生物群影响宿主葡萄糖稳态的机制。拥有 为了更好地理解这种关系，研究人员需要评估特定细菌的作用 胆汁酸生物转化并研究其对肠道腔生态、代谢物通量和 营养物质，最终是传统饲养（而不是微生物组耗尽）宿主的生理学。因此， 迫切需要一种工具来促进将特定细菌功能敲入肠道 微生物组并研究它们对宿主葡萄糖代谢和胰岛素敏感性的影响。 研究人员展示了一种创新策略，可以使用工程原生来满足这一需求 细菌。这种新颖的方法可以快速有效地将有益功能敲入肠道 微生物组。在传统饲养的宿主中，该功能是持续的，有可能是永久的。 治疗且无需消除微生物组。迄今为止，研究人员已经证明， 可以对易处理的天然细菌进行工程改造，以离体修饰胆汁酸，重新引入宿主，植入 整个肠道，提供预期的有益功能，按预期改变管腔和血清代谢物，影响宿主 新陈代谢，甚至逆转疾病。这些功能影响宿主生理机能并有可能减轻疾病。 使用这种新方法，研究人员将通过解决以下中心假设来追求总体目标： 肠道微生物组通过胆汁酸解偶联影响宿主胰岛素敏感性，这些功能可以通过 用于治疗2型糖尿病。 在接下来的四年中，研究人员将通过三个具体目标来追求该提案的中心假设。 第一个目标是确定细菌胆汁酸解离是否影响回肠和肝脏葡萄糖调节转录本 在传统饲养的 C57Bl6 小鼠中。最终这个目标将决定细菌胆汁之间的关系 酸修饰和宿主胆汁酸信号传导、糖异生和肠降血糖素产生。第二个目标将 确定微生物胆汁酸解离的葡萄糖调节作用是否由法尼醇 X 介导 受体（FXR），一种主要的胆汁酸受体。这将使用工程化的天然细菌来完成，有或没有 FXR 基因敲除小鼠中的 BSH。最终，这个目标将决定 FXR 在调解中的作用的重要性 肠道微生物组的代谢影响。第三个目标将确定饮食如何影响细菌胆汁酸 使用饮食诱导的肥胖模型（其中 使用高脂肪饮食）和 ob/ob 小鼠（使用正常饮食）。因为胆汁酸信号传导很严重 受饮食影响，该目标将进一步阐明细菌胆汁酸修饰、营养物质之间的关系 摄入量和宿主的葡萄糖调节反应。 这些研究的预期结果是更好地了解 a) 肠道微生物组如何影响宿主 葡萄糖调节；b) 是否可以操纵肠道微生物组来提高胰岛素敏感性。这 结果将产生积极的转化影响，因为它将导致使用 T2D 的新治疗靶点 肠道微生物组采用的信号传导途径和功能。