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: 10617180
• 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/10617180
• 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; Engraftment; 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; theories; 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.

项目摘要/摘要 目前，美国有3420万成年人患有糖尿病，约占总人口的10.3%。这个 退伍军人的糖尿病患病率是退伍军人的两倍(20.5%)，是肾衰竭的主要原因， 在退伍军人和普通人群中，都存在截肢和成人致盲。在过去的几年里 二十年来，多项新陈代谢研究表明，胆汁酸发挥着意想不到但却很重要的作用 在血糖稳态和代谢综合征中的作用。相关的16s和元基因组学研究表明 肠道微生物区系可通过胆汁酸的修饰影响宿主的血糖稳态。这个项目的总体目标是 建议确定肠道微生物区系影响宿主葡萄糖动态平衡的机制。为了拥有 为了更好地了解这种关系的功能，研究人员需要评估特定细菌的作用 胆汁酸的生物转化及其对肠道生态、代谢产物和代谢产物通量的影响 营养，并最终在常规培养(而不是微生物组耗尽)宿主中的生理学。因此， 迫切需要一种工具来帮助将特定的细菌功能敲入肠道 微生物组，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的策略，该策略使用工程原生技术解决了这一需求 细菌。这种新的方法可以快速有效地将有益的功能输入肠道 微生物组。这种作用是持续的，可能是永久的，在传统上提高的宿主中具有单一的 治疗，而不需要微生物群枯竭。到目前为止，调查人员已经证明 易驯服的本地细菌可以被改造成在体外修饰胆汁酸，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。这些功能会影响宿主的生理，并有可能缓解疾病。 使用这一新方法，调查人员将通过解决以下中心假设来追求总体目标 肠道微生物群通过胆汁酸去结合作用影响宿主的胰岛素敏感性，这些功能可以 用于治疗2型糖尿病。 在接下来的四年里，调查人员将以三个具体目标来研究该提案的核心假说。 第一个目标是确定细菌胆汁酸解结合是否会影响回肠和肝脏的糖调节转录本。 在常规饲养的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、糖异生和胰岛素的产生。第二个目标是 确定微生物胆汁酸解结合的血糖调节效应是否由法尼醇X介导 受体(FXR)，一种主要的胆汁酸受体。这将使用经过工程改造的原生细菌来完成。 FXR基因敲除小鼠的BSH。最终，这一目标将决定FXR在调解中的作用的重要性 肠道微生物群的代谢效应。第三个目标将决定饮食如何影响细菌胆汁酸。 去共轭对宿主代谢动态平衡的影响，使用饮食诱导肥胖模型(这两种模型 使用高脂肪饮食)和肥胖/肥胖小鼠(使用正常饮食)。因为胆汁酸信号很强 受饮食的影响，这一目标将进一步阐明细菌胆汁酸修饰、营养 摄取和宿主的糖调节反应。 这些研究的预期结果是更好地了解a)肠道微生物群如何影响宿主 血糖调节和b)肠道微生物组是否可以被操纵来改善胰岛素敏感性。这个 结果将产生积极的翻译影响，因为它将导致使用T2D的新治疗靶点 肠道微生物群所采用的信号通路和功能。