R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease

R01：FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂

• 批准号: 10671560
• 负责人: Andrew Patterson
• 金额: $ 35.27万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671560
• 关键词: 16S ribosomal RNA sequencing; ADME Study; Address; Animals; Antioxidants; Bile Acid Biosynthesis Pathway; Bile Acids; Biochemical Pathway; Biological Availability; Biology; Ceramides; Chemical Engineering; Chemicals; Communities; Data; Development; Diet; Disease model; Enterohepatic Circulation; Enzymes; Excretory function; Genetic; Genetic Models; Glucose; Glycine; Goals; Human; In Vitro; Intestines; Knock-out; Knowledge; Laboratories; Lactobacillus; Lead; Link; Lipids; Liver; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolism; Metagenomics; Mixed Function Oxygenases; Modeling; Modification; Organic Synthesis; Pathogenesis; Pharmacodynamics; Prevention; Property; Receptor Signaling; Reporting; Research; Scientist; Signal Pathway; Signal Transduction; Small Intestines; Specificity; Techniques; Tissues; Toxic effect; Universities; Weight Gain; absorption; antagonist; bile salts; chronic liver disease; cost; design; diet-induced obesity; drug-like compound; genome-wide; gut microbiome; gut microbiota; host microbiota; in vivo; innovation; interest; metabolomics; metatranscriptomics; mid-career faculty; mouse model; muricholic acid; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; novel therapeutics; prevent; professor; programs; receptor; reconstruction; sensor; skills; tempol; therapeutic target

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most prevalent chronic liver diseases in the world, with non-alcoholic steatohepatitis (NASH) being an extreme form of NAFLD. Our team proposes to investigate the novel concept that intestine-selective FXR antagonism has the potential to prevent or reverse NAFLD/NASH. FXR is the major bile acid sensor in the body and serves to mediate the dialog between the liver and small intestine regarding bile acid levels, bile acid synthesis, transport, and enterohepatic circulation, and also regulates lipid and glucose levels in the liver. As such, FXR was identified in human trials as a promising target for the prevention and/or amelioration of many metabolic diseases, including NAFLD/NASH. We have recently established intestinal FXR as a major regulator of diet-induced obesity and NAFLD, particularly through antagonism of the receptor with the conjugated bile acid tauro-β-muricholic acid (TβMCA). We reported that tempol, a potent antioxidant, inhibited the FXR signaling pathway, due to accumulation of intestinal TβMCA, an antagonist of FXR, resulting from reduced activity of the Lactobacillus-associated bile salt hydroxylase enzyme. We further developed glycine-β-muricholic acid (GlyβMCA), a potent, intestine-selective FXR antagonist that similarly prevents or reversed NAFLD in diet-induced NAFLD models or genetic models, suggesting intestinal FXR as a promising therapeutic target for NAFLD. These observations have led to the novel central hypothesis: Antagonism of intestinal FXR prevents the development of NAFLD In this proposal we plan to address two fundamental gaps in knowledge with respect to FXR antagonism and NAFLD. First, we will identify using a combination of in vitro and in vivo approaches what chemical features define an FXR antagonist and develop a better understanding for how these modifications influence the absorption, distribution, metabolism, and excretion (ADME) of the antagonist and its pharmacodynamic properties. Second, through the innovative use of cutting-edge techniques—including 16S rRNA gene sequencing, metagenomics, metatranscriptomics, and metabolomics—and unique mouse models, we plan to identify how FXR signaling and the gut microbiota are linked in NAFLD pathogenesis. This combination of approaches will allow us to identify new therapeutic FXR antagonists and to accurately assess how these compounds influence downstream FXR signaling pathways with the ultimate goal of developing new NAFLD therapies.

摘要 非酒精性脂肪性肝病（NAFLD）是世界上最常见的慢性肝病之一。 非酒精性脂肪性肝炎（NASH）是NAFLD的一种极端形式。我们的团队建议 研究新的概念，即精氨酸选择性FXR拮抗作用有可能预防或逆转 NAFLD/NASH。FXR是体内主要的胆汁酸传感器，用于介导肝脏与肝脏之间的对话。 和小肠，关于胆汁酸水平、胆汁酸合成、转运和肠肝循环，以及 还调节肝脏中的脂质和葡萄糖水平。因此，FXR在人体试验中被确定为一种有前途的 靶向用于预防和/或改善许多代谢疾病，包括NAFLD/NASH。我们有 最近确定肠道FXR作为饮食诱导的肥胖和NAFLD的主要调节剂，特别是通过 结合胆汁酸牛磺-β-鼠胆酸（TβMCA）拮抗受体。我们报道了 Tempol是一种有效的抗氧化剂，由于肠道TβMCA的积累， FXR拮抗剂，由乳酸杆菌相关胆盐羟化酶活性降低引起。 我们进一步开发了甘氨酸-β-鼠胆酸（GlyβMCA），这是一种有效的肠道选择性FXR拮抗剂， 在饮食诱导的NAFLD模型或遗传模型中类似地预防或逆转NAFLD，这表明肠 FXR作为NAFLD的一个有前途的治疗靶点。这些观察导致了新的中心假设： 拮抗肠道FXR可预防NAFLD的发生 在本提案中，我们计划解决关于FXR拮抗作用的两个基本知识空白， NAFLD。首先，我们将使用体外和体内方法相结合来确定哪些化学特征 定义FXR拮抗剂，并更好地了解这些修饰如何影响 拮抗剂的吸收、分布、代谢和排泄（ADME）及其药效学 特性.第二，通过创新使用尖端技术--包括16 S rRNA基因 测序、宏基因组学、元转录组学和代谢组学以及独特的小鼠模型，我们计划 确定FXR信号传导和肠道微生物群在NAFLD发病机制中的联系。的这种组合 这些方法将使我们能够识别新的治疗性FXR拮抗剂，并准确评估这些拮抗剂的作用。 化合物影响下游FXR信号通路，最终目标是发展新的NAFLD 治疗

项目成果

Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer.

• DOI: 10.1038/s41467-023-36089-9
• 发表时间: 2023-02-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sun, Lulu;Zhang, Yi;Cai, Jie;Rimal, Bipin;Rocha, Edson R.;Coleman, James P.;Zhang, Chenran;Nichols, Robert G.;Luo, Yuhong;Kim, Bora;Chen, Yaozong;Krausz, Kristopher W.;Harris, Curtis C.;Patterson, Andrew D.;Zhang, Zhipeng;Takahashi, Shogo;Gonzalez, Frank J.
• 通讯作者: Gonzalez, Frank J.

Glycine-β-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice.

• DOI: 10.1002/hep4.2099
• 发表时间: 2022-12
• 期刊: Hepatology communications
• 影响因子: 5.1