Intestine FXR activation by LGG-derived nanoparticles in alcohol-associated liver disease

LGG 衍生纳米颗粒在酒精相关性肝病中激活肠道 FXR

• 批准号: 10531712
• 负责人: WENKE FENG
• 金额: $ 53.2万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531712
• 关键词: Alcohols; Animal Model; Attenuated; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Biological Markers; Biological Process; Cessation of life; Cholestasis; Clinical Research; Clinical Trials; Communities; Data; Detergents; Development; Down-Regulation; Enzymes; Epithelial Cells; Evaluation; Exhibits; FDA approved; FGF19 gene; Fatty Liver; Fatty acid glycerol esters; Feces; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genetic Transcription; Goals; Hepatic; Hepatitis; Hepatocyte; Homeostasis; Hormones; Human; Intestines; Knock-out; Knowledge; Lactobacillus casei rhamnosus; Lead; Ligands; Lipids; Liver; Liver diseases; Mediating; Medical; MicroRNAs; Molecular; Mus; Nuclear Receptors; Pathology; Pathway interactions; Patients; Pharmacology; Play; Prevention strategy; Probiotics; Property; Receptor Activation; Regulation; Reporting; Role; Sampling; Serum; Signal Transduction; Signaling Molecule; Supplementation; Testing; Therapeutic; Transcriptional Activation; Translating; Treatment Efficacy; Urine; absorption; alcohol abuse therapy; base; exosome; feeding; gut microbiome; gut microbiota; improved; interest; intestinal epithelium; lipid biosynthesis; liver injury; mRNA Expression; mouse model; nanoparticle; novel therapeutic intervention; overexpression; probiotic supplementation; protective effect; receptor

Numerous studies have reported the efficacy of probiotics for alcohol associated liver disease (ALD). This reflects a strong interest among the scientific and medical communities in identifying alternative or adjunctive approaches for ALD, for which there is no current effective or widely accepted therapeutic option. However, in depth molecular knowledge on how probiotics render their effects is lacking. Patients with ALD often exhibit manifestations of cholestasis, a liver pathology defined by accumulation of hepatic bile acids (BAs), which are toxic and are an important causative factor in hepatocyte death and liver injury in ALD. Excess hepatic BA concentration is partially a result of increased BA de novo synthesis. We have identified a miRNA (miR194) that is overexpressed in the intestinal epithelial cells in mice fed alcohol. MmiR194 suppresses a nuclear receptor FXR that is activated by BAs and regulates intestine-derived hormone, FGF15, expression, which plays a major role in maintaining hepatic BA homeostasis by suppressing BA synthesis via down-regulation of Cyp7A1. While the BA activation of FXR is well-studied, how FXR is regulated transcriptionally is less clear. Our preliminary data showed that probiotic Lactobacillus rhamnosus GG-derived nanoparticles (LDNPs) administration reduced intestinal miR194 and increased FXR and FGF15 expression, and decreased hepatic BAs and fatty liver in mice with ALD. We hypothesize that alcohol suppresses both the transcriptional expression and ligand-mediated activation of FXR in the intestine through upregulating miR194 and disturbing gut-microbiome-BA transformation, respectively, which lead to the increases in hepatic de novo BA synthesis, lipogenesis and ALD and that LDNP supplementation can diminish alcohol-induced increases in BA synthesis and lipogenesis and attenuate ALD through suppressing intestinal miR194 expression and regulating gut microbiome BA transformation. The following specific aims will be pursued to test this hypothesis: Aim 1. Determine the role of intestinal miR194 in the alcohol-induced dysregulation of liver BA synthesis and lipogenesis. Aim 2. Determine the role of LDNPs in the regulation of intestinal miR194-FXR-FGF15 signaling in ALD. AIM 3. Determine whether LDNP treatment alters gut microbiota and BA profile that contribute to FXR activation in ALD. Aim 4. Evaluate the intestinal miR194 and FXR activity in patients with AH. In summary, the proposed study represents the first molecular study on how intestinal miRNA regulates liver BA homeostasis and how a probiotic product targets intestinal miRNA194-FXR-FGF15 singling in ALD. The results obtained from this study may lead to improved management of ALD.

许多研究报告了益生菌对酒精相关性肝病 (ALD) 的功效。这 反映了科学界和医学界对寻找替代或辅助药物的强烈兴趣 目前尚无有效或广泛接受的治疗选择。然而，在 目前缺乏关于益生菌如何发挥作用的深入分子知识。 ALD 患者经常表现出 胆汁淤积的表现，这是一种由肝胆汁酸（BA）蓄积定义的肝脏病理学，其是 有毒，是ALD肝细胞死亡和肝损伤的重要致病因素。肝脏BA过多 浓度部分是由于 BA 从头合成增加的结果。我们已经鉴定出一种 miRNA (miR194) 在喂食酒精的小鼠的肠上皮细胞中过度表达。 MmiR194 抑制核受体 FXR 被 BA 激活并调节肠源性激素 FGF15 的表达，该激素在 通过下调 Cyp7A1 抑制 BA 合成，在维持肝脏 BA 稳态中发挥作用。尽管 FXR 的 BA 激活已得到充分研究，但 FXR 的转录调控方式尚不清楚。我们的初步 数据显示，益生菌鼠李糖乳杆菌 GG 衍生纳米颗粒 (LDNP) 的施用可减少 肠道 miR194 并增加 FXR 和 FGF15 表达，并减少小鼠肝脏 BA 和脂肪肝 与酒精性肝病。我们假设酒精抑制转录表达和配体介导的 通过上调 miR194 和干扰肠道微生物组 BA 转化来激活肠道中的 FXR， 分别导致肝脏从头合成 BA、脂肪生成和 ALD 以及 LDNP 增加 补充剂可以减少酒精引起的 BA 合成和脂肪生成增加，并减轻 ALD 通过抑制肠道 miR194 表达并调节肠道微生物组 BA 转化。这 我们将追求以下具体目标来检验这一假设： 目标 1. 确定肠道 miR194 在 酒精引起的肝脏 BA 合成和脂肪生成失调。目标 2. 确定 LDNP 在 ALD 中肠道 miR194-FXR-FGF15 信号传导的调节。 AIM 3. 确定是否进行LDNP治疗 改变肠道微生物群和 BA 谱，有助于 ALD 中 FXR 的激活。目标 4. 评估肠道 AH 患者的 miR194 和 FXR 活性。总之，拟议的研究代表了第一个分子 研究肠道 miRNA 如何调节肝脏 BA 稳态以及益生菌产品如何靶向肠道 ALD 中的 miRNA194-FXR-FGF15 单选。这项研究获得的结果可能会改善管理 酒精性肝病。