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.

大量研究报道了益生菌对酒精相关肝病（ALD）的疗效。这 反映了科学和医学界对识别替代或辅助的浓厚兴趣 ALD的方法，目前没有有效或广泛接受的治疗选择。但是，在 关于益生菌如何缺乏其作用的深度分子知识。 ALD患者经常表现出来 胆汁淤积的表现，这是一种由肝胆汁酸（BAS）积累定义的肝病病理学（BAS） 有毒，是ALD中肝细胞死亡和肝损伤的重要病因。多余的肝ba 浓度部分是从头合成增加的结果。我们已经确定了miRNA（miR194） 在喂养酒精的小鼠的肠上皮细胞中过表达。 MMIR194抑制核受体 FXR被BAS激活并调节肠衍生的激素FGF15表达，它发挥了一项主要作用 通过下调CYP7A1，通过抑制BA合成来维持肝BA稳态的作用。尽管 FXR的BA激活经过了充分研究，如何在转录上调节FXR不太清楚。我们的初步 数据表明，益生菌乳酸乳杆菌GG衍生的纳米颗粒（LDNP）降低了 肠道miR194并增加了FXR和FGF15表达，并降低了小鼠的肝BAS和脂肪肝 与Ald。我们假设酒精抑制了转录表达和配体介导的 通过上调miR194和干扰肠道微生物组的转化，肠中FXR的激活， 分别导致从头ba合成，脂肪生成和ALD的增加以及LDNP的增加 补充可以减少酒精引起的BA合成和脂肪生成的增加，并减弱ALD 通过抑制肠道miR194表达并调节肠道微生物组BA转化。这 将追求以下特定目标来检验这一假设：目标1。确定肠道mir194在 酒精诱导的肝BA合成和脂肪生成的失调。目标2。确定LDNP在 ALD中肠道miR194-FXR-FGF15信号的调节。目标3。确定LDNP是否治疗 改变肠道微生物群和BA谱，导致ALD中的FXR激活。目标4。评估肠道 AH患者的miR194和FXR活性。总而言之，拟议的研究代表了第一个分子 研究肠道miRNA如何调节肝BA稳态以及益生菌产品如何靶向肠道 mirna194-fxr-fgf15 Ald中的单打。从这项研究中获得的结果可能会导致管理的改善 Ald。