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: 10794805
• 负责人: WENKE FENG
• 金额: $ 51.98万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794805
• 关键词: Alcoholic Hepatitis; Alcoholic Liver Diseases; 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; Ligands; Lipids; Liver; Liver diseases; Mediating; Medical; MicroRNAs; Molecular; Mus; Nuclear Receptors; Pathology; Pathway interactions; Patients; 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; exosome; feeding; gut microbiome; gut microbiota; improved; interest; intestinal epithelium; lipid biosynthesis; liver injury; mRNA Expression; mouse model; nanoparticle; novel therapeutic intervention; overexpression; pharmacologic; posttranscriptional; probiotic supplementation; probiotic therapy; 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性肝病（ALD）的疗效。这