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Principal Investigator: WENKE FENG
Organization: UNIVERSITY OF LOUISVILLE
Fiscal Year: 2022
Award: $531,959
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <Alcohol Chemical Class><Alcohols><Animal Model><Animal Models and Related Studies><Attenuated><Autoregulation><Bile Acid Biosynthesis><Bile Acid Biosynthesis Pathway><Bile Acids><Bile Duct Obstruction><Biliary Stasis><Binding><Biological Function><Biological Markers><Biological Process><Blood Serum><Cell Communication and Signaling><Cell Signaling><Cessation of life><Cholestasis><Clinical Research><Clinical Study><Clinical Trials><Communities><DNA Synthesis Factor><Data><Death><Detergents><Development><Down-Regulation><Downregulation><Endocrine Gland Secretion><Endothelial Cell Growth Factor><Enzyme Gene><Enzymes><Epithelial Cells><Evaluation><Exhibits><FDA approved><FGF><FGF Receptors><FGF-R><FGF19><FGF19 gene><FGFR><Fats><Fatty Liver><Fatty acid glycerol esters><Feces><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Factor Receptor Family><Fibroblast Growth Factor Receptors><Fibroblast Growth Regulatory Factor><Fibroblast growth factor 19><GI microbiome><GI microbiota><Gastrointestinal microbiota><Gene Transcription><Genetic Transcription><Goals><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatitis><Hepatocyte><Homeostasis><Hormones><Human><Injury to Liver><Intestinal><Intestines><Intracellular Communication and Signaling><Knock-out><Knockout><Knowledge><L rhamnosus><L. rhamnosus><Lactobacillus casei rhamnosus><Lactobacillus rhamnosus><Lead><Ligands><Lipids><Liver><Liver Cells><Liver Steatosis><Liver diseases><Mediating><Medical><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Nuclear Receptors><Pathology><Pathway interactions><Patients><Pb element><Pharmacology><Physiological Homeostasis><Play><Preventative strategy><Prevention strategy><Preventive strategy><Probiotics><Property><RNA Expression><Receptor Activation><Receptor Protein><Regulation><Reporting><Role><Sampling><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Supplementation><Testing><Therapeutic><Therapeutic Hormone><Transcription><Transcription Activation><Transcriptional Activation><Translating><Treatment Efficacy><Urine><Urine Urinary System><absorption><adipogenesis><alcohol abuse therapy><alcohol abuse treatment><alcohol treatment><base><bile acid anabolism><bile acid biosynthetic process><bile acid formation><bile acid synthesis><bile obstruction><bile occlusion><bio-markers><biologic marker><biological signal transduction><biomarker><bowel><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><developmental><digestive tract microbiome><enteric microbial community><enteric microbiome><enteric microbiota><exosome><feeding><gastrointestinal microbial flora><gastrointestinal microbiome><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><heavy metal Pb><heavy metal lead><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><improved><interest><intervention efficacy><intestinal biome><intestinal epithelium><intestinal flora><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><lipid biosynthesis><lipogenesis><liver damage><liver disorder><liver injury><mRNA Expression><miRNA><miRNAs><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><pathway><probiotic supplement><probiotic supplementation><protective effect><receptor><social role><stool><supplementation with probiotics><therapeutic efficacy><therapy efficacy>