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

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $531,959

## Abstract

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.

## Key facts

- **NIH application ID:** 10531712
- **Project number:** 1R01AA030424-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** WENKE FENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,959
- **Award type:** 1
- **Project period:** 2022-08-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531712

## Citation

> US National Institutes of Health, RePORTER application 10531712, Intestine FXR activation by LGG-derived nanoparticles in alcohol-associated liver disease (1R01AA030424-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10531712. Licensed CC0.

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