# Probiotic and intestinal miR194 regulation of bile acid metabolism in alcoholic liver disease

> **NIH NIH F31** · UNIVERSITY OF LOUISVILLE · 2020 · $32,130

## Abstract

Patients with alcoholic liver disease (ALD) often exhibit manifestations of cholestasis, a liver pathology defined
by accumulation of hepatic bile acids (BAs), which are toxic and an important causative factor in hepatocyte
death and liver injury in ALD. Excess hepatic BA concentration is a result of increased BA de novo synthesis
and decreased BA secretion to bile. BA metabolism is regulated by farnesoid X receptor (FXR) signaling in
intestine and liver. Previous study suggests that intestinal FXR is likely a major player to regulate hepatic BA
synthesis. Intestinal FXR activation is regulated by gut lumen BA species and concentration. Primary BA
chenodeoxycholic acid (CDCA) is an agonist of FXR, which is antagonized by taurine-β-murine cholic acid
(TβMCA). Previous studies have demonstrated that gut BA is dysregulated in ALD patients and in experimental
ALD mice. Modulation of dysregulated BA signaling in the intestine improves experimental ALD. Interestingly,
our preliminary data showed that, in the NIAAA binge-on-chronic alcohol feeding model, intestinal FXR mRNA
was markedly reduced, along with decreased intestinal fibroblast growth factor (FGF) 15/19 (mouse/humans)
and increased hepatic Cyp7a1 expression, elevated BA concentration and liver injury. Targeting intestinal FXR,
both in transcription and in activation, may be a plausible strategy for inhibiting ALD. FXR transcription is
regulated by microRNA194 (miR194), which is highly expressed in the intestine. Our preliminary data showed
that alcohol feeding significantly increased intestinal miR194. Interestingly, miR194 is suppressed by taurine
upregulated gene 1(TUG1), a long non-coding RNA regulated by taurine concentration. Therefore, it is likely that
alcohol-induced miR194 causes a reduction of intestinal FXR in ALD. Supplementation of probiotic Lactobacillus
rhamnosus GG (LGG) is protective against experimental ALD through multiple mechanisms. Our preliminary
study showed that LGG suppressed alcohol-increased miR194 and -decreased FXR in the intestine. These
previous and preliminary studies strongly suggest that LGG may exert its function in hepatic BA synthesis
through modulation of intestinal miR194-FXR signaling. We thus hypothesize that alcohol exposure increases
intestinal miR194 and suppresses FXR and FGF15 leading an increase in hepatic de novo BA synthesis and
liver injury; and LGG supplementation inhibits intestinal miR194 and suppresses hepatic BA synthesis and liver
injury in mice. To test our hypothesis, we design following specific aims: Aim 1 will determine the role of miR194
in the regulation of intestinal FXR signaling and hepatic BA homeostasis in ALD. Aim 2 will determine the role of
intestinal miR194-FXR-FGF15 signaling in the protective effects of LGG on ALD. Aim 3 will identify the
mechanism(s) of miR194 regulation in ALD. Collectively, the training and research proposed here will not only
fill a significant need for the development of ALD treatments, but will al...

## Key facts

- **NIH application ID:** 10068121
- **Project number:** 1F31AA028725-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Mengwei Jiang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,130
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068121

## Citation

> US National Institutes of Health, RePORTER application 10068121, Probiotic and intestinal miR194 regulation of bile acid metabolism in alcoholic liver disease (1F31AA028725-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068121. Licensed CC0.

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