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Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation.
Jiang, Mengwei; Li, Fengyuan; Liu, Yunhuan; Gu, Zelin; Zhang, Lihua; Lee, Jiyeon; He, Liqing; Vatsalya, Vatsalya; Zhang, Huang-Ge; Deng, Zhongbin; Zhang, Xiang; Chen, Shao-Yu; Guo, Grace L; Barve, Shirish; McClain, Craig J; Feng, Wenke.
Afiliación
  • Jiang M; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • Li F; Department of Pharmacology and Toxicology , University of Louisville , Louisville , Kentucky , USA.
  • Liu Y; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Gu Z; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • Zhang L; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Lee J; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • He L; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Vatsalya V; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • Zhang HG; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Deng Z; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • Zhang X; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Chen SY; Department of Medicine , University of Louisville , Louisville , Kentucky , USA.
  • Guo GL; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • Barve S; Alcohol Research Center , University of Louisville , Louisville , Kentucky , USA.
  • McClain CJ; Department of Chemistry , University of Louisville , Louisville , Kentucky , USA.
  • Feng W; Hepatobiology & Toxicology Center , University of Louisville , Louisville , Kentucky , USA.
Hepatology ; 77(4): 1164-1180, 2023 04 01.
Article en En | MEDLINE | ID: mdl-35689610
ABSTRACT
BACKGROUND AND

AIMS:

Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice. APPROACH AND

RESULTS:

Binge-on-chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand-mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco-2 cells and mouse enteriods. The alcohol feeding-reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased-miR194 expression was mediated by taurine-upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3-day oral administration of LDNPs increased bile salt hydrolase (BSH)-harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal FxrΔIEC and Fgf15-/- mice. We further showed that miR194 was upregulated, whereas BSH activity and taurine levels were decreased in fecal samples of patients with ALD.

CONCLUSIONS:

Our results demonstrated that gut microbiota-mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Hepatopatías Alcohólicas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Hepatopatías Alcohólicas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hepatology Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos