MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis

Hongbo Zhang; Chaoyue Li; Lin Han; Yao Xiao; Ji Bian; Chao Liu; Lan Gong; Zhigang Liu; Min Wang

doi:10.1080/19490976.2024.2367342

Gut Microbes (Dec 2024)

MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis

Hongbo Zhang,
Chaoyue Li,
Lin Han,
Yao Xiao,
Ji Bian,
Chao Liu,
Lan Gong,
Zhigang Liu,
Min Wang

Affiliations

Hongbo Zhang: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
Chaoyue Li: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
Lin Han: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
Yao Xiao: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
Ji Bian: Kolling Institute, Sydney Medical School, Royal North Shore Hospital, University of Sydney, Sydney, Australia
Chao Liu: Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, P.R. China
Lan Gong: UNSW Microbiome Research Centre, St George and Sutherland Clinical Campus, University of New South Wales, Sydney, Australia
Zhigang Liu: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
Min Wang: College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China

DOI: https://doi.org/10.1080/19490976.2024.2367342
Journal volume & issue: Vol. 16, no. 1

Abstract

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Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.

Published in Gut Microbes

ISSN: 1949-0976 (Print); 1949-0984 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.tandfonline.com/journals/kgmi

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