Urolithin A alleviates chronic alcohol-related liver disease via gut-microbiota-liver axis
Description
Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of fatalities associated with liver cancer. Gut microbiome dysbiosis is associated with the development of ALD, with gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and the underlying mechanism mediated by microbiota remains elusive. Here, we demonstrated that UA supplementation relieved metabolic disorders and endoplasmic reticulum (ER) stress in a mouse model of ALD via a specific gut-microbiota-liver axis mediated by hepatic major urinary protein 1 (MUP1). Moreover, UA displayed a potential to restore the intestinal microbial balance in ALD mice by enriching the abundance of bacteria Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila) as well as their derived metabolite propionic acid. Depletion of gut microbiota using antibiotics partially attenuated the hepatoprotective effects exerted by UA. The microbiota-dependent effects of UA in ALD were then assessed by fecal microbiota transplantation (FMT) experiment. FMT from UA-treated mice demonstrated a similar effect to UA treatment in terms of attenuating ER stress through MUP1 modulation. It was worth noting that strong associations were observed among host gene expression including MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched gut bacteria B. sartorii, P. distasonis and A. muciniphila can enrich propionic acid to effectively suppress ER stress via MUP1, mimicking UA treatment. These findings suggested a potential therapeutic effect of UA for treating ALD by activating hepatic MUP1, through explicitly targeting the specific gut bacteria and their derived propionic acid. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.