Effects of low methionine intake on hepatic steatosis in patients and alcohol-induced hepatic steatosis model mice: Role of the indole-3-acetic acid pathway.

Abstract

AIMS: This study aims to explore relationship between methionine levels and hepatic steatosis in population, as well as protective effects of a methionine restriction (MR) diet and its underlying mechanisms in preventing hepatic steatosis in alcohol-induced mice. MATERIALS AND METHODS: This study integrated population data analysis based on the National Health and Nutrition Examination Survey (NHANES), and combined with animal experiments to establish mouse model of alcohol-induced hepatic steatosis. KEY FINDINGS: The population data showed a significant positive correlation between methionine intake levels and the risk of hepatic steatosis, with restricted methionine intake linked to a lower risk. Furthermore, the effect of MR on alcoholic liver injury has not been reported. In this study, the alcohol-induced fatty liver (AFL) model mice were used and the results demonstrate that MR significantly attenuated hepatic lipid accumulation. Microbiomics and metabolomics analyses revealed that MR can enhance the production of indole-3-acetic acid (IAA), a metabolite of tryptophan, by increasing the abundance of beneficial bacteria Akkermansia and Bacteroides that promote tryptophan metabolism. Acting as a key signaling messenger in the gut-liver axis, IAA reaches the liver and modulates the hepatic AhR/PPARγ/SREBP-1c pathway, thereby alleviating hepatic steatosis in AFL mice. SIGNIFICANCE: These findings establish a positive correlation between methionine intake and hepatic steatosis and elucidate the role and mechanism by which MR ameliorates alcohol-induced hepatic steatosis. The study provides key insights into the mechanisms underlying the protective effects conferred by the MR diet, and serves as a guide for the prevention and management of AFL.