Hydroxytyrosol Improves Metabolic Dysfunction-Associated Fatty Liver Disease Dependent on the Modulation of Gut Microbiota

The global threat of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, but effective measures are still lacking. To explore the potential impact of hydroxytyrosol (HT), a plant polyphenol, in the metabolic outcomes of MAFLD and the mediating role of the gut microbiota, we performed an 8-week randomized placebo-controlled clinical trial in MAFLD patients and collected fecal bacteria for metagenomics analysis and targeted metabolomics. In this population-based trial, we have revealed that HT mitigates liver injury and steatosis in patients with MAFLD, as well as systemic glucolipid metabolism disorder. Through analysis of the differences in bacterial taxon and functional profiles, as well as correlation analysis between species and metabolic indicators, it was found that <i>Fusicatenibacter saccharivorans</i> (<i>F. saccharivorans</i>), the microbial species with the greatest difference after HT intervention, was also the most significantly correlated with metabolic parameters of MAFLD and showed a significant positive correlation with the content of fecal butanoic acid. Butanoic acid was further associated with MAFLD-related metabolic indexes. To confirm the potential causal relationship between alterations in gut microbiota induced by HT intervention and improved MAFLD metabolic phenotypes, fecal microbiota transplantation (FMT) was conducted using a model of pseudogerm-free mice. We have further demonstrated that the fecal microbiota from donors of MAFLD patients receiving HT supplementation can ameliorate liver and systemic phenotypes in western-diet-induced MAFLD mice, interpreting the robust action of gut microbiota remodeled by HT in improving MAFLD. Consequently, HT supplementation may represent a tactic for improving MAFLD by modulating the composition and functionality of the gut microbiota.