Differential effects of ellagic acid on non-alcoholic fatty liver disease in mice: grouped by urolithin A-producing capacity.

Ellagic acid (EA) exhibits protective effects on non-alcoholic fatty liver disease (NAFLD). However, the ability to produce urolithins and the health benefits associated with EA consumption differ considerably among individuals. Therefore, the different effects of EA on high-fat and high-fructose diet (HFFD)-induced NAFLD, considering variability in urolithin-producing ability, were explored. Our results showed that EA could effectively reduce body weight, lipid accumulation and insulin resistance, and improve oxidative stress and inflammation in NAFLD mice. The metabolomics analysis indicated that liver metabolism disorder induced by HFFD was obviously improved by EA mainly through the regulation of unsaturated fatty acid biosynthesis and amino acid metabolism. In particular, the improvement effect of EA on NAFLD in mice with high urolithin A production was better than that in their low counterparts. Moreover, EA treatment reshaped the gut microbiota imbalance caused by HFFD. Specifically, compared to the model group, the lower abundances of (by 95.11%), (by 208.14%), (by 449.37%), and (by 172.64%), while higher abundances of and (by 425.0%) were observed in the high-UroA-producing group ( < 0.05). This study provided new insights into EA's anti-NAFLD effectiveness and suggested that the response capacity of the gut microbiota to EA greatly determined the performance of EA in alleviating the development of NAFLD.