Intermittent Fasting Improves Non-Alcoholic Fatty Liver Disease by Remodeling the Gut Microbiota to Upregulate 3-Indolepropionic Acid Levels

Intermittent fasting (IF) is a form of periodic energy restriction that has demonstrated benefits for natural weight management, metabolic syndrome, and longevity. However, its potential impact on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanisms remain poorly understood. In this study, we demonstrated that an intermittent fasting regimen effectively reduced intrahepatic fat accumulation and improved obesity related metabolic dysfunction induced by a chronic high-fat diet in a mouse model of NAFLD. Mechanistically, intermittent fasting alleviated NAFLD via the microbiota-metabolite-hepatic axis, remodeling the gut microbiota, increasing the abundance of Clostridium, Lachnospiraceae, and Muribaculaceae, and upregulating levels of the gut metabolite 3-indolepropionic acid (IPA). Intermittent fasting induced metabolic shifts in hepatocytes by activating the peroxisome proliferator-activated receptor (PPAR)-a pathway via acetyl-CoA synthetase short-chain family member 2 (ACSS2), leading to improvements in fatty liver and inhibition of hepatocyte apoptosis. Further, transplantation of the gut microbiota from fasting mice ameliorated NAFLD and metabolic dysfunction in the disease model group, while antibiotic-mediated depletion of the microbiota only partially abolished fasting's protective effects on intrahepatic fat accumulation. Additionally, the administration of IPA to the NAFLD mice produced effects similar to those of intermittent fasting, improving NAFLD and metabolic dysfunction. In conclusion, our study provides comprehensive evidence that intermittent fasting can serve as both a preventive and therapeutic strategy for NAFLD by ameliorating hepatic and metabolic dysfunction via the microbiota-metabolite-liver axis.