Gut Microbiota Mediates HFPO–DA-Induced Hepatotoxicity via Arginine Reprogramming in Lean NAFLD Mice

Emerging evidence indicates that individuals with lean nonalcoholic fatty liver disease (NAFLD) exhibit a distinct gut microbial metabolic profile, rendering them uniquely susceptible to environmental chemicals. Using a lean NAFLD mouse model, this study demonstrates that hexafluoropropylene oxide dimer acid (HFPO–DA), a commonly regarded safer alternative to perfluorooctanoic acid, promotes hepatotoxicity by disrupting gut microbial homeostasis. While the lean NAFLD diet increased Akkermansia abundance in the intestine, HFPO–DA exposure significantly reduced Akkermansia and enriched Jeotgalicoccus. The evolution of microbiota in the intestine impaired gut-liver bile acid homeostasis and suppressed arginine anabolism. Integrated multiomics analyses revealed that HFPO–DA redirected host arginine metabolism, leading to hepatic argininosuccinate accumulation and exacerbated metabolic dysregulation. Consistently, when the bile acid homeostasis of lean NAFLD mice was restored by farnesoid X receptor (FXR) agonist intervention, the re-enrichment of Akkermansia and the promoted arginine and energy metabolism further evidenced the critical role of gut microbiota in lean NAFLD. This study identified a novel gut-liver axis mediated by arginine and bile acids, elucidating how gut microbiota confer HFPO–DA hepatotoxicity via arginine metabolic reprogramming in lean NAFLD.