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.