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

Area of Science:

• Environmental Health
• Microbiology
• Hepatology

Background:

• Lean nonalcoholic fatty liver disease (NAFLD) patients show unique gut microbial profiles, increasing susceptibility to environmental chemicals.
• Hexafluoropropylene oxide dimer acid (HFPO-DA), a perfluorooctanoic acid alternative, is under scrutiny for potential health effects.

Purpose of the Study:

• To investigate the hepatotoxicity of HFPO-DA in a lean NAFLD mouse model.
• To elucidate the role of gut microbiota and arginine metabolism in HFPO-DA-induced liver injury.

Main Methods:

• Utilized a lean NAFLD mouse model exposed to HFPO-DA.
• Analyzed gut microbiota composition (16S rRNA sequencing) and multiomics data (metabolomics, transcriptomics).
• Investigated the effects of farnesoid X receptor (FXR) agonist intervention.

Main Results:

• HFPO-DA exposure reduced intestinal Akkermansia abundance and enriched Jeotgalicoccus, disrupting gut microbial homeostasis.
• HFPO-DA impaired gut-liver bile acid homeostasis and suppressed arginine anabolism, leading to hepatic argininosuccinate accumulation.
• FXR agonist intervention restored bile acid homeostasis, re-enriched Akkermansia, and improved arginine and energy metabolism.

Conclusions:

• HFPO-DA promotes hepatotoxicity in lean NAFLD by disrupting gut microbial homeostasis and arginine metabolism.
• A novel gut-liver axis involving arginine and bile acids mediates HFPO-DA-induced liver injury.
• Targeting gut microbiota and arginine metabolism may offer therapeutic strategies for HFPO-DA-related liver damage.