Gut microbiota dysbiosis amplifies thiram hepatotoxicity via a mitochondrial-autophagy-apoptosis nexus orchestrated by the gut-liver axis

Abstract

Thiram, an environmentally persistent pesticide, poses significant hepatotoxic risks through oral exposure. However, the mechanisms linking gut dysbiosis to hepatic cell death remain unclear. Using a 5-week thiram exposure mouse model, we demonstrate that thiram-induced gut microbiota dysbiosis amplifies hepatotoxicity by disrupting the mitochondrial-autophagy-apoptosis axis via the gut-liver axis. We found that oral thiram exposure severely compromises intestinal barrier integrity, evidenced by colonic muscular layer thinning, goblet cell depletion, and downregulation of tight junction proteins (ZO-1, Occludin). Simultaneously, thiram induces dysbiosis characterized by an elevated Firmicutes/Bacteroidetes (F/B) ratio and altered abundances of Muribaculum intestinale, Bacteroides caecimuris, Lactobacillus johnsonii. These gut-derived perturbations triggered hepatic mitochondrial dynamics imbalance, driving aberrant de novo fatty acid synthesis and β-oxidation. Crucially, thiram disrupted autophagic flux and activated the mitochondrial apoptosis pathway, establishing a self-amplifying cycle of metabolic dysfunction and cellular demise. Our findings reveal that gut-mediated disruption of fatty acid metabolism orchestrates the collapse of crosstalk between mitochondria, autophagy, and apoptosis, ultimately culminating in hepatotoxicity. This work establishes the gut-liver axis as a central regulator of environmentally triggered apoptotic cell death.