The gut microbiota mediates METH-induced hepatotoxicity via the PPARα/NF-κB pathway

Methamphetamine (METH) abuse poses a significant threat of systemic toxicity, particularly acute liver injury; however, the role of the gut-liver axis in this context remains incompletely understood. Here, we demonstrate that gut microbiota dysbiosis acts as a critical mediator of METH-induced hepatotoxicity. In mice, METH exposure disrupted the gut microbial composition—characterized by an elevated microbial dysbiosis index (MDI) and the opportunistic expansion of Lactobacillaceae —leading to increased intestinal permeability, systemic LPS translocation, and subsequent cholestatic liver injury. Mechanistically, METH suppressed hepatic PPAR α while activating the NF- κ B pathway, as evidenced by increased p -NF- κ B phosphorylation. Crucially, broad-spectrum antibiotic (Abx) pretreatment attenuated hepatic damage and inflammatory signaling, whereas fecal microbiota transplantation (FMT) from METH-treated donors (FMT-M) recapitulated the phenotype in naive recipients, confirming causality. Conversely, healthy FMT or pharmacological activation of PPAR α via the agonist WY14643 effectively restored PPAR α expression, suppressed NF- κ B activation, and alleviated liver injury. Collectively, these findings establish a gut microbiota–PPAR α /NF- κ B axis as a central driver of METH-induced hepatotoxicity and highlight preemptive microbiota modulation as a promising intervention strategy against METH-associated complications. Diagram showing that the gut microbiota mediates METH-induced hepatotoxicity in mice via the PPAR α /NF- κ B pathway. Created with Figdraw ( https://www.figdraw.com ). Gut microbiota dysbiosis mediates METH‑induced hepatotoxicity via the gut‑liver axis. 16S sequencing reveals METH‑altered gut microbial composition, partially restored by healthy FMT. METH suppresses hepatic PPAR α and activates NF‑ κ B; PPAR α agonist pretreatment reverses this axis. Healthy FMT and PPAR α agonism offer preventive strategies against METH‑induced hepatotoxicity.