Pathological α-synuclein propagation via the gut-liver axis induces liver injury in gut-origin Parkinson's disease mouse models.

Parkinson's disease (PD) pathogenesis involves α-synuclein (α-syn) aggregation in substantia nigra. The "gut-origin hypothesis" proposes α-syn propagates from gut to brain, but its peripheral effects remain unclear. Using a gut-origin PD mouse model by intestinal wall injecting α-syn preformed fibrils (α-syn PFFs), we tracked hepatic pathology for 8 months. Hepatic α-syn pathology appeared at 6 months post-injection, hepatic senescence and inflammation were induced, with increased p16, p21, and senescence-associated secretory phenotype factors, alongside decreased LaminB1. By 8 months, proliferation markers PCNA, Ki67, SOX2 declined; fibrosis markers α-SMA, MAO-A/B, Col1α1/2, Col3α1 and hepatic hydroxyproline (HYP) rose; and serum aspartate aminotransferase (AST) and AST/ALT ratio increased, indicating liver fibrosis and dysfunction. In PD patients, serum ALT levels were significantly elevated compared to healthy controls, while AST showed a similar trend. Meanwhile, hyaluronic acid (HA) and procollagen III N-terminal peptide (PIIINP) were significantly elevated compared to healthy controls, suggesting subclinical hepatic injury and fibrotic activity. We further found that hepatic TLR4/NF-κB pathway was upregulated from 6 months. In vitro, the TLR4 inhibitor mitigated α-syn PFFs-induced activation of the TLR4/NF-κB pathway, thereby alleviating hepatocyte senescence and hepatic stellate cell activation. This study provides first evidence that gut-origin α-syn may spread to the liver, associated with senescence, inflammation, and fibrosis via triggering TLR4/NF-κB, highlighting gut-liver-brain axis in PD progression.