Microbiota-regulated TCDCA associates with Parkinson's disease severity and promotes BBB dysfunction through VSMC TGR5 signaling in mice.

Parkinson's disease (PD) is a systemic disorder linked to gut dysbiosis, yet key microbiota-regulated metabolites remain unclear. Here, we observe elevated taurochenodeoxycholic acid (TCDCA) in patients with PD that correlates with disease severity. Reduced bile salt hydrolase (BSH) gene abundance correlates inversely with circulating TCDCA, consistent with altered bile acid deconjugation. Exogenous TCDCA correlates with aggravated motor and gastrointestinal deficits, impaired blood-brain barrier (BBB) integrity, and accelerated dopaminergic neurodegeneration in a PD mouse model. Mechanistically, TCDCA links to TGR5 signaling activation in vascular smooth muscle cells (VSMCs), alongside PKCα-dependent mitochondrial apoptosis and BBB disruption. VSMC-specific Tgr5 deletion coincides with neurovascular protection. Supplementation with a BSH-high Lactobacillus reuteri strain reduces TCDCA concentrations, improves gut and BBB integrity, mitigates inflammation, and alleviates PD-like phenotypes in a BSH-dependent manner. These data support a gut-BBB-brain axis linked to PD, identifying TCDCA as a candidate pathological marker.