GDNF signaling modulation by Akkermansia muciniphila ameliorates constipation–depression comorbidity in Parkinson’s disease

Constipation and depression are prevalent non-motor symptoms (NMS) of Parkinson's disease (PD) that often co-occur, yet their shared pathophysiology remains unclear. Here, we identify enteric glial cells (EGCs) as central regulators of the gut-brain axis, wherein aberrant activation of the TLR4/NEDD4/CX43 signaling axis drives sustained ATP release, impairing serotonin (5-HT) synthesis in enterochromaffin (EC) cells. This ATP-mediated purinergic toxicity provides a unifying molecular mechanism for PD-associated constipation and depression (PD-CD). Mechanistically, TLR4 activation promotes TRAF6-dependent ubiquitination and degradation of NEDD4, reducing CX43 clearance. CX43 accumulation at the plasma membrane enhances ATP release, suppressing EC-derived 5-HT and contributing to gut dysmotility and mood disturbances. Critically, glial cell-derived neurotrophic factor (GDNF) stabilizes NEDD4 via the Ret-Src pathway, restores CX43 ubiquitination, limits ATP leakage, and rescues 5-HT synthesis, alleviating constipation and depressive phenotypes in PD mice. The probiotic Akkermansia muciniphila Akk11 (Akk11) similarly induces endogenous GDNF, producing comparable protective effects. Together, these findings establish an "EGC-EC axis" model for PD-CD and highlight GDNF-centered interventions as a promising multi-target strategy for PD NMS.