A molecular convergence in the triad of Parkinson's disease, depressive disorder and gut health is revealed by the inflammation-miRNA axis

Background Parkinson's disease (PD) is a multisystem disorder frequently comorbid with non-motor symptoms like depressive disorder (DD) and gastrointestinal (GI) dysfunction. Chronic neuroinflammation and disruption of the gut-brain axis are implicated as shared pathological drivers, but the precise molecular mechanisms connecting these conditions remain elusive. We hypothesized that a common microRNA (miRNA)-mediated inflammatory profile underlies this clinical triad, representing a point of pathological convergence. Methods We analyzed the expression of a panel of inflammatory bowel disease (IBD)-associated miRNAs, key inflammatory markers, and glial response in postmortem brain tissue (dorsolateral prefrontal cortex and caudate nucleus) from patients with PD, DD, and matched healthy controls. To investigate causality and gut-brain axis involvement, two mouse models were used: (i) PD-associated α-synucleinopathy was induced in dorsal raphe serotonin (5-HT) neurons; and (ii) DD-like based on corticosterone (CORT)-induced stress. Mice were assessed for depressive-like behaviors and GI dysmotility, and their brain (medial prefrontal cortex and caudate-putamen) and ileum tissues were analyzed for the same molecular markers. Results We identified a conserved miRNA pattern in the brains of both PD and DD patients, characterized by the significant downregulation of miR-199a-5p and miR-219a-5p and the upregulation of miR-200a-3p. This dysregulation was strongly associated with a pro-inflammatory state, as evidenced by increased expression of TNFα, IFN-γ, and NFκB1, as well as changes in the glial response. Mice with α-synucleinopathy in the 5-HT system exhibited a depression-like phenotype and reduced intestinal motility, accompanied by increased Iba1 and GFAP signal. Comparable effects were observed in mice subjected to CORT-induced stress. Notably, the same pattern of miRNAs and inflammatory cytokines observed in the human brain was replicated in the brain and ileum of DD-PD-like mice, providing direct evidence of a parallel pathological process spanning the gut-brain axis. Conclusion This study identifies a specific miRNA-inflammatory axis as a common molecular mechanism connecting the pathophysiology of PD, DD, and gut dysfunction. This pattern represents a critical point of convergence that drives a shared, bidirectional inflammatory cascade along the gut-brain axis. Targeting this miRNA triad could provide a new therapeutic approach for addressing the motor, psychiatric, and GI symptoms of these interconnected disorders simultaneously.