Microbiota-metabolite dysregulation in depressive and non-depressive Parkinson’s disease: mechanistic and therapeutic implications

Parkinson’s disease (PD) is a progressive neurodegenerative disorder frequently accompanied by non-motor symptoms, among which depression is one of the most prevalent and disabling manifestations, affecting approximately 35%-50% of patients. Emerging evidence implicates gut microbiota dysbiosis and associated metabolic alterations in PD pathophysiology through the microbiota-gut-brain axis. This narrative review distinguishes between non-depressive Parkinson’s disease (NDPD) and depressive Parkinson’s disease (DPD) as clinically relevant phenotypes and synthesizes current evidence describing how microbiota-derived metabolites may contribute to their overlapping yet partially distinct neurobiological features. We focus on alterations in short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and tryptophan-kynurenine pathway metabolites, which have been shown to influence immune activation, neuroinflammation, and monoaminergic signaling. Rather than functioning as independent disease drivers, these microbial and metabolic alterations are discussed as upstream modulators converging on shared molecular pathways, including Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling, serotonergic dysfunction, and stress-associated neuroendocrine regulation. These mechanisms are implicated in both α-synuclein pathology and depressive symptomatology, providing a potential mechanistic basis for the coexistence of motor and depressive symptoms in PD. We further propose a gut-brain axis-centered framework in which microbiota-derived signals act as common upstream regulators of neurodegenerative and neuropsychiatric processes. Key microbial taxa, including Faecalibacterium prausnitzii, Bifidobacterium, and Lactobacillus, are highlighted as potential modulators of neuroimmune and neurochemical homeostasis. Collectively, current evidence supports the gut microbiota as a convergent biological interface linking neurodegeneration and depression in PD, with implications for biomarker discovery and microbiota-targeted therapeutic strategies.