Gut Permeability and Microbiota in Parkinson’s Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatonergic Pathways

Background: Increased gut permeability (leaky gut) and alterations in gut microbiota are now widely accepted as relevant to the etiology, course and treatment of many neuropsychiatric disorders, including Parkinson disease (PD). Although a wide array of data on the biological underpinnings of PD has not yet been linked to such gut-associated changes, increased gut permeability and dysregulated microbiota alter many pathways germane to PD. Methods: In this article we review and integrate these wider biological changes in PD, including increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways. Results: These wider biological changes in PD are compatible with alterations in gut permeability and changes in gut microbiota. By driving tryptophan down the kynurenine pathway, pro-inflammatory cytokines and chronic stress-driven activation of the hypothalamic-pituitary-adrenal axis decrease the availability of serotonin as a precursor for activation of the melatonergic pathways. Conclusion: Decreased local melatonin synthesis in glia, gut, neuronal and immune cells is likely to be important to the etiology, course and management of PD.