Brain-gut-microbiota axis in Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Keywords: Brain-gut-microbiota axis; Enteric nervous system; Gastrointestinal dysfunction; Gut microbiota; Parkinson’s disease.

Figure 1

The link between gut dysbiosis, intestinal permeability and neurological dysfunction. There is a close mutual relationship between gut dysbiosis, intestinal permeability and gut inflammation. The enteric nervous system (ENS) is a key player participating in these interactions. Changes in the intestinal permeability may promote translocation of bacteria and endotoxins across the epithelial barrier inducing immunological response associated with the production of pro-inflammatory cytokines. The activation of both enteric neurons and glial cells may result in neurological dysfunction spreading along the brain-gut axis.