Conclusions: This review summarizes a model of microbiota-gut-brain-axis regulation of neuroinflammation in PD including several new mechanisms. We conclude with the need for clinical trials in PD patients to test this model for beneficial effects of Mediterranean based high fiber diets.

IntroductionParkinson's disease (PD) is the second most common neurodegenerative disease associated with aging. PD patients have systemic and neuroinflammation which is hypothesized to contribute to neurodegeneration. Recent studies highlight the importance of the gut-brain axis in PD pathogenesis and suggest that gut-derived inflammation can trigger and/or promote neuroinflammation and neurodegeneration in PD. However, it is not clear whether microbiota dysbiosis, intestinal barrier dysfunction, or intestinal inflammation (common features in PD patients) are primary drivers of disrupted gut-brain axis in PD that promote neuroinflammation and neurodegeneration.ObjectiveTo determine the role of microbiota dysbiosis, intestinal barrier dysfunction, and colonic inflammation in neuroinflammation and neurodegeneration in a genetic rodent model of PD [α-synuclein overexpressing (ASO) mice].MethodsTo distinguish the role of intestinal barrier dysfunction separate from inflammation, low dose (1%) dextran sodium sulfate (DSS) was administered in cycles for 52 days to ASO and control mice. The outcomes assessed included intestinal barrier integrity, intestinal inflammation, stool microbiome community, systemic inflammation, motor function, microglial activation, and dopaminergic neurons.ResultsLow dose DSS treatment caused intestinal barrier dysfunction (sugar test, histological analysis), intestinal microbiota dysbiosis, mild intestinal inflammation (colon shortening, elevated MPO), but it did not increase systemic inflammation (serum cytokines). However, DSS did not exacerbate motor dysfunction, neuroinflammation (microglial activation), or dopaminergic neuron loss in ASO mice.ConclusionDisruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice.

Introduction: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. While genetics are important in the development of AD, environment and lifestyle are also important factors influencing AD. One such lifestyle factor is alcohol consumption. Unhealthy and excessive chronic alcohol consumption is associated with a greater risk of all types of dementia, especially AD. Alcohol consumption has numerous effects on the body, including alterations to the intestinal microbiota (dysbiosis) and intestinal barrier dysfunction (leakiness and intestinal hyperpermeability), with evidence indicating that inflammation resulting from dysbiosis and barrier dysfunction can promote neuroinflammation impacting brain structure and function.Objective: This study sought to determine the impact of alcohol-induced dysbiosis and barrier dysfunction on AD-like behavior and brain pathology using a transgenic rodent model of AD (3xTg-AD).Methods: Alcohol (20%) was administered to 3xTg-AD mice in the drinking water for 20 weeks. Intestinal (stool) microbiota, intestinal barrier permeability, systemic inflammation (IL-6), behavior, and AD pathology (phosphorylated tau and β-amyloid), and microglia were examined.Results: Alcohol consumption changed the intestinal microbiota community (dysbiosis) and increased intestinal barrier permeability in both control and 3xTg-AD mice (oral/urine sugar test and lipopolysaccharide-binding protein (LBP)). However, alcohol consumption did not influence serum IL-6, behavior, or β-amyloid, phosphorylated tau, or microglia in 3xTg-AD mice. Important differences in genotype and sex were noted.Conclusion: Alcohol-induced microbiota dysbiosis and intestinal barrier dysfunction did not exacerbate behavior or AD-like brain pathology in the 3xTg-AD mouse model of AD which could, in part, be the result of a lack of systemic inflammation.