Roles of α‑synuclein in gastrointestinal microbiome dysbiosis‑related Parkinson's disease progression (Review)

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease amongst the middle-aged and elderly populations. Several studies have confirmed that the microbiota-gut-brain axis (MGBA) serves a key role in the pathogenesis of PD. Changes to the gastrointestinal microbiome (GM) cause misfolding and abnormal aggregation of α-synuclein (α-syn) in the intestine. Abnormal α-syn is not eliminated via physiological mechanisms and is transported into the central nervous system (CNS) via the vagus nerve. The abnormal levels of α-syn aggregate in the substantia nigra pars compacta, not only leading to the formation of eosinophilic Lewis Bodies in the cytoplasm and mitochondrial dysfunction in dopaminergic (DA) neurons, but also leading to the stimulation of an inflammatory response in the microglia. These pathological changes result in an increase in oxidative stress (OS), which triggers nerve cell apoptosis, a characteristic of PD. This increase in OS further oxidizes and intensifies abnormal aggregation of α-syn, eventually forming a positive feedback loop. The present review discusses the abnormal accumulation of α-syn in the intestine caused by the GM changes and the increased levels of α-syn transport to the CNS via the MGBA, resulting in the loss of DA neurons and an increase in the inflammatory response of microglial cells in the brain of patients with PD. In addition, relevant clinical therapeutic strategies for improving the GM and reducing α-syn accumulation to relieve the symptoms and progression of PD are described. Contents 1. Introduction 2. An aberrant GM affects α-syn accumulation in the intestine of patients with PD 3. α-syn accumulation contributes to neurodegeneration in the CNS of patients with PD 4. Novel treatments based on the MGBA and α-syn for PD 5. Conclusion

Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson’s Disease

“…The gut microbiota may influence brain function and behavior through neurological, immunological, and endocrine pathways, establishing the microbiota–gut–brain axis (MGBA) [ 7 , 8 ]. Clinical investigations have shown that both the composition and abundance of gut bacteria and the produced metabolites are drastically altered in patients with PD compared to those in healthy patients [ 9 ].…”

Evaluation of the disease-modifying effects of Aureobasidium pullulans AFO-202 strain produced Beta-Glucan in Parkinson’s disease – Results of a pilot clinical study

“…Because the gut microbiota and its metabolites control neuroinflammation, barrier function, and neurotransmitter activity, it has been hypothesised that these factors contribute to the aetiology of PD. The microbiota-gutbrain axis may offer a route for the transmission of misfolded a-synuclein because of the bidirectional contact between the enteric nervous system and central nervous system (CNS) in humans [10]. a-Synuclein misfolding and aberrant aggregation are caused by changes in the gastrointestinal microbiome (GM) in the intestine, especially an increase in pathogenic bacteria such as Enterobacteriaceae that produce curli proteins and abnormal amyloids.…”

Are We What We Eat? Impact of Diet on the Gut–Brain Axis in Parkinson’s Disease

“…A decrease in Prevotellaceae in PD patients may be related to the reduction in mucin production defining an amplified intestinal permeability, known also as "leaky gut", that can be associated with α-synuclein aggregates through the bacteria translocation and the production of bacterial products that induce inflammation [88] (i.e., gut-derived lipopolysaccharide (LPS) that can support the impairment of the blood-brain barrier [89]) and the reactive oxygen species production in the GI system thus starting the α-synuclein accumulation at the level of ENS [90]. In an in vivo study, using rats injected at the level of substantia nigra with LPS, an induction of inflammation was observed, leading to damage of the nigrostriatal dopaminergic neurons, thus suggesting that this event could be implicated in neurodegeneration processes [91].…”