Current understanding of the pathophysiology of Parkinson‘s disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson‘s disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.

Dysbiosis of the gut flora accompanies Parkinson disease (PD), yet no specific cause-effect link has been identified so far. The gut microbiota produce molecular hydrogen (H₂), a ubiquitous molecule recently recognized as a biologically active gas with antioxidant, antiapoptotic, anti-inflammatory, cytoprotective, and signaling properties. Here, we discuss an idea that an impaired production of endogenous H₂ by intestinal microbiota might play a role in PD pathogenesis, with supplemental H₂debated as a possible therapy for this progressive neurodegenerative disease.

The exact mechanism of gut dysfunction in Parkinson‘s disease and, conversely, the role of gutpathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1 week) or subchronic (3 weeks) gutinflammation did not show a significant increase in colonic α-synuclein and phosphorylated α-synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gutdisturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation.

Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson‘s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson‘s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson‘s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson‘s disease patients.

Molecular communications in the gut-brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson‘s diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut-brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut-brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut-brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor.

BACKGROUND:

We previously reported gut dysbiosis in patients with Parkinson‘s disease (PD).

OBJECTIVE:

The aim of this study is to examine whether gut dysbiosis correlates with the progression of PD.

RESULTS:

A change of total UPDRS scores in 2 years was predicted by the counts of Bifidobacterium and Atopobium cluster at year 0 with a correlation coefficient of 0.52. Correlation analysis additionally revealed that low counts of Bifidobacterium and Bacteroides fragilis at year 0 were associated with worsening of UPDRS I scores in 2 years. In addition, low counts of Bifidobacterium at year 0 were associated with worsening of hallucinations/delusions in 2 years. Similarly, low counts of B. fragilis at year 0 were associated with worsening of motivation/initiative in 2 years. The patients were evenly divided into the deteriorated and stable groups based on the degree of worsening of total UPDRS scores. The deteriorated group had lower counts of Bifidobacterium, B. fragilis, and Clostridium leptium than the stable group at year 0 but not at year 2, suggesting that the deteriorated group may demonstrate accelerated lowering of these bacteria at year 0.

CONCLUSIONS:

The total counts of intestinal bacterial decrease in the course of PD progression. Temporal profiles of lowering of bacterial counts are likely to be different from bacteria to bacteria, and also between the deteriorating and stable groups, which may be able to be exploited to differentiate patients with rapidly and slowly progressive PD pathology