What is the role of dysbiosis in Parkinson’s disease?

Parkinson’s disease (PD) is an incurable neurological illness that affects one in every hundred individuals worldwide, ranking second only to Alzheimer’s disease in terms of population. Yet, the method by which it occurs remains unknown. In a new study, experts from the University of Geneva’s Centre Médical Universitaire in Switzerland collaborated with colleagues to investigate the role of gut dysbiosis in the etiology of Parkinson’s disease.

PD is a complex disease with polygenic inheritance in more than one-third of individuals with high-risk genetic variations. Environmental factors such as air pollution and pesticide exposure, as well as epigenetic alterations in the genome and aging-related changes, all play a role. Tobacco, coffee, and participation in sports, on the other hand, have a protective impact.

The current study on the human microbiota – the sum of all bacteria in and on a human body in life – is being driven by the desire to understand how environmental risk factors affect the onset of PD. The microbiota is recognized to perform a number of critical roles in the body’s metabolic, immune, nutritional, and other activities.

Is Parkinson’s disease a peripheral disease?
The new study, which was published in the journal Revue Neurologique, is based on the concept that dysbiosis, or unfavorable alterations in the gut and oral microbiota, is a critical component of Parkinson’s disease pathogenesis. This viewpoint is based on the observation that half of the newly diagnosed persons reported a history of decreased smell and constipation, a quarter reported postprandial bloating, and one in seven reported a loss of taste.

Based on the occurrence of motor symptoms such as stiffness, akinesia, and tremor produced by degenerative alterations in the central nervous system, these symptoms existed even before Parkinson’s disease was recognized (CNS). Autopsies revealed the predicted -synuclein aggregates in the CNS, but also in the peripheral nervous system (PNS). They were found at higher levels in upper body neurons than in lower body neurons, as well as in gut biopsy material taken before Parkinson’s disease was clinically identified.

These findings led to Braak et altwo-hit .’s hypothesis, which proposed a peripheral genesis of Parkinson’s disease (in the nose and intestine) that advanced to affect the brain. Eventually, two-thirds of Parkinson’s disease patients were discovered to have this “body-first” pattern, whereas the remainder had a “brain-first” model, affecting the olfactory bulb or amygdala first. The illness subsequently spreads contralaterally across synapses, with -synuclein aggregates acting as a trigger for the misfolding of neighboring -synuclein.

Simultaneously, there is a decrease in -synuclein breakdown, which causes the aberrant protein to accumulate, and mitochondrial malfunction, which causes increased oxidative stress. Neuroinflammation is another crucial component in this vicious cycle, contributing to the onset and progress of Parkinson’s disease. It is widespread in other chronic inflammatory disorders that raise the risk of Parkinson’s disease, such as Crohn’s disease and ulcerative colitis.

Higher inflammatory cytokines are detected in PD bodily fluids, with microglia in the substantia nigra activating more than controls. In PD, there is also intestinal inflammation and increased permeability, which promotes the formation of -synuclein aggregates, which can subsequently spread to the brain via the vagus nerve.

The axis of the gut-brain
770 kinds of bacteria and many more microbial species contribute to the oral microbiome. Each intraoral region has its own type of community, which is influenced by dietary components, cigarette usage, dental care, and antibiotic use.

Over the course of a person’s life, the oral microbiota evolves in response to host variables. Its advantages include infection prevention and the metabolism of nitrates and other vasoactive chemicals. It has an impact on the microbiota in many different areas of the body, including the gut and the lungs.

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Infective endocarditis, arthritis, autoimmune illness, diabetes, and various malignancies of the mouth, pancreas, and colon are all linked to oral dysbiosis.

The gut microbiome includes all bacteria found in the human digestive tract, from the mouth to the anus. It aids in the maintenance and fortification of the intestinal epithelial barrier, promotes immune system development and maturation of gut-associated lymphoid tissue, inhibits potential pathogen colonization of the gut, and regulates gut processes such as motility, cell differentiation, vascular supply of the intestine, and enteric nervous system growth.

It also breaks down dietary fiber that has remained undigested in the stomach, producing useful byproducts such as short-chain fatty acids (SCFAs), which have anti-inflammatory characteristics and protect brain tissue from harm. They act as an energy source for colonic cells, keeping the colon wall intact as a barrier against gut microorganisms entering the blood and system.

Nervous impulses, immunological response pathways, and endocrine substances communicate between the gut and the brain. Brain signals influence the gut microbiota by affecting the pace of gastrointestinal transit, the amount and character of gut secretions, and the permeability of the gut wall. Via its microbiome-driven interactions with the brain, the gut, in turn, helps influence immune response, endocrine secretions, neuronal signaling, and neurotransmitter levels.

What did the study reveal?
The researchers discovered dysbiosis of the gut and oral cavity in Parkinson’s disease patients in this investigation. Certain gut species, such as the groups Akkermansiaceae, Bifidobacteriaceae, and Ruminococcaceae, increased in PD, but Lachnospiraceae and Prevotellaceae decreased. PD enhanced the relative abundance of Firmicutes, Lactobacillaceae, Scardovia, and Actinomyces in the mouth.

Dysbiosis has been associated with an increase in the frequency of motor and non-motor symptoms such as constipation and polyneuropathy. In animal models, only those with a higher hereditary risk for Parkinson’s disease displayed symptoms in the presence of dysbiosis. This suggests that dysbiosis raises the risk of Parkinson’s disease but does not cause it.

The underlying mechanisms are most likely a slew of metabolic changes. Dysbiosis causes decreased SCFA production and increased intestinal permeability. As a result, there is a systemic and intestinal inflammation, amyloid synthesis from gut bacteria, which promotes -synuclein aggregation, and a decrease in the number of bacteria that make SCFAs.

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More proteins are fermented, resulting in the release of harmful metabolites such as p-cresol, which causes constipation. Slow-growing microorganisms or those with alternate energy sources benefit from this. Dysbiosis has also been associated to folic acid deficiency and hyperhomocysteinemia, both of which may contribute to polyneuropathy.

Oral and gut dysbiosis eventually limit the efficacy of levodopa, the most effective medicine for Parkinson’s disease control. The gut bacterial dopa decarboxylase converts the levodopa taken in the jejunum into dopamine within the gut lumen. Dopamine decreases gastrointestinal motility and may promote harmful bacterial colonization.

Many therapies have been proposed to return the gut microbiota to health. Dietary treatments, probiotics, intestinal purification, and fecal microbiota transplantation are among them.

The composition of the microbiota could aid in the diagnosis of Parkinson’s disease, yet its performance is lacking. Inducing changes in the gut microbiota through dietary techniques such as the Mediterranean diet (MD) or FMT, for example, could be a therapeutic target. This could be due to the beneficial bacteria’s impact on the gut epithelial barrier, reduced inflammation, increased insulin sensitivity, and decreased prostaglandin synthesis.

The ketogenic diet and adjustments to the MD aimed at decreasing hypertension and neurodegeneration may also help to postpone the onset of Parkinson’s disease. Intestinal decontamination therapy is an intriguing technique that involves enema followed by oral rifaximin and polyethylene glycol for seven and ten days, respectively, and has shown promising effects in preliminary tests.

The ketogenic diet and adjustments to the MD aimed at decreasing hypertension and neurodegeneration may also help to postpone the onset of Parkinson’s disease. Intestinal decontamination therapy is an intriguing technique that involves enema followed by oral rifaximin and polyethylene glycol for seven and ten days, respectively, and has shown promising effects in preliminary tests.

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