Parkinson's disease (PD) is an incurable neurodegenerative disease that affects one in a hundred people the world over, second only to Alzheimer's disease in the number of people affected. However, the mechanism by which it arises is still unclear. In a new research paper, scientists from the University of Geneva, Centre Médical Universitaire, Switzerland, teamed up with others to explore the role played by gut dysbiosis in the pathogenesis of PD.
Review: Oral and intestinal dysbiosis in Parkinson's disease. Image Credit: Kotcha K / Shutterstock
Introduction
PD is a multifactorial condition, with polygenic inheritance in over a third of cases that show high-risk genetic variants. However, environmental factors such as air pollution and pesticide exposure, epigenetic modifications of the genome, and aging-related changes also play a part. Conversely, lifestyle factors like tobacco, coffee, and playing sports have a protective effect.
The need to understand how environmental risk factors affect the occurrence of PD is driving current research on its link to the human microbiota – the sum of all microbes in and on a human body in life. The microbiota is known to play several essential roles in the normal functioning of the body's metabolic, immunologic, nutritional, and other processes.
Peripheral origin of PD?
The current study, published in the journal Revue Neurologique, is based on the hypothesis that dysbiosis, or unhealthy variations in the gut and oral microbiota, is a key component of PD pathogenesis. This view is based on the observation that half of newly diagnosed individuals reported a history of reduced smell and constipation, while a quarter had postprandial bloating, and one in seven had a loss of taste.
These symptoms were present long before PD was diagnosed, based on the presence of motor symptoms like rigidity, akinesia, and tremor, caused by degenerative changes in the central nervous system (CNS). Autopsies showed the characteristic α-synuclein aggregates in the CNS, as expected, but also in the peripheral nervous system (PNS). These were present at higher levels in upper body neurons compared to the lower body and in gut biopsy material taken before PD was clinically diagnosed.
These observations led to Braak et al.'s two-hit hypothesis, which considered a peripheral origin of PD (in the nose and the intestine), that then progressed to involve the brain. Recently, two-thirds of PD patients were found to have this "body-first" pattern, but the rest had a "brain-first" model, affecting the olfactory bulb or amygdala initially. The disease then spreads contralaterally via the synapses with the formation of more pathologic polymers, with α-synuclein aggregates being a catalyst for the misfolding of adjacent α-synuclein.
Simultaneously, there is decreased breakdown of α-synuclein, causing the abnormal protein to accumulate, and mitochondrial dysfunction causing increased oxidative stress. Neuroinflammation is another key component in this vicious cycle, helping to initiate and promote the spread of PD. It is common to other chronic inflammatory conditions like Crohn's disease and ulcerative colitis that increase the risk of PD.
Increased inflammatory cytokines are found in the body fluids in PD, with microglia within the substantia nigra showing greater activation compared to controls. Intestinal inflammation and higher permeability are also present in PD, promoting the build-up of α-synuclein aggregates that could then propagate to the brain via the vagus nerve.
The gut-brain axis
The oral microbiome is contributed by ~770 species of bacteria with many other microbial species. Each of the intraoral regions has its own type of community, which is affected by exposure to dietary components, tobacco, dental care, or the use of antibiotics.
The oral microbiota changes with host factors over the lifespan of the individual. Its beneficial effects include the prevention of infection and the metabolism of nitrates and other vasoactive substances. It affects the microbiota at many other related body sites like the gut and the lungs.
Oral dysbiosis contributes to infective endocarditis, arthritis, autoimmune disease, and diabetes, as well as some cancers of the mouth, pancreas, and colon.
The gut microbiome comprises all the microbes in the human digestive tract from mouth to anus. It helps maintain and fortifies the intestinal epithelial barrier, promotes immune system development and maturation of gut-associated lymphoid tissue, inhibits the colonization of the gut by potential pathogens, and regulates gut processes such as motility, differentiation of the different cell types, vascular supply of the intestine and the growth of the enteric nervous system.
It also breaks down dietary fiber remaining undigested in the gut, producing valuable byproducts such as short-chain fatty acids (SCFAs) that possess anti-inflammatory properties as well as shielding neural tissue against injury. These serve as an energy source for the colonic cells, keeping the colon wall intact as a defense against the entry of the gut microbes into the blood and the system.
The gut and the brain talk to each other via nervous impulses, immune response pathways, and endocrine chemicals. The brain signals regulate the gut microbiome by altering the speed of gut transit, the amount and nature of gut secretions, and the gut wall permeability. The gut, in turn, helps modulate the immune response, endocrine secretions, neural signaling, and neurotransmitter levels via its microbiome-driven interactions with the brain.
What did the study show?
In the present study, the researchers found dysbiosis of the gut and oral cavity in patients with PD. Some gut species were increased in PD, such as the families Akkermansiaceae, Bifidobacteriaceae, and Ruminococcaceae, while Lachnospiraceae and Prevotellaceae showed a decline. In the mouth, the relative abundance of Firmicutes, Lactobacillaceae, Scardovia, and Actinomyces, among others, was increased in PD.
Dysbiosis was linked to a higher frequency of motor and non-motor symptoms, including constipation and polyneuropathy. In animal models, only those individuals that were at a higher genetic risk for PD developed PD symptoms in the presence of dysbiosis. This indicates that dysbiosis contributes to a higher risk for PD but doesn't cause it.
The underlying mechanisms probably include a host of metabolic alterations. The presence of dysbiosis leads to reduced production of SCFAs, and higher intestinal permeability. In turn, this causes systemic and gut inflammation, amyloid production from gut bacteria promoting α-synuclein aggregation, and a reduction in the number of bacteria that produce SCFAs.
More proteins are fermented, releasing toxic metabolites like p-cresol, causing constipation. This favors slow-growing bacteria or those with alternative energy sources. Dysbiosis was also linked to folic acid deficit and hyperhomocysteinemia, perhaps contributing to polyneuropathy.
Eventually, oral and gut dysbiosis reduce the efficacy of levodopa, the most effective drug to be used in the control of PD. The levodopa absorbed in the jejunum is turned into dopamine within the gut lumen via gut bacterial dopa decarboxylase. The dopamine slows down gut motility and may trigger the colonization of pathogenic bacteria.
"An increase in the number of levodopa-metabolizing bacteria decreases the effectiveness of dopamine replacement therapy, creating a vicious circle which enhances bacterial overgrowth."
Interventions
Several interventions have been proposed that could restore the gut microbiota to its healthy state. These include dietary interventions, pro-biotics, intestinal decontamination, and fecal microbiota transplantation.
The composition of the microbiota could help diagnose PD, though its performance leaves much to be desired. The induction of changes in the gut microbiome could be a therapeutic target, using dietary strategies like the Mediterranean diet (MD) or FMT, for instance. This could be via the effects of protective bacteria on the gut epithelial barrier, reduced inflammation, higher insulin sensitivity, and reduced prostaglandin production.
The ketogenic diet and modifications of the MD aimed at reducing hypertension and neurodegeneration could also delay the start of PD. Intestinal decontamination therapy is an interesting technique that empties the gut by enema followed by oral rifaximin and polyethylene glycol for seven and ten days, respectively, and has shown some good results in early studies.
What are the implications?
PD appears to be intimately linked to gut and oral dysbiosis.
"Since the composition of the microbiota can be modified, interventions aiming at correcting dysbiosis open a new avenue of therapeutic research. Moreover, microbial communities could represent a new biomarker of PD."
Studies link gut dysbiosis to pancreatic cancer, offering pathways for early detection