SUMMARY: Parkinson’s disease is characterized by destruction of dopamine producing neurons in the substantia nigra, a loss of these neurons leads to the motor symptoms associated with the disease. There is also impaired synaptic transmission in the prefrontal cingulate cortex and substantia nigra and dysfunction in these areas can lead to the nonmotor symptoms. Another feature of Parkinson’s disease is the accumulation of Lewy bodies in various parts of the brain and body. Besides the aforementioned parts of the brain, other areas that are included in Lewy body deposition include cerebral cortex, vagus nerve, sympathetic ganglia and the intestinal nerves. The Lewy bodies are cellular membranes composed of misfolded alpha-synuclein. Alpha-synuclein is a protein that is made and involved in neurotransmitter release in neurons. Recent research has articulated the gut microbiome as a major cause of misfolded alpha-synuclein in the nervous system leading to Parkinson’s disease.
Changes in the gut microbiome and the gut bacteria lead to activation of pattern recognition receptors which promote disease onset. Pattern recognition receptors are receptors that function as a surveillance system for bacteria and viruses in our body. Research has shown that certain types of bacteria specifically gram negative aerobes contribute to alpha-synuclein misfolding and accumulation.
Alpha-synuclein is a protein mostly made in the nervous system but is made in blood cells and cells made by the bone marrow. It is found in presynaptic terminals of neurons and is important in healthy neurotransmitter production and function. Fibrillated alpha-synuclein is associated with Lewy bodies that lead to destruction of the nerves in the areas of the brain described above. Alpha-synuclein is critical for the development of dopaminergic neurons and plays an important role in the transport of dopamine. The role of alpha-synuclein as an essential to dopamine neuronal function explains why dopaminergic neurons are preferentially destroyed in Parkinson’s disease since alpha-synuclein fibrillation and Lewy body deposition is the main feature of the disease. When alpha-synuclein accumulates in the nervous system of the intestine called enteric nervous system, colonic dysmotility is induced. Therefore, it can be deduced that alpha-synuclein pathology in the gut may be associated with gastrointestinal symptoms such as constipation which is a characteristic of the disease. Alpha-synuclein may be generated in the enteric nervous system and when propagated through the enteric nerves can actually arrive in the central nervous system by way of the vagus nerve. Recent research has shown that the vagus nerve can transport proteins and chemicals and metabolites via retrograde axonal transport from the intestine to the brain. Furthermore, proteins and metabolites from bacteria or viruses can also enter the brain by transporting along the unmyelinated preganglionic fibers of the vagus nerve.
Intestinal permeability induced by gut dysbiosis is known to decrease short chain fatty acid production and patients with low short chain fatty acid production have increased permeability of the blood brain barrier making the brain even more susceptible to inflammatory metabolites made by gut bacteria that travel to the brain via the vagus nerve. Research is therefore articulating that not only can alpha-synuclein from the gut to the brain via the vagus nerve but also it can develop in the brain as a result of altered short chain fatty acid production from the gut.
Furthermore, alpha-synuclein fibrillation can be enhanced by certain inflammation inducing bacterial metabolites such as lipopolysaccharide which is commonly made by encapsulated gram negative aerobic bacteria which are characteristically dominant in the intestines of patients who have consumed an abundant amount of antibiotics. Animal studies have shown that altered short chain fatty acid production can induce microglial activation in the brain which can also promote alpha-synuclein aggregation and fibrillation.
Researchers have shown that patients with Parkinson’s have higher levels of Enterobacteria compared to healthy patients and excess Enterobacteria are associated with worse motor symptoms in patients with Parkinson’s. Also patients with Parkinson’s are known to have lower levels of butyrate producing bacteria such as Faecalibacterium prausnitzii. Also patients have lower levels of beneficial short chain fatty acids specifically acetate, proprionate and butyrate. Short chain fatty acids are known to be essential to maintaining a healthy blood brain barrier and the blood intestinal barrier. Short chain fatty acids are one of the few substances that can actually cross the blood brain barrier as a result of normal physiology. Decreased levels of intestinal short chain fatty acids can lead to increased gut and blood brain permeability and is associated with triggering alpha-synuclein aggregation and fibrillation.
Recent studies have shown that lipopolysaccharide is a major contributor to aggregation and fibrillation of alpha-synuclein leading to the Parkinson’s disease. Furthermore, there is other data suggesting that alpha-synuclein may function as a messenger to alert the microglia of the presence of pathogenic bacteria which essentially function as a threat to the immune system. Microglial cells are the essential white blood cells of the brain and appear to be controlled by the gut microbiome and gut bacteria.
Alpha-synuclein has been shown to be associated with gut inflammation independent of any neurologic disease. Alpha-synuclein appears to be present and express during both acute and chronic gastrointestinal inflammatory processes and contributes to activation of the immune cells which promote repair in such states.
Constipation is one of the most common symptoms in patients with Parkinson’s and often the constipation is extremely severe causing patients to have a bowel movement only once or twice a week or even less frequent. The cause of such constipation and why it is so difficult as constipation routinely is treated with laxatives or stool softeners is that the cause of it may be altered gut microbial profile and so the constipation in Parkinson’s cannot be meaningfully treated without manipulating the gut bacteria in a beneficial way.
At the Columbia Center for Integrative Medicine, we offer our gut microbiome assessment and repair program for patients with Parkinson’s disease. Typically, patients begin by having severe constipation and movement symptoms along with autonomic symptoms such as postural instability, dizziness and possibly impairment of bladder or bowel sphincter control. Patients with Parkinson’s in our experience typically have had an extraordinary amount of exposure to antibiotics both from exposure to antibiotics in the food system as well as from prescribing doctors in the community. Typically, this leads to antibiotic resisting gram negative aerobes that secrete lipopolysaccharide dominating the intestine.
Our PCR and cultural diagnostic techniques typically pick up a domination of gram negative aerobes, a loss of short chain fatty acid producing Firmicutes species, a loss of short chain fatty acids, increased intestinal permeability, altered TGF-beta levels, and an abnormal total quantity of gut bacteria. We assess all of this as part of our diagnostic methods and we focus on balancing the bacterial system by first suppressing gram negative aerobic bacteria, increasing short chain fatty acid producing bacterial levels, lessening intrinsic inflammation within the intestine, increasing beneficial immunomodulatory substances such as IgA, vitamin A, and vitamin D. We expect constipation to resolve as the first sign of progress followed by improvement in movement disorders.
In conjunction with our gut microbiome repair programs, we also offer IV vitamin C at high doses which has been shown to be beneficial for patients with Parkinson’s as vitamin C promotes a decrease in brain inflammation while promoting dopamine production. We work tirelessly to suppress alpha-synuclein production and microglial activation via our gut microbiome repair program. We monitor patients enterobacterial levels and also focus on lifestyle and diet. Diet ends up being the major contribution of gut microbiome bacterial diversity and overall balance. Evidence shows that dietary interventions represent an essential approach in the treatment and may be even prevention of neurodegenerative and CNS disorders. One diet that has been shown to be evidence based for patients with gut dysbiosis is a keotgenic diet which is significantly low in simple carbohydrates which has been shown to increase cerebral blood flow and increase levels of Akkermansia and Lactobacillus while increasing blood brain barrier integrity.
Dushyant Viswanathan, MD, ABIM, ABOIM, AACE