The Gut and Microbiota : Impacts on Parkinson's Disease

Parkinson’s disease affects between 1–2% of the population over the age of 65 and is becoming a growing concern as the baby boomers advance in age. The condition is characterized by gait abnormalities, tremor, muscle rigidity, and slowing down of movement typically seen as difficulty walking or getting up out of a chair. Parkinson’s disease is classified as a neurodegenerative movement disorder and has a complicated story in terms of its pathophysiology and cause. Several epidemiological studies link pesticides, toxins, and light pollution with increased risk of PD development. At the same time, observation studies report protection with increased coffee intake and exercise. The genetic predisposition is mild, accounting only for 10% of the conditions presentation.

alpha-Synuclein

There are several processes known to contribute to the neuronal loss of cells within the substantia nigra. These include iron deposition, oxidative stress, mitochondrial damage, and accumulation of a protein called alpha-synuclein. alpha-Synuclein is believed to be involved in the transport of vesicles containing neurotransmitters from the cell body to the axons, to participate in the synapse. Parkinson’s disease is not the only condition that sees the aggregation of this protein.^[1] Synucleinopathies, term given to the family of conditions characterized by pathological accumulation of this protein, include Lewy body disease and multiple system atrophy.

The Gut

In addition to the motor symptoms, Parkinson’s disease also includes nonmotor abnormalities such as loss of sense of smell, sleep disturbances, and digestive complaints. The common culprit in these seemingly unrelated symptoms is the aggregation of alpha-synuclein in the peripheral nerves within the olfactory nerve and vagus nerve of the digestive tract. Braak’s hypothesized that Parkinson’s disease may originate in the gut, with alpha-synuclein accumulations propagated via the vagus nerve from the digestive tract into the brain. In fact, the initial degeneration within the brain begins with the cell bodies of the vagus nerve. Furthermore, the symptom of constipation precedes the development of motor symptoms, adding weight to this hypothesis. Observation data on the microflora of the digestive tract of patients with Parkinson’s disease provided another piece to this puzzle. Parkinson’s disease microflora is significantly different from that of healthy age-matched controls, in terms of composition and diversity.^[1] Specifically, patient with Parkinson’s disease have an increase in Christensella minuta, Catabacter hongkongensis, Lactobacillus mucosae, Ruminococcus bromii and Papillibacter cinnamivorans.^[2] In comparison, healthy controls yield the following bacteria: Bacteroides massiliensis, Stoquefichus massiliensis, Bacteroides coprocola, Blautia glucerasea, Dorea longicatena, Bacteroides dorei, Bacteroids pebeus, Prevotella copri, Coprococcus eutactus and Rumino coccuscallidus.

Microflora are now considered the “forgotten organ”, as we learn more about their significant impact on our health and disease. Microflora are known to contribute to the digestion of food, formation of nutrients and toxins, regulation of our immune system, maintenance of the blood-brain barrier, and communication with our nervous system. They influence the production of serotonin, a neuro-hormone responsible for pain and motility within the digestive tract, as well as mood. Additionally, microflora can promote the production of brain-derived neurotrophic factors that regulate development of new connections between neurons, as well neurogenesis itself. Mice deprived of microflora in their infancy develop poor spatial and object recognition, with observable alterations within the hippocampus. Until recently, it was unclear how exactly this change in microflora could contribute to the development of Parkinson’s disease.^[1]

The Microflora

A recent study by Timothy Sampson and his team examined the role of microflora on the etiology of Parkinson’s disease. They collected the fecal matter containing microflora from the patients with Parkinson’s disease, transplanted them to the digestive tract of mice, and compared to the transfer of fecal matter from healthy controls. The mice with the microflora from patients with PD developed motor abnormalities within 8 weeks. The fecal matter from these mice was collected and analyzed, demonstrating a rise in short-chain fatty acid–producing bacteria. The short-chain fatty acids, such as butyrate and propionate, were also increased. When examining the nerves themselves, researcher observed alpha-synuclein aggregations in response to the microflora from PD donors. This creates support for the idea that microflora can stimulate alpha-synuclein aggregations.^[1]

The study went further to explore the role of these short-chain fatty acids. Feeding the mice with short-chain fatty acid–rich mixture resulted in an increase in tumor necrosis factor alpha (a marker of inflammation), in alpha-synuclein aggregation, and in reduced motor function. Giving anti-inflammatory medications interfered with this process and prevented the motor dysfunction along with the protein aggregation. This suggests that the microflora stimulate alpha-synuclein accumulation by producing large amounts of short-chain fatty acids, and that counteracting short-chain fatty acids may prevent the development of motor symptoms.^[1]

The role of short-chain fatty acids and the bacteria that produce them is not as clear as it would seem, as other study reports contradictory results. Microflora was isolated from patients with Parkinson’s disease, analyzed and compared to that of health controls. The results demonstrate a reduction in short-chain fatty acid–producing bacteria in the patients with Parkinson’s disease.^[3] In fact, the study demonstrates a statistically significant reduction of butyrate and priopionate, as opposed to the elevation described by Sampson and his team. The Bacteriodetes and Lactobacilli are consistently reported to be reduced in patients with Parkinson’s disease, while Bifidobacterium and Enterobacteriacea are reported to be elevated, similar to the Sampson study. Short-chain fatty acids are known to influence not only the colonic health, but neurological as butyrate has been implicated in promoting integrity of the blood brain barrier, and some studies report that it can influence the activity of neurons within the enteric nervous system.

Diet and Lifestyle

There are many factors that influence the composition and diversity of the microflora. Naturally, antibiotic use will provide a significant impact, as we know that it can take up to 6 months to recolonize the digestive tract post antibiotic use. By removing some microflora and allowing others to prosper, these medications can alter the composition, in either direction: creating a positive environment by removing the offending, pathogenic bacteria, or stimulating a pro-inflammatory environment by damaging the beneficial and commensal bacteria.

Exposure to environmental pollutants and toxins can also influence the composition by favoring one genus of bacteria over another. What is considered a toxin to one species may be a nutritional substrate to another, thus allowing them to prosper. Furthermore, the growth of a particular species can influence the prosperity of another since the bacteria produce their own byproducts that influence not only our nervous and immune systems, but the health of other organisms in the digestive tract. Pesticides, which have been implicated as a risk factor for developing Parkinson’s disease, can change the composition of the microflora by destroying particular families of microbes. On the other hand, some bacteria are known to have the capacity to breakdown pesticides, potentially protecting us from their toxic effects. Lactobacillus fermentum and Lactobacillus lactis degrade chlorpyrifos, a commonly used organophosphorus insecticide.^[4] Escherichia coli also break them down but to a significantly lower extent. It is possible that the change in microflora composition in patients with Parkinson’s disease results in exposure to a larger amount of environmental pollutants and toxins that are typically cleared by the microflora present in the gut of healthy controls.

Your diet is likely the most significant factor involved in regulating the composition of the microflora. It provides a source of bacteria, as well as nutrients and substrates required for their growth. Prebiotics are composed largely of fiber, indigestible carbohydrates that promote the growth of beneficial bacteria. Observational data on the risks and protective factors of Parkinson’s disease provide evidence for the beneficial role of coffee and blueberries, as well as the harmful effects of dairy.^[5] These foods influence motor function by providing a rich supply of antioxidants, nutrients, and anti-inflammatory effects that provide protection to the neurons and offset the increase in oxidative stress seen with Parkinson’s disease. That being said, it’s possible that these foods are also protective because of their influence on the digestive tract. The fruits and vegetables that are frequently cited as beneficial for neurodegenerative conditions are also high in fiber and can serve as an important source of prebiotic.

The list of factors that can influence the microflora is diverse and growing as research of these organisms continues to evolve. Some of these additional factors include geographic region, sex, hormones, age, comorbid conditions; these influence the function of the immune system, which in turn influences the bacteria that can colonize the digestive tract. Mood, anxiety, and other neurological changes can also influence gastrointestinal function, and thus, the microflora.

Conclusion

While our understanding of the exact nature of this complicated relationship between microflora and Parkinson’s disease continues to evolve, current evidence suggests that microflora may be at the root of the problem. The ability to trigger motor dysfunction in mice by transplanting fecal matter from patients with Parkinson’s strengthens the hypothesis that the etiology of Parkinson’s disease lies in the digestive tract. Thus, it is reasonable to hypothesize that the cure to Parkinson’s disease may also reside in the digestive tract and that this may be the place to focus on with respect to therapeutic approaches.