How the gut microbiota affects neurological disorders: An Insight into Parkinson’s Disease

By Yuki Agarwala

Our gut is home to approximately 100 trillion bacteria, both good and bad, which are collectively known as the gut microbiota (Can gut bacteria, 2016). This represents 10 times the number of cells in the human body, and a stunning 3 million genes. Interestingly, only around 1~3% of these bacteria are common in the population, and approximately two thirds of the bacteria are unique to each individual (Yang et al., 2019) With such a large bacterial population living in our gut, we can only imagine the numerous complex interactions they are responsible for. Therefore, it is not surprising to learn that the composition of the gut microbiota influences various gastrointestinal disorders such as Crohn’s disease, colorectal cancer, and celiac disease. However, have you ever wondered how microbes in our gut could affect neurological disorders? (Cryan et al., 2019; Nagao, 2016)

The gut microbiota is important for sensing, filtering, and modifying large amounts of chemical signals from the environment which circulate throughout the body. The gut microbiota has been shown to influence the “gut-brain axis”, which is a network of connections important for bidirectional communication between the gastrointestinal, nervous, and immune systems. These communications involve direct and indirect chemical signaling pathways which are all crucial for maintaining homeostasis of the various organ systems (Morais, 2020; Ma et al., 2019). Pre-clinical studies in mouse models have shown that the composition and imbalance of the gut microbiota can have severe implications on neurological diseases. For example, germ-free mice which were devoid of the gut microflora displayed learning and memory deficiencies and experienced changes to their emotional behaviors. In humans, conditions such as depression and autism have been linked to gastrointestinal pathology. This exemplifies the role of the gut microbiota in the gut-brain axis. Although the gut microbiota might seem unrelated to the nervous system at first glance, research in this emerging field could provide an interesting target for therapeutic treatment of neurological disorders such as Parkinson’s disease (Ma et al., 2019). 

Parkinson’s disease (PD) is common neurodegenerative disorder characterized by tremors, muscle rigidity, stiffness, and impaired balance (National Institute, 2017). Complex genetic and environmental factors are associated with the development of this disease, and the symptoms become more difficult to manage as the disease progresses. PD is associated with a loss of dopaminergic neurons and aggregation of alpha-synucleins in the substantia nigra. Dopaminergic neurons play a crucial role in important brain functions such as movement and behavioral processes (Chinta and Anderson, 2005) and the aggregation of the alpha-synucleins proteins cause dysfunctionality and degeneration of neurons in PD (Gomez-Benito et al., 2020). By the end of life, up to 70% of the dopaminergic neurons in the substantia nigra may be affected. This is responsible for the symptoms concerning movement, and for vagal nerve dysfunction, which is the pathway between the gut and the brain (Yang et al., 2019). 

New evidence suggests that diseases related to alpha-synuclein aggregation (alpha-syncleinopathies) initially occur in the enteric nervous system which is the part of the peripheral nervous system that controls gastrointestinal function (Rao and Gershon, 2016). Research in mice overexpressing human alpha-synuclein but lacking a gut microbiota have shown reduced short chain fatty acid production, and thus reduced alpha-syncleinopathies. When these mice were transplanted with the gut microbiota of PD patients, the motor symptoms worsened compared to transplantation with microbiota of healthy individuals. This shows that the imbalance of the gut microflora exacerbated the motor symptoms, which provides further evidence for the link between the gut microbiota and the development of PD (Morais et al., 2020).

The composition of the gut microbiota and a few distinct symptoms have been found when comparing PD patients to healthy individuals. For example, digestive symptoms such as constipation have been reported in up to 80% of individuals in the years leading up to PD diagnosis (Morais et al., 2020). Feces from PD patients have also shown a higher proportion of pro-inflammatory gut bacteria and reduced numbers of bacteria with anti-inflammatory properties. This corresponds to the inflammation observed due to the misfolding of alpha-synuclein. Moreover, the severity of symptoms and posture stability have been shown to be influenced by an increase in bacteria of the Enterobacteriaceae family. These bacteria are associated with the inflammatory bowel disease, Crohn’s disease, and patients with Crohn’s disease are known to be at increased risk of developing PD. Likewise, patients treated with anti-inflammatory drugs for Crohn’s disease are at reduced risk of developing PD. Additionally, lack of Lachnospiraceae bacteria leads to more severe motor symptoms (Ma et al., 2019). Certain strains of Escherichia Coli, which are found in higher numbers in patients with PD, can produce amyloid proteins called curli, which promote alpha-synuclein aggregation. Mice with curli dependent alpha synuclein aggregates showed increased motor symptoms. Furthermore, mice treated with an inhibitor of amyloid showed reduced motor symptoms, indicating that certain bacteria in the gut microbiota could be responsible for the symptoms of PD (Morais et al., 2020)

Due to the complexity of the interactions between the gut microbiota and neurological diseases such as Parkinson’s disease, there are still many missing links that are yet to be investigated. However, early evidence has shown how dysbiosis, or the imbalance, in the gut microbiota has resulted in worsening of the symptoms which are commonly associated with PD. Thus, this strongly suggests that identifying the relationships between the microbiota and the development of PD could potentially shed light on new targets for antibiotics or probiotics, leading to more effective treatment of the disease.

References:

Can gut bacteria improve your health? [Online] (2016). Available from: https://www.health.harvard.edu/staying-healthy/can-gut-bacteria-improve-your-health [Accessed: 10 February 2021].

Yang, D., Zhao, D., Shah, S.Z.A., Wu, W., et al. (2019) The Role of the Gut Microbiota in the Pathogenesis of Parkinsons Disease. Frontiers in Neurology. [Online] 10. Available from: doi:10.3389/fneur.2019.01155.

Cryan, J.F., Oriordan, K.J., Sandhu, K., Peterson, V., et al. (2019) The gut microbiome in neurological disorders. The Lancet Neurology. [Online] 19 (2), 179–194. Available from: doi:10.1016/s1474-4422(19)30356-4.

Nagao-Kitamoto, H., Kitamoto, S., Kuffa, P. & Kamada, N. (2016) Pathogenic role of the gut microbiota in gastrointestinal diseases. Intestinal Research. [Online] 14 (2), 127. Available from: doi:10.5217/ir.2016.14.2.127.

Morais, L.H., Schreiber, H.L. & Mazmanian, S.K. (2020) The gut microbiota–brain axis in behaviour and brain disorders. Nature Reviews Microbiology. [Online] Available from: doi:10.1038/s41579-020-00460-0.

Ma, Q., Xing, C., Long, W., Wang, H.Y., et al. (2019) Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. Journal of Neuroinflammation. [Online] 16 (1). Available from: doi:10.1186/s12974-019-1434-3.

National Institute on Aging (2017) Parkinson’s Disease. [Online]. Available from: https://www.nia.nih.gov/health/parkinsons-disease [Accessed: 12 February 2021].

Chinta, S.J. & Andersen, J.K. (2005) Dopaminergic neurons. The International Journal of Biochemistry & Cell Biology. [Online] 37 (5), 942–946. Available from: doi:10.1016/j.biocel.2004.09.009.

Gómez-Benito, M., Granado, N., García-Sanz, P., Michel, A., et al. (2020) Modeling Parkinson’s Disease With the Alpha-Synuclein Protein. Frontiers in Pharmacology. [Online] 11. Available from: doi:10.3389/fphar.2020.00356.

Rao, M. & Gershon, M.D. (2016) The bowel and beyond: the enteric nervous system in neurological disorders. Nature Reviews Gastroenterology & Hepatology. [Online] 13 (9), 517–528. Available from: doi:10.1038/nrgastro.2016.107.

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