• Parkinson_gut

Does Parkinson’s begin in the gut?

Introduction

Parkinson’s disease is one of the most known progressive neurodegenerative diseases. (Hayes, 2019)

It is characterized by aggregates of alpha-synuclein called Lewy bodies and loss of dopaminergic neurons located in the substantia nigra.

It causes tremors and uncoordinated movements.

There are several hypotheses stating that Parkinson’s disease has two subtypes. The first one is called “Brain-first” type where the pathology starts in the brain and then develops further into the peripheral autonomic nervous system. The second one is named “Body first” type where, inversally the illness originates in the enteric or peripheral autonomic nervous system and later spreads to the brain by retrograd vagal transport ( Horsager et al., 2020 ).

We are going to focus our research based on the latter one.

Connection between the brain and the gut

“All disease begins in the gut.”

–Hippocrates of Kos (Hippokrátēs ho Kṓos: c. 460–c. 370 BCE) (Cryan et al., 2019)

Parkinson's disease (PD) is known to be mainly caused by the presence of the Lewy Bodies, which are majorly constituted by a misfolded, neuronal protein called α-synuclein, in the brain and the peripheral nerves. This α-synuclein in a healthy and normal brain, is important at the level of the synapses in the neurons which is the main site of connection between the brain cells. But its abnormal deposits (Lewy Bodies) in the brain affects the neurons and their affectivity, as well as some brain chemicals and their normal activity. (Borghammer and Van Den Berge, no date)

Many studies have suggested the possibility of the PD starting from the gut, and this has been strongly supported when aggregates of α-synuclein were found in the enteric nerves of people suffering from this disease. As a result, this proves the presence of many connections between the Brain and the Gut also known as the Gut-Brain Axis. (Cryan et al., 2019)

Autonomic nervous system (ANS)

The Autonomic Nervous System is a neural pathway and is a part of the peripheral and central nervous systems. It regulates, autonomously, many physiological processes such as heart rate, digestion, water balance, urinations, sexual responses…and that by supplying the blood vessels and the different internal organs such as the stomach, intestines, lungs, heart, bladder, kidney, liver, genitals and the glands (digestive, sweat and salivary). (Waxenbaum, Reddy and Varacallo, 2021)

The ANS comprises 2 main divisions, sympathetic and parasympathetic branches, containing afferent and efferent fibers connecting the 2 nerve cells of this bidirectional autonomic nervous pathway. These latter sets of nerve bodies are associated with:

• Preganglionic neuron with its cell body located in the Central Nervous System CNS
• Postganglionic neuron having a set of fibers connecting the ganglia to the cell body situated in the target organ’s periphery (Waxenbaum, Reddy and Varacallo, 2021)

Sympathetic nervous system (SNS)

The activation of this system after receiving information presenting a danger or a threat to the body, leads to the ‘fight-or-flight’ reaction which prepares the body for a stressful situation by increasing heart and breathing rates, increasing muscular strength. It also causes the pupil dilation, increases the sweat production and slows down digestion and urination. The sympathetic neurons have their preganglionic cell bodies located in the intermediolateral cell column of the spinal cord and the preganglionic fibers leave the spinal cord at the level of T1-L3 through the ventral root pass through the paravertebral ganglia, which are adjacent to the spine forming a sympathetic chain. Arriving to the prevertebral ganglia, the preganglionic fibers synapse with the postganglionic fibers and then finally reach the terminal ganglia lying near or within the effector organ (stomach, intestines, lungs, glands…) (Waxenbaum, Reddy and Varacallo, 2021).

Parasympathetic nervous system (PNS)

• The PNS is active during the ‘rest-and-digest’ phases and stimulates digestion, by stimulating the digestive enzymes production, and urination. It also decreases the blood pressure, heart and respiratory rates. (Waxenbaum, Reddy and Varacallo, 2021) The preganglionic cell bodies of the parasympathetic neurons are located in the sacral region of the spinal cord and in the brain stem. The preganglionic fibers exit the central nervous systems with the cranial nerves (CN) III, VII, IX, and X, and exits the spinal cord at the level of S2-S4 nerve roots. (Waxenbaum, Reddy and Varacallo, 2021)

The vagus nerve (CN X)

• The Vagus Nerve is composed of around 75% of the parasympathetic fibers and innervates most of the internal organs of the thoracic and abdominal cavities and is responsible for the internal organs functions regulation (Waxenbaum, Reddy and Varacallo, 2021). It represents especially the most important and direct pathway relating the brain and the gut by sending to the brain, via afferent fibers, signals from the digestive system and vice versa through efferent fibers (Figure 1). The VN mainly innervates the gut through its hepatic and celiac branches, after it has exited from the medulla oblongata and gave many branches to the pharynx, larynx muscles, heart…(Cryan et al., 2019) (Waxenbaum, Reddy and Varacallo, 2021) The Vagus nerve represents a bidirectional connection for the brain-gut-axis, by linking the cognitive and emotional brain areas with the peripheral intestinal functions. The vagal afferent fibers play a major role in the activation and regulation of the Hypothalamic-Pituitary-Adrenal axis (HPA axis) which is the central system responsible for the stress responses and so, both the HPA axis and the vagus nerve combine to allow the mutual influence between the brain and the intestinal functions. (Breit et al., 2018)

Studies

In the beginning of the 21st century, Heiko braak and his colleagues carried out studies regarding the transmission of Parkinson's disease from the gut to the brain ( Heather Wood, 2019 ). They targeted their research on the implication of the vagus nerve. Indeed, they concluded that this latter one played an important role in the transmission of the alpha-synuclein pathology from the gut to the brain. Their conclusions arised from post-mortem studies ( Heather Wood, 2019 ).

• Further studies were carried out directly on rodents. These animals enabled the scientifics to get as close as possible to a representation of the gut-brain alpha synuclein transmission as of now ( Heather Wood, 2019 ) .

Ted Dawson and Han Seok Ko ( Johns Hopkins University School of Medicine, Baltimore, USA ) based their studies on mices. They injected alpha- synuclein PFFs ( Pre-formed fibrils ) into their pylorus and duodenum. A month after their injection, they could observe alpha-synuclein aggregates in the dorsal motor nucleus of the vagus nerve and in the locus coeruleus ( LC ). In the PD, the LC is believed to be the first region affected by degeneration ( Paredes-Rodriguez et al., 2020 ). These aggregations of pathological alpha-synuclein then reached the substantia nigra. Heather Wood ( 2019 ) stated that : ”The spread of the pathology was paralleled by loss of dopaminergic neurons and was also associated with the emergence of motor and non-motor symptoms resembling idiopathic Pd”. Han Seok Ko added that based on their experiments, rodents who underwent truncal vagotomy or had a diminished presence of endogenous alpha-synuclein did not show any signs of pathology. In conclusion, this study permitted the researchers to prove the role the vagus nerve has in the transmission of the pathology from the gut to the brain.

• Another experiment was carried out using a human PD brain lysate ( A fluid containing the contents of lysed cells is called a lysate - wikipedia ) in an in vivo animal model ( Holmqvist et al., 2014 ). Alpha-synuclein proteins were present in the fluid. This latter one was injected into the animal’s intestinal wall. Once again, after a certain time, the role of the vagus nerve was proved to be major : it transported the alpha-synuclein proteins all the way towards the dorsal motor nucleus of the nerve ( Holmqvist et al., 2014 ). Anew, this experimental evidence supports the idea of the propagation from the gut to the brain of pathology.

Enteric nervous system (ENS)

• The enteric nervous system is a quasi-autonomic nervous system independent from the rest of the nervous system and controls the gastrointestinal system. It includes numerous neural pathways to control the motor functions of the digestive system, the mucosal secretion and absorption, the blood flow…(Costa, Brookes and Hennig, 2000) This nervous system has 2 ganglionated plexuses: the myenteric plexus which controls the coordination of the motility of the gut muscles, and the submucosal plexus which controls the fluid movements across the intestinal wall. (Waxenbaum, Reddy and Varacallo, 2021)

  The ENS is part of the brain-gut axis and communicates with the CNS via afferent intestinofugal neurons which have their cell bodies in the wall of the gut and are connected to sympathetic ganglia, transporting sensory information along the spinal and vagal afferent pathways (Figure 1). These latter create a way for the elements present in the gut, like the gut microbiota, to travel to the brain, and so, not only influence the gut activity but also the CNS. (Cryan et al., 2019)

Neurotransmitters

• Many studies have shown that the gut and brain are connected through numerous neurotransmitters which control not only the feelings and emotions, but also influence the GI functions by affecting the gut motility, the absorption of nutrients... Many of these neurotransmitters are produced by the gut microbiota and are clearly influenced by them. In some diseases, such as PD or the inflammatory bowel disease, their levels are dysregulated.(Mittal et al., 2017)

Serotonin

• Serotonin (5-hydroxytryptamine, 5-HT) is mainly synthesized (more than 90%) in the gut from tryptophan via the TPH enzyme by the GI tract’s enterochromaffin cells (ECs), and is regulated by the microbiota. Some of the serotonin is also produced in the CNS This 5-HT contributes to the general mood stabilization and to the feelings of happiness as it plays the role of a brain neurotransmitter, and influences the digestion and the enteric system reflexes.(Yano et al., 2015) The dysregulation of this neurotransmitter leads to many diseases such as bipolar disorder, major depressive disorder, irritable bowel syndrome…(Anguelova, Benkelfat and Turecki, 2003)(Yano et al., 2015) and this made many researchers conclude the influence of the gut microbiota of 5-HT along the gut microbiota-gut-brain axis.

GABA

• Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the CNS, is produced by the gut bacteria from the conversion of amino acid glutamate.This neurotransmitter controls the neural excitability by reducing anxiety, depression and fear sensations. The disruption of the GABA levels causes many CNS disorders (behavioral, sleep…) and ENS disorders (acid secretion, gastric motility…) The GABA levels are influenced by the microbiota since it was found out that germ-free animals have low levels of luminal and serum GABA, even though the cerebral GABA levels remained unchanged (Strandwitz, 2018)

Catecholamines

• There are 3 principal catécholamines: (Mittal et al., 2017)

• Dopamine which is a central acting catecholamine.
• Norepinephrine (noradrenaline) and Epinephrine (adrenaline)
  • These catecholamines influence the gut motility and functions, as it has been shown that many bacteria which can be found in the GI tract can produce these catecholamine. (Strandwitz, 2018)

    According to a study made recently, it was suggested that the microbiota influences the levels of catecholamines when it was shown that germ free mice (GF) have reduced levels of norepinephrine in the cecal lumen. In addition, GF mice had increased levels of dopamine and norepinephrine in the brain. (Strandwitz, 2018) Even with all the evidence about the effects of the catecholamine on the GI tract microbiota, the influence of the bacterial neurotransmitters on the host physiology and its implication is still unknown.

Gut’s microbiota

Gastrointestinal tract and patients having Parkinson

• It is known that the gut microbiota interacts with the host via several biochemical and functional reactions. This results in affecting the owner’s homeostasis and health. In general, the microbial composition is stable in healthy people . It can be altered by several motives, for example antibiotics or diseases that affect the recovery of the microbiota. Nevertheless, it always comes back to its original composition. It is important to underline that repeated damage can be a factor for slow recovery of the microbiota, as much as aging that affects it and the balance of the brain and of the gut. (Valentina Caputi and Maria Cecilia Giron, 2018). The attention towards the gastrointestinal disorders was focused further when it was noticed during the study of Edwards et al (1992), that Parkinson patients had several problems with their digestive tract. This includes delayed gastric emptying, nausea, and constipation (Agata Mulak and Bruno Bonaz, 2015). On top of that, some disturbances in oral and pharyngeal swallowing are known to be common in other neurological illnesses and this brought suspicions that it could also be linked to the sickness itself. (Valentina Caputi and Maria Cecilia Giron, 2018) In fact, it was noticed that expressions such as constipations is a major enteric dysfunction of Parkinson disease and anticipates motor symptoms years before the manifestation of the sickness and takes part of the earliest biomarkers of the pathological evolution of Parkinson (Valentina Caputi and Maria Cecilia Giron, 2018). Moreover, cases with peptic ulcer and Heliobacter pylory ( Hp) are progressively discovered in Parkinson’s patients. (Valentina Caputi and Maria Cecilia Giron, 2018) This is because the gut microbiota composition is altered in Parkinson’s patients and related to the physical symptoms of the disease. (Valentina Caputi and Maria Cecilia Giron, 2018)

Microbiome alterations

• The enteric nervous system is one of the largest nervous systems. It regulates most functions in the gastrointestinal tract. In fact, the enteric neurons and glial cells form a big communication network closely connected with the gut microbiota. Therefore, the enteric nervous system can be without doubt affected by any gut microbiome changes and be ramified in gastrointestinal disorders and thus, neurodegenerative diseases (Valentina Caputi and Maria Cecilia Giron, 2018).

Enterobacteriaceae and Prevotellaceae

• Two main bacterias play an important role in Parkinson's disease: Enterobacteriaceae and Prevotellaceae. Their abundance in the gut has a significant consequence on the patients suffering from the sickness. It is stated in a report of Scheperjans and colleagues ( 2015), that higher levels of Enterobacteriaceae are proven to have an impact with the pace and the posture incapability level. However, there is also the decrease of Prevotellaceae ( Agata Mulak and Bruno Bonaz, 2015). One of it’s roles consists in the production of mucin in the gut mucosal layer. Therefore, when their population decreases, the synthesis of mucin also does and the intestinal permeability is aggrandized ( also known as leaky gut syndrome). This brings to a bigger exposure towards bacterial antigens, endotoxins, and more importantly to a potential development of alpha- synucleinopathy and leads it in the enteric nervous system due to inflammation and oxidative stress ( Valentina Caputi and Maria Ccecilia Giron, 2018). As it is known, Parkinson disease is also linked with dopamine activity. Enterobacteriaceae population increases such as the one of Lactobacillaceae. The later one reduces the amount of the gut hormone ghrelin, in control of the physiological nigrostriatal dopamine activity. Thus, diminishing the content of ghrelin, there is less dopamine and in consequence, less motility abilities ( Valentina Caputi and Maria Cecilia Giron, 2018).

Lypolysacharides

• There is another factor that causes neuroinflammation, and on top of that, damage in the substantia nigra. It occurs when there is a high proportion of pro- inflammatory, bacterial endotoxin lipopolysaccharides derived from the gut ( Valentina Caputi and Maria Cecilia Giron, 2018). It can deteriorate the blood brain barrier whose components such as endothelial cells, microglia, and neurons, preserve the brain homeostasis ( Jessica Maiuolo, Micaela Gliozzi et al, 2018). This not only may increase the alpha- synuclein uptake, stated by Sui et al (2014), but also leads to facilitating the travelling of numerous toxins to the brain, resulting in neurodegenerative diseases such as the Parkinson ( Agata Mulak and Bruno Bonaz, 2015). Dysbiosis of the microbiota is believed to be linked with the development of Parkinson's disease. Indeed, its disbalanced composition produces abnormal products which are linked with the alpha synucleinopathy. Emily Fitzgerald et al ( 2019 ) stated that “ Recent studies suggests that the bacterial LPS may play a large role in the inflammatory process of neurodegenerative disease (Changyoun et al., 2016; Stolzenberg et al., 2017; Terada et al., 2018)“. Some researchers wanted to point out the link between LPS and alpha synucleinopathies. One mice was injected alpha-synuclein intracerebrally and exposed to LPS positive bacteria, while the other was exposed to LPS negative bacteria. When comparing the two rodents, it could be deducted that the display to LPS encouraged the alpha-synuclein to change its configuration to fibrillar form ( Changyoun et al., 2016). In conclusion, Chen et al. ( 2021 ) stated that “ Therefore, bacterial contact, especially LPS positive bacteria, may be the driving force of α -SYN disease”. Gut mucosa is in contact with environmental elements that can carry external triggers such as diet derived molecules, toxins and microbes. This causes changes in the intestinal flora and brings the enteric bacteria to produce abnormal compounds with toxic effects for instance D-lactic, ammonia as neurotoxic molecules in addition to other neurotoxins. They can reach the central nervous system thanks to the systemic circulation or to the extrinsic afferent nerve fibres from the gut to the brainstem, resulting in neuronal injury. Not only that, but they can also give rise to the excessive production of alpha-synuclein. They can affect the initiation of Parkinson disease in a case of genetic vulnerability and spread it, thanks to the wide connexion of the gut ( Valentina Caputi and Maria Cecilia Giron, 2018).

Conclusion

• Even if most studies suggest that the initiating point of Parkinson’s disease might be elsewhere in the body, such as the brain itself, we know that, based on our research, there are other starting points and the gut might be one of them. (Though the dysbiosis of the gut has been proved to be linked to the susceptibility of developing parkinson disease, it is not the only factor that will trigger this neurodegenerative disease) However, as mentioned above, most of the information that was gathered are mostly hypotheses so further research on the gastrointestinal tract and its environment is needed to bring to light all the points of the disease.

References

Anguelova, M., Benkelfat, C. and Turecki, G. (2003) ‘A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders’, Molecular Psychiatry, 8(6), pp. 574–591. doi: 10.1038/sj.mp.4001328.

Borghammer, P. and Van Den Berge, N. (no date) ‘Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis’, Journal of Parkinson’s Disease, 9(Suppl 2), pp. S281–S295. doi: 10.3233/JPD-191721.

Breit, S. et al. (2018) ‘Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders’, Frontiers in Psychiatry, 9. doi: 10.3389/fpsyt.2018.00044.

Caputi, V. and Giron, M. C. (2018) ‘Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson’s Disease’, International Journal of Molecular Sciences, 19(6), p. 1689. doi: 10.3390/ijms19061689.

Chen, Z.-J. et al. (2021) ‘Association of Parkinson’s Disease With Microbes and Microbiological Therapy’, Frontiers in Cellular and Infection Microbiology, 11. doi: 10.3389/fcimb.2021.619354.

Costa, M., Brookes, S. J. H. and Hennig, G. W. (2000) ‘Anatomy and physiology of the enteric nervous system’, Gut, 47(suppl 4), pp. iv15–iv19. doi: 10.1136/gut.47.suppl_4.iv15.

Cryan, J. F. et al. (2019) ‘The Microbiota-Gut-Brain Axis’, Physiological Reviews, 99(4), pp. 1877–2013. doi: 10.1152/physrev.00018.2018.

Fitzgerald, E., Murphy, S. and Martinson, H. A. (2019) ‘Alpha-Synuclein Pathology and the Role of the Microbiota in Parkinson’s Disease’, Frontiers in Neuroscience, 13. doi: 10.3389/fnins.2019.00369.

Hayes, M. T. (2019) ‘Parkinson’s Disease and Parkinsonism’, The American Journal of Medicine, 132(7), pp. 802–807. doi: 10.1016/j.amjmed.2019.03.001.

Holmqvist, S. et al. (2014) ‘Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats’, Acta Neuropathologica, 128(6), pp. 805–820. doi: 10.1007/s00401-014-1343-6.

Horsager, J. et al. (2020) ‘Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study’, Brain. doi: 10.1093/brain/awaa238.

Liddle, R. A. (2018) ‘Parkinson’s Disease from the Gut’, Brain research, 1693(Pt B), pp. 201–206. doi: 10.1016/j.brainres.2018.01.010.

Maiuolo, J. et al. (2018) ‘The “Frail” Brain Blood Barrier in Neurodegenerative Diseases: Role of Early Disruption of Endothelial Cell-to-Cell Connections’, International Journal of Molecular Sciences, 19(9), p. 2693. doi: 10.3390/ijms19092693.

Mittal, R. et al. (2017) ‘Neurotransmitters: The critical modulators regulating gut-brain axis’, Journal of cellular physiology, 232(9), pp. 2359–2372. doi: 10.1002/jcp.25518.

Mulak, A. and Bonaz, B. (2015) ‘Brain-gut-microbiota axis in Parkinson’s disease’, World Journal of Gastroenterology, 21(37), pp. 10609–10620. doi: 10.3748/wjg.v21.i37.10609.

Paredes-Rodriguez, E. et al. (2020) ‘The Noradrenergic System in Parkinson’s Disease’, Frontiers in Pharmacology, 11, p. 435. doi: 10.3389/fphar.2020.00435.

Strandwitz, P. (2018) ‘Neurotransmitter modulation by the gut microbiota’, Brain research, 1693(Pt B), pp. 128–133. doi: 10.1016/j.brainres.2018.03.015.

Waxenbaum, J. A., Reddy, V. and Varacallo, M. (2021) ‘Anatomy, Autonomic Nervous System’, in StatPearls. Treasure Island (FL): StatPearls Publishing. Available at: http://www.ncbi.nlm.nih.gov/books/NBK539845/ (Accessed: 9 May 2021).

Yano, J. M. et al. (2015) ‘Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis’, Cell, 161(2), pp. 264–276. doi: 10.1016/j.cell.2015.02.047

Other sources :

Definition of Lysate - https://en.wikipedia.org/wiki/Lysis

Figure 1 : https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2018000200067&fbclid=IwAR0bLV2OmnvxD2CER76a3lE5fxNDfG-FO1u4pJLvIEA430VuIRRxKs-SRu4