The Digestive Tract and Parkinson's Disease: A Possible Link
A Disease That Might Start in the Gut
Parkinson’s disease is a neurodegenerative disorder which primarily affects movement. It’s chronic and progressive, although the severity of the symptoms and the speed of deterioration vary in different patients. The disease involves specific brain changes. These include loss of dopamine and the appearance of Lewy bodies containing tangles of a protein called alpha-synuclein. There is a growing suspicion that the digestive tract also plays a role in Parkinson's disease, however. Some evidence suggests that the disease actually begins in the digestive tract and reaches the brain later. Understanding the cause of the disorder could lead to the creation of better treatments.
An Overview of Parkinson's Disease
Parkinson's disease is named after James Parkinson, a Scottish physician. In 1817, he published an article entitled "An Essay on the Shaking Palsy" in which he described the typical symptoms of Parkinson's disease. The disease was eventually renamed in his honour. Today it's also known as Parkinson's or as PD.
Some common symptoms of the disease are listed below. A particular patient may not have all of the symptoms. In addition, the symptoms that are present may indicate the presence of a different health problem. Anyone who has the symptoms should visit a doctor for a diagnosis and treatment recommendations.
- muscle tremors
- slow and difficult movement
- balance problems
- rigid muscles
- difficulty in speaking
- difficulty in writing
Non-motor symptoms may also be present, including:
- mood disorders
- cognitive problems
- problem related to sleep
- vision problems
- changes in the ability to smell and taste
- urinary frequency
James Parkinson was born on April 11th, 1755. Today April 11th is known as World Parkinson's Day.
Dopamine Loss and Lewy Bodies
Researchers have discovered that a region of the brain called the substantia nigra is affected in people with Parkinson's disease. The region is normally dark in colour due to the presence of a pigment called neuromelanin. In PD, neurons in the substantia nigra that normally produce dopamine no longer do their job. Dopamine is a neurotransmitter, or a chemical that transmits a signal from one neuron to another. Neuromelanin is made during the production of dopamine, so the substantia nigra becomes lighter in colour in people with PD.
Another brain change is the appearance of Lewy bodies and Lewy neurites inside neurons. Lewy bodies are relatively large, roughly spherical to oval structures. They are found in the cell body of a neuron. Lewy neurites are long and narrow structures that are located in the axons of neurons. Both structures are made of multiple substances, including tangles of alpha-synuclein fibrils. They are found in the substantia nigra and in other parts of the brain.
Protein molecules have a distinct and complex shape, which is required in order for them to do their jobs. The alpha-synuclein molecules in the brain of a Parkinson's disease patient are misfolded as well as tangled. The misfolded strands have the ability to cause nearby strands of alpha-synuclein with a normal structure to misfold. The protein is said to have prion-like propagation. A prion is a misfolded piece of protein that causes other proteins to misfold and produces some serious diseases, including Creutzfeldt-Jakob disease or CJD.
The normal function of alpha-synuclein in the body is unknown. It has been found around synaptic vesicles, which are involving in transmitting the nerve impulse between neurons. The vesicles release neurotransmitter molecules, which stimulate the next neuron. Alpha-synuclein may therefore have something to do with neurotransmission.
Constipation Before Parkinson's Disease
Some people experience constipation along with movement problems in Parkinson's disease. When some British researchers analyzed published reports, however, they discovered that a significant number of people mentioned in the studies experienced constipation before the muscle problems of Parkinson's appeared. The researchers also discovered that the constipation sometimes began more than a decade before the Parkinson's symptoms. (The constipation was an ongoing problem and not the occasional condition that healthy people might experience.) The early constipation may be caused by a different factor from the constipation that develops later.
The researchers examined the results of nine studies involving a total of 741,593 people. The pooled OR (odds ratio) of someone with constipation later developing Parkinson's disease was 2.27 compared to those without constipation. An OR of greater than 1 is significant. When the researchers restricted their analysis to constipation more than a decade before the first muscle problems, the pooled OR was 2.13. It's important to note that the results indicate an association and not necessarily a causal relationship. Nevertheless, they do suggest that a problem in the large intestine (where feces is produced) might be related to the development of Parkinson's disease.
The digestive tract is also known as the gastrointestinal tract, the GI tract, the alimentary canal, and the gut. The stomach, small intestine, and large intestine are major parts of the digestive tract.
Alpha-Synuclein in the Intestinal Nerves
The intestine is surrounded by a network of nerves that travel through the intestinal wall and make up the enteric nervous system. The system is sometimes referred to as a "second brain". Some Parkinson's patients have been found to have alpha-synuclein in both their enteric nervous system and their brain. The vagus nerve connects the enteric nervous system to the brain.
In 2014, a multinational team of researchers created a mixture of various types of human alpha-synuclein, some of which came from Parkinson's patients. They injected the mixture into the gut wall of rats. They found that the protein entered the vagus nerve and travelled up the nerve to the brainstem. The scientists say that this is the first experimental evidence that different forms of alpha-synuclein can travel from the gut to the brain (at least in rats).
Alpha-Synuclein and Gut Inflammation
One fact that puzzles researchers is why alpha-synuclein collects in the nerves around the gut. In 2017, a US research team found that protein had collected in the enteric nervous system of children who were experiencing gut inflammation as a result of various conditions, including an infection by norovirus. They also discovered that the amount of the protein in the nerves correlated with the severity of the inflammation in the gut.
In lab equipment, the alpha-synuclein attracted cells from the immune system, including neutrophils and monocytes (types of white blood cells). The researchers believe that the protein produced the intestinal inflammation as part of an immune response instead of the inflammation triggering the appearance of the protein. Inflammation is often a helpful process for repairing injuries and getting rid of pathogens, but not if it's excessive.
The scientists propose that alpha-synuclein production in the gut is a normal activity in the immune system that becomes out of control in Parkinson's disease. Specific pathogens in the gut may trigger an excessive production of alpha-synuclein with abnormal properties, especially if infections are severe and repeated or if they are chronic.
According to the researchers, one chronic infection that may trigger abnormal alpha-synuclein production is caused by the bacterium named Helicobacter pylori. The researchers say that there is an association between a chronic H. pylori infection in the gut and an increased risk of PD. H.pylori is the bacterium that produces peptic ulcers. A vagotomy (removal of part of the vagus nerve) is sometimes used to treat the ulcers. Patients who receive this treatment have a decreased risk of PD.
A Possible Effect of Another Gut Microbe
An interesting experiment with animals indicates that a protein made by specific gut bacteria can trigger alpha-synuclein deposits in both the intestine and the brain of rats. The protein is made by some Escherichia coli bacteria and is known as amyloid protein curli, or curli for short.
The animals involved in the experiment were elderly rats. After bacteria producing curli were placed in the gut of the animals, an increased amount of alpha-synuclein was found in the nerves of both the gut and the brain of the animals. In addition, researchers observed a change in behaviour of the glial cells in the central nervous system in response to the increased level of alpha-synuclein. Neither of these effects were produced when bacteria that couldn't produce curli were placed in the rats.
Role of the Olfactory Bulb
Although multiple researchers are exploring the role of the digestive tract in Parkinson's disease, some are paying attention to the olfactory bulb instead. The bulb is located at the base of the brain and in involved in the sense of smell.
Nerves and receptors extend from the bulb into the lining of the nasal cavity. The receptors send signals to the olfactory bulb, which then sends messages to other parts of the brain. People with PD may experience problems with their sense of smell years before movement problems appear.
Scientists at the Max Planck Research Unit for Neurogenics and the University of Auckland have discovered that people with Parkinson's have half the total volume of functional units (glomeruli) in their olfactory bulb compared to the situation in healthy people. In addition, the distribution of the functional units is different.
Some researchers say that Lewy bodies are found in the olfactory bulb before they are found in the substantia nigra (at least in the cases that they've studied). They suspect that a substance that enters the nose may cause or increase the risk of PD. These substances may include viruses, pesticides, and heavy metals.
Even if the pathology (of Parkinson's disease) is very much driven by brain abnormalities, it doesn't mean that the process starts in the brain.— Michael Schlossmacher, Ottawa Hospital Research Institute, via Scientific American
Looking to the Future
The interactions between processes in the body and between the body and the environment are numerous and complex. The situation is becoming increasingly interesting as more discoveries are made. The often intricate web of activities that take place inside us and the genetic variations in humans can make understanding disease difficult, however. It's important that we understand the body so that we can treat disease.
Additional research projects besides the ones mentioned in this article support the idea of a link between the gut and Parkinson's disease. More details about the potential relationship are needed, however. Clarification of the circumstances under which alpha-synuclein is helpful (if it in fact is) and under which it's harmful are essential.
There may be multiple causes or sites of origin of Parkinson's disease and multiple processes in the body that can make the disease worse. Some researchers suspect that this variation is why different patients have different symptoms and different rates of disease progression. Understanding the factors that control the disease could be very useful with respect to improving its treatment.
- Information about Parkinson's Disease from the Mayo Clinic
- Constipation preceding Parkinson's disease from the US National Library of Medicine
- Alpha-synuclein travels from the gut to the brain in rats from Springer
- Alpha-synuclein and gastrointestinal immunity from the Journal of Innate Immunity, Karger
- Exposure to a bacterial protein triggers alpha-synuclein aggregation in animals from the US National Library of Medicine
- Parkinson's and the gut from Scientific American
- Parkinson's disease involves degeneration of the olfactory system from Max-Planck-Gessellschaft
Questions & Answers
© 2018 Linda Crampton