We have long known that constipation is a common non-motor feature of Parkinson disease (PD) (1). One study of 7000 men over a period of 24 years showed that those with initial constipation (less than one bowel movement per day) had a three-fold risk of PD after an average of 10 years (2). Thus, unexplained and persistent constipation in adults is associated with an increased risk of PD: 1/3 will have constipation a year prior to PD diagnosis, and 2/3 will have constipation after diagnosis (3,4). Ultimately, greater than 80% of PD patients will have GI dysfunction of some type early in disease. Investigators have tried to explain this for many years. In the 1970s, one idea was the “slow transit hypothesis,” the idea that slowing down of the gut allowed the absorption of toxins which might trigger PD (5). Though this fell out of mainstream discussion, and may have seemed an oversimplification, the idea is not so far from current thought.
To understand what we now call the gut-brain axis, it helps first to know that your gut, or your digestive tract, contains a lot of bacteria, tens of trillions of them. Largely because of the population in the gut, there are more bacteria than human cells in our bodies. One way they get away with this is that they tend to be much smaller than our cells. Bacteria tend to be about 0.1-5 micrometers in size (millionths of a meter). Human cells range from about 10 to 100 micrometers, so our cells tend to be many times bigger than bacteria. And, as long as they stay in specific locations, bacteria work with, not against us; but when they go to the wrong place, illness occurs: think diarrhea, nausea, vomiting, etc. Under ideal circumstances, among several jobs, many gut bacteria help us to digest food and collect certain nutrients we otherwise would not be able to extract or produce. In exchange for this, they are given food, shelter, and a chance to move along to some other environment – a great reason why we should all wash our hands when leaving a restroom. Half of the dry weight of our stool is bacteria, and if it winds up travelling the fecal-oral route, e.g., hand to doorknob to someone else’s hand to mouth, the consequences can be bad. A few minutes spent in a busy public restroom will alert you that hand washing is not a universal practice.
A healthy gut requires a healthy population of bacteria. To understand this a little better, let’s define a few terms. A single bacterial cell is a microbe. The terms microbiome and microbiota are used a lot when discussing this topic, and for our purposes, they are the collection of bacteria in the gut. There is a group of over a thousand different species of microbes in the gut. Their library of unique genes is over 100 times larger than the number of genes in a person’s DNA library. That is a considerable genetic power. The balance among types of organisms present in the gut is important as well. When there is too much or too little of one type or another, this is imbalance, which we call dysbiosis. Dysbiosis has been linked to inflammation, metabolic disease, certain cancers, and neurologic disease.
Dysbiosis can cause disease because one of the roles of a healthy microbiome is to regulate gut and bodily inflammation. They do this by the release of tiny chemical messengers. In PD, delayed gastric emptying and slow transit of stool may increase the over-production of some types of bacteria, which not only upsets the local balance, but creates the symptoms of gas, colic, and inflammation (6,7). This makes it even easier to get their messengers into the bloodstream. Further, as if pretending to be nerve cells, bacteria can produce neurotransmitters and neuromodulators such as GABA, serotonin, dopamine, or short-chain fatty acids (8). This may allow bacteria to communicate with our nervous system (9).
It also goes the other way. The drugs PD patients take may influence the microbiome (10). One study evaluated 197 PD patients and 130 controls without PD. They were able to identify the types and numbers of microbes taken from stool of each person. Investigators took into account 39 potential confounders such as medications, diet, GI symptoms, and demographics. The gut microbiome was different in PD, and multiple families of bacteria were much more robust. In the PD patients there were also different balances corresponding to different drugs, such as COMTs and anticholinergics. In the study, the effect of L-dopa could not be separated out as 90% of PD patients were taking the drug.
Another reason dysbiosis may be a risk factor for disease is that our gut bacteria protect us by breaking down xenobiotics (herbicides, flame retardants, insect repellents we encounter in the environment). Living in agricultural settings is a known risk factor for PD and this may explain why. In the lab we know that xenobiotics can cause the death of dopamine-producing cells and motor abnormalities in animal models of PD. Therefore, dysbiosis might expose humans to toxins which would otherwise have been broken down. The toxins may trigger disease. The evidence that this may be happening is supported by the observation that the pathologic hallmark of PD, the Lewy body, may be seen in neurons of the gut years prior to the development of motor symptoms of PD, and may be seen in the gut of lab animals given xenobiotics. These observations helped lead to the hypothesis that PD starts in the gut (11).
The most common protein in Lewy bodies is called alpha-synuclein (aSyn). This little protein is found at the point of communication between neurons called the synapse. The job of aSyn is to stabilize little bags of dopamine (vesicles), and to help control synaptic plasticity (the formation of new neural pathways in the brain involved with learning). This protein, like all others, has a very specific three-dimensional shape which it must maintain in order to work. This is similar to a key, which must be shaped a certain way to fit into a lock and turn the tumblers. If the key is bent, it will not work. If aSyn is misfolded, it does not work, dopamine is not released, and new pathways are not made. It may be that exposure to certain toxins triggers the misfolding of aSyn, or there may be other factors such as gene mutations. Whatever the cause, misfolded aSyn may behave very much like a prion, where one bad protein warps others of the same class (think one bad apple spoils the whole bunch).
Testing this idea, researchers exposed lab mice to the pesticide rotenone, which has long been associated with risk of PD in humans (12). The mice developed misfolded aSyn in the gut. Abnormal aSyn in the gut activates immune cells in the brain known as microglia (13). These microglia are then primed to destroy neurons containing abnormal aSyn. This is one of the ways PD patients lose neurons. If present long enough, misfolded aSyn will also travel up the long vagus nerve to the brainstem, where it will spread upwards in the same way the protein spreads in humans with PD. Of note, mice and men with a severed vagus nerve have a lower risk of PD.
In order to test the effects of microbes and molecules on animals, researchers relied on the first gene abnormality identified in PD, the PARK1 gene (14). The PARK1 gene causes the overproduction of aSyn. When the gene is present in mice, they manifest a form of parkinsonism very early in life. However, if the mice are treated with antibiotics to kill the microbiome, motor symptoms of disease become minimal, and there is reduced activation of microglia (15). This led the investigators to raise PARK1 mice in a sterile environment with no microbiome. These mice too, had minimal motor issues. When colonized with a microbiome (transplanted feces) from humans without PD, the mice were unchanged. When given the microbiome from PD patients, the mice developed impaired motor function. This supports the “two-hit” hypothesis, that PD is likely caused by genes and environment. In other words, if someone is predisposed to develop PD because of genes, they may not do so until exposed to some trigger such as a toxin. Researchers were also able to normalize the affected mice by adding normal chemical messages such as short chain fatty acids that a normal microbiome would produce.
Thus, the gut-brain axis raises several interesting questions:
- Would a simple stool test reveal risk to PD and other diseases?
- Would understanding the microbiome help physicians in selecting the appropriate drugs for people with PD, or lead to the formation of new treatments?
- Would changing the microbiome improve disease for people with PD?
If you know, tell me. Otherwise, stay tuned. This is a big topic in PD.
Stylistic and copy editing of this article, as well as helpful insights, by Sarah Savard, RN, and Liz Stamey, RN.
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