Are neurodegenerative diseases diseases of the gut?
Despite knowing about the existence of bacteria for almost 400 years, there are still many unsolved mysteries about what they do and how they do it. Nowhere is this more true than with the bacteria that reside on our bodies. There are more than 100 trillion bacteria on an average human with about 10 trillion cells. By number, but fortunately not mass, bacterial cells outnumber ours 10 to 1. We are just 10% human on a cellular level. It’s therefore extremely important that we work out what the bacteria are doing. There is a whole branch of science dedicated to finding out.
A lot of modern research is focused on the link between the bacteria in your gut and your metabolism. Some scientists are exploring true scientific wildernesses and looking at the influence bacteria have on our brains. They have come to some startleling conclusions, such as certain bacteria underpinning the pathology of Parkinson's disease. Overall these interactions are complex and difficult to pin down but the idea that small microscopic organisms can have dramatic on human physiology is not new, nor indeed shocking: just look at chlamydia, cholera or tuberculosis. There are more than 200 so called classical bacterial induced infectious diseases.
Our microbiomes influence us in a plethora of unexpected ways
The bacteria that reside in and on your body, comprising your microbiome, are more than mere freeloaders. Almost half of the body’s dopamine, the famous happy hormone, is produced in our guts with the help of bacteria. The relationship between you and your bacteria is so important that humans even evolved an organ that might act as a reservoir of "good" bacteria: the humble appendix. After we’ve been sick and our intestinal bacteria are in disarray, bacteria from the appendix can, so the claim goes, be used repopulate the gut. This is good news since bacteria are now linked to everything from weight control to autism, so we want to make sure we have the right ones. And there is some evidence that we can control which bacteria are present. Indeed, our ability to influence our bacteria, and their influence on us, mean that feedback loops establishing a status quo are created. This is great when the bacteria are keeping you slim, but less so when they are driving Parkinson's disease.
Parkinson’s disease is a debilitating neurodegenerative disease. Patients progressively lose control of their muscles. As disease of the brain, the idea that some of its symptoms might start in the gut seems surreal. But this is actually what the data suggest. Patients with Parkinson's disease have markedly different gut bacteria compared to healthy people. However, correlation doesn’t necessarily mean causation. For this reason scientists have performed functional experiments, on mice, to work out whether certain gut bacteria can cause Parkinson’s, or whether Parkinson’s, by chance, just results in an altered gut environment that favours different bacteria. The answer, as with most science, is not so straightforward.
Parkinson's disease can arise from mutations in the α-Synuclein gene
Recent exciting work suggests that you need both a genetic predisposition to Parkinson’s and certain gut bacteria to get the disease. In 1997 the first genetic link to Parkinson’s was discovered. Scientists studied families where the illness was inherited and found that the affected individuals had abnormalities in their α-synuclein genes. But heritable Parkinson’s is actually quite rare - most patients are termed sporadic or idiopathic and get the disease by what, superficially, appears to be bad luck. Initially the link between the α-Synuclein gene and Parkinson’s was thought to be specific to the families unlucky enough to have the disease, particularly since mutations in other genes can cause heritable Parkinson’s.
Scientists have since discovered that many patients with sporadic Parkinson’s share different mutations in α-synuclein but not other genes linked to heritable Parkinson’s. At first glance you might conclude that mutations in α-Synuclein mean you get Parkinson's. However, it's not so clear-cut: healthy people also carry mutations in these genes and never end up with the disease. Even if you are from a family with heritable Parkinson’s, your risk of getting the disease is only 40%. So why do some people with mutations in the α-synuclein gene get Parkinson’s and other people, with the same mutation, don’t?
Using genetically altered mice to test whether bacteria play a role in Parkinson's disease
To answer this question scientists genetically altered the α-synuclein gene in mice so that it looked similar to the mutations found in patients. They then formulated a brave hypothesis: that the altered microbiome in patients with Parkinson’s may be contributing to the disease. They used the genetically altered mice to test this hypothesis. Groups of mutated and normal mice were placed into one of four groups: mutated mice brought up under germ free conditions, germ free normal mice, and both mutated mice and normal mice with normal bacteria. As expected, none of the normal mice, with or without germs, got any Parkinson’s disease. The scientists tested them to confirm that simply performing the experiments, that is raising mice in germ free environments, does not cause the rodent equivalent of Parkinson's disease.
But germ free mutated mice showed dramatically reduced disease severity. The scientists were able to confirm that both bacteria and mutated α-synuclein are necessary for Parkinson’s by treating the really sick mice (mutants raised in normal conditions) with antibiotics. These mice got much better. Although they were not cured, it's important to keep in mind that dramatically slowing Parkinson's, and reducing its severity, can massively improve the quality of life of afflicted individuals.
What does this mean for humans?
Mice are not humans, and as with any biomedical science, conclusions drawn about human physiology on the basis of mouse work alone should be treated with a degree of skepticism. However, supporting evidence suggests that transposing these findings on to humans is not premature. The microbiome profiles of diseased mice and human Parkinson's patients are extremely similar. The same types of bacteria that are present in sick humans compared to healthy humans are also overrepresented in the sick mice. The scientists even went on to identify the molecules made by the bacteria in the sick mice, and these too have been found at much higher levels in people with Parkinson’s.
For the final piece of evidence to support the genetic-and-bacteria-combination hypothesis, scientists demonstrated, using faecal transplants, that the bacteria from patients can cause Parkinson’s in germ free mutant mice. It is just as gruesome as it sounds! Cleaned up faeces from one animal is deposisted directly into the intestines of another; we actually do this already with humans as a treatment for some superbug infections and obesity. When scientists performed faecal transplants on normal germ-free mice nothing happened, the mice stayed healthy. This is further support for the hypothesis that you need both the bacteria and the α-synuclein mutation to get sick.
The obvious therapeutic potential of this research, of using antibiotics or faecal transplants to treat or at least slow the progression of Parkinson’s, is not the most exciting question that it raises, at least in my opinion. The normal and mutant mice raised in normal conditions were initially exposed to the same bacteria. Similarly people with Parkinson’s are exposed to the same bacteria as healthy people. In both scenarios something about mutations in the α-synuclein gene leads to changes in the gut microbiome. Remarkably, despite the innumerable differences between mice and humans, the resulting microbiome is almost interchangeable between sick individuals of the two species.
A bold new gut-brain connection
The mouse experiments showed convincingly that it’s the new gut microbiome that triggers the disease. So what I want to know is how this happens and why simply having the same microbes without the genetic mutation isn’t enough to cause Parkinson’s? The latter is still an open question but we are starting to fill in the gaps for the former. Research into Alzheimer's disease, perhaps the more famous neurodegenerative disease, may answer how mutations in α-synuclein cause microbial changes in the gut.
Work in Alzheimer's disease has suggested that the disease-causing agent, a protein called beta-amyloid, may have antimicrobial properties, acting as an antibiotic produced by the body. So might a similar thing be happening with α-synuclein? Perhaps normal α-synuclein acts as an antibiotic that selectively kills off bacteria that are harmful to the body? When it is mutated, harmful bacteria are no longer controlled and go on to dominate the gut, eventually producing a molecule that is absorbed into the blood through the intestines and eventually makes its way into the brain. There it will interact with neurons to contribute the the progression of Parkinson's.
α-synuclein proteins are also found in the brain. This is one of the reasons scientists were orginally so excited when they linked α-synuclein to Parkinson's. They thought they stumpled onto the perfect disease aetiology: mutations in a single gene cause a single disease. Modern research is increasingly showing this to be no more than a myth - diseases are far more complex than that and the majority of genetic diseases seem to have, at least a small, environmental component. Parkinson's is a great example of this.
α-synuclein functions in at least 2 places and you need to deregulate both of them to get Parkinson's. Mutated α-synuclein in the gut prevents the control of harmful bacterial species. In the right circumstances, harmful bacteria will colonies such a compromised gut. The end result is a bacterially-produced molecule entering the brain via the highways of the blood. Here it will interact with neurons, probably through α-synuclein, ultimately damaging them and causing Parkinson's. This is why healthy people with a similar microbiome don't get Parkinson's: the bacterially-produced molecule needs to interact with the damaged α-synuclein on neurones before it can cause Parkinson's.
It is almost surreal to think of two of the most harmful neurodegenerative diseases originating, at least in part, from the gut. At the same time, I feel very hopeful. Infections are much more easy to treat than mental decline, providing we find a way to beat widespread antibiotic resistance and superbugs. Work in mice has shown that treating sick mice with antibiotics slows dramatically the progression of Alzheimer's and Parkinson’s. It is unlikely that antibiotics are going to be the only answer, but we can add them to a - currently - pretty meagre toolkit to tackling these devastating diseases...