Going over: Sampson et al. “Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease.” 2016, Cell, 167(6):1469-1480.
If you have been following news about Parkinson’s research, you’ve probably been hearing about the microbiome a lot. This is due to a recent paper published in Cell by Sampson et al., which can be accessed here. Before we jump into what the researchers did, what they found, and what we can conclude, let’s review some key aspects of what the microbiome is, what roles it plays (which our understanding of is ever expanding), and what can affect it.
The microbiome refers to micro-organisms (such as bacteria) which reside on essentially every surface of our bodies. It’s estimated that there are somewhere near 10 to 100 trillion microbial cells on a typical human, compared to the 10 trillion human cells that an adult human typically has. In other words, there are likely as many microbial cells as human cells residing in/on you. With such an abundance of microbial cells, it’s not surprising that the microbiome is known to play many roles in human health and disease. The GI tract is our biggest microbiome reservoir, and this study analyzes the GI microbiome.
So what do the bacteria in our gut do? Some bacteria ferment dietary fiber (which we cannot absorb) into short chain fatty acids (which we can absorb). Other bacteria synthesize vitamins B and K, while others metabolize bile acids and sterols. While these functions sound productive, our microbiome can cause also disease. Perhaps the best known example of this is C. difficile colitis, which occurs following the overgrowth of certain bacteria (C. difficile). This type of colitis can occur after taking certain antibiotics, and can be very difficult to treat. Interestingly, what works in very severe cases is to do fecal transplantation, to put a healthy microbiome back in to the GI tract.
What can affect our microbiome? What you eat, how you were born, your lifestyle, antibiotic usage, where you live, your gender, your age, and what pets you may have can all affect your microbiome. Some of those factors - what we eat, our lifestyle, and to a degree antibiotic use are actually things which we can control. Perhaps there is more truth to the saying “you are what you eat” than many of us believe.
Now that you have some microbiome basics down, let’s jump into the study. This may get a bit technical…
This study used mice referred to as ASO, which are mice that produce high levels of α-synuclein, as well as WT (wild-type/normal) counterparts. The mice were either raised in a germ-free environment (no microbiome), or were able to develop a microbiome. Using a combination of motor function tests and molecular biology techniques (antibody staining and western blotting), the authors provided data indicating that ASO mice with microbiomes had worse motor function and more α-synuclein deposition than ASO mice grown in a germ-free environment. Extending this further, when ASO mice that initially were germ-free were colonized (gained a gut microbiome), their motor functions and α-synuclein deposition were on par with ASO mice that were never germ-free. This was not true for WT mice. In addition, depletion of the microbiota using a cocktail of antibiotics for 7 weeks resulted in similar motor functions between WT and ASO mice (meaning that when ASO mice took antibiotics, they had better motor function than their non-antibiotic treated microbiome-containing ASO counterparts). Taken together, this is strong evidence that in the ASO model of PD, the microbiome can have negative effects on motor function and pathology.
The next questions addressed in the study are how this could be occurring. What might be a mechanism whereby bacteria in your gut affect complex neurological pathways?
To assess for inflammation, they looked at microglia activation. Microglia are the macrophages of the nervous system, meaning they are the “eaters” of debris, infected cells, foreign material, etc. They found that for both ASO and WT mice, the presence of a microbiota increase microglial activation in certain areas of the brain compared to their respective germ-free counterparts. This essentially says that gut bacteria can affect the brain’s immune cells, raising more questions for other studies to ask.
What did they look into next? Short-chain fatty acids. As I mentioned before, it’s well known that gut bacteria affect levels and composition of short-chain fatty acids. Based on other studies linking microglial activation during viral infection to SCFA (thus linking inflammation and SCFA), they fed their germ-free mice SCFA. Their results? Feeding germ-free ASO mice a certain combination of SCFA recapitulated the motor deficits and microglial activation seen in ASO mice with a microbiome. This is perhaps one of the most surprising findings, and also one that seems to be counter to many claims about the health benefits of SCFA. Given that normally, there IS a microbiome present, and that SCFA do have impacts at the local bacteria level, I don’t think any clear conclusions can be made yet.
Last but not least, they did fecal transplants into germ-free ASO and WT mice, using the microbiota from 6 individuals with PD and 6 without. When the resulting microbiomes were analyzed post-transplant, they found that mice that were transplanted with PD microbiota had microbiomes which were more similar to each other than the microbiomes were among mice transplanted with non-PD microbiota. ASO mice who received microbiota from individuals with PD had greater motor dysfunction than ASO mice receiving control microbiota. It is important to note that this only occurred in the presence of an underlying genetic predisposition to motor dysfunction (ASO mice, not WT). When they analyzed the types of bacteria present in ASO and WT mice following colonization with PD microbiota, they saw that some species of bacteria increased in abundance while others decreased relative to non-PD microbiota. Of these, they found that some were increased or decreased only in ASO mice. They also identified some SCFA-producing families among the bacteria with differential abundance in PD and non-PD microbiota.
Yes, there is a huge amount of data (it is a Cell paper…), and a lot to think about.
Here are a few take-aways that I think are important.
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It’s pretty likely that in humans, the microbiome can affect PD pathology.
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The cause-and-effect relationship between the gut microbiome and Parkinson’s is not clear… in other words, are similarities between the microbiomes of individuals with PD caused by PD, or are people more likely to develop Parkinson’s symptoms when they have a certain microbiome composition?
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Can the “PD microbiota” be altered by diet modification, probiotics, antibiotics, or fecal transplant in humans after the onset of PD symptoms?
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SCFA somehow affect pathology in this mouse model of PD… and whether this is consistent in humans and how mechanistically this works remains to be seen.
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There is no data in this paper indicating that the microbiome itself causes Parkinson’s (only ASO mice and not WT mice were affected). The data does not show that anything transferred during fecal transplant causes Parkinson’s in mice that are not genetically predisposed to PD.
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What does it mean for you? Well, it can be taken as further evidence and motivation for you to eat well and listen to your body. Perhaps individuals with PD who feel much better after changing their diets feel better because they improve their gut microbiome. Maybe some of the benefits of exercise could be through affecting your gut microbiome. This study provides new avenues of possible therapeutics, but is still just a piece of the overall PD puzzle.
Have more questions or want to discuss this further? Post comment below!
Sources and Further Reading:
http://www.newyorker.com/magazine/2014/12/01/excrement-experiment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735932/
https://www.sciencedaily.com/releases/2015/09/150929070122.htm