Friday, December 30, 2016

Microbiome accelerates neurodegeneration

Parkinson disease (PD) is a neurodegenerative disease characterized by motor deficits and aggregates of a protein called α-synuclein (α-syn) in the brain (pronounced sin-NU-clee-in). Genetics plays a role in PD, because there are some early-onset forms of PD that are caused by mutations in α-syn that cause it to more readily clump together and form the protein aggregates. The purely genetic forms of the disease, though, are relatively rare, so the environment must also play a role in most cases. A recent paper published in Cell by Sampson et al. explores how the microbiome in the gut affects development of PD symptoms.

The microbiome is the community of bacteria and fungi living in and on us (watch this awesome video about the microbiome). It has previously been shown that the normal gut microbiome is disrupted in various diseases such as autism and in Parkinson’s patients. It’s always hard to know, though, what is the cause and what is the effect. Does the disease cause the microbiome to change, or does the change in the microbiome cause the disease? Maybe a little of both.

Mouse model

To address the role of the microbiome in Parksinson Disease, the authors relied on an established mouse model of PD. These mice overexpress the normal human form of α-syn in all their neurons. Even though this isn’t the mutant form of the gene, the fact that it is overexpressed all over the brain causes the characteristic α-syn aggregates. These mice are slow in motor tasks, including removing a piece of tape from their noses (sounds like a frustrating, but also adorable behavioral task). They also have impaired gastrointestinal function, which is to say they don’t produce as much poo as other mice. [An aside: normal mice apparently drop about 7 fecal pellets every 15 minutes!]

The researchers took these mice with mouse-Parkinson’s and raised half of them in a super sterile environment where they have no microbiome (called “germ free” mice), and the other half got all dirty so they had a microbiome (I will call these “dirty mice”). The PD mice with a microbiome had way more motor impairments than the mice without a microbiome! Yes, I wrote that correctly. I thought the microbiome was supposed to help its host? Well, not in these mice overexpressing α-syn.

Get this: if you give the dirty mice antibiotics from age 5-13 weeks old and then test them, they were more like the germ free mice – no motor impairments and better fecal output. Not that you would want to give humans antibiotics for their entire lives (that could cause some autoimmune diseases and serious digestive issues), but this does demonstrate that it is the gut microbiome that is affecting the symptoms of Parkinson Disease.

Short chain fatty acids

The bacteria living in our gut produce all sorts of chemicals that can get into our blood and nervous system. Bacteria produce short-chain fatty acids (SCFA), which are basically just little fats that can cross over the intestinal lining and get into our bodies. Parkinson’s patients produce more SCFAs, so the authors tested the role of SCFAs in their mouse model.

Germ free mice overexpressing α-syn are relatively normal, right? The authors fed these mice a bunch of SCFAs to mimic what the gut bacteria would be making and the mice became impaired like the dirty mice (can’t get that tape off their nose). This is amazing to me. So short-chain fatty acids that are normally made by the gut bacteria are sufficient to cause the Parkinson’s symptoms. Note that feeding SCFAs to normal mice without all that α-syn did not cause Parkinson's symptoms.

           α-syn mice no microbiome + SCFAs = impairments of α-syn mice with microbiome

Microbiome and the immune system

What are the short-chain fatty acids doing to the nervous system? One important role of the microbiome is to train the host’s immune system so it knows what to attack and what to ignore. This is why the microbiome plays a role in the development of autoimmune diseases, where the body attacks the wrong things (like a harmless pollen molecule or the body’s own cells like in type I diabetes). SCFAs can get up into the brain and regulate the immune cells of the nervous system, called the microglia (pronounced micro-GLEE-a). Indeed, the dirty mice with a full microbiome had more activated microglia in the brain than the germ free mice. Likewise, the germ free mice fed SCFAs also had activated microglia.

An overactive immune system promotes protein aggregation, so here’s the model: something causes the microbiome to become unhealthy, which causes the release of a lot of SCFAs, which activate the immune system in the brain, leading to neuron death and protein aggregation. The diagram below has some extra information in it, but the pathway in black is what they showed in this paper.

What about human patients?

Okay, so the microbiome plays a role in this one particular mouse model of PD, but what about in humans? Remember that the microbiome and the amount of short-chain fatty acids in Parkinson’s patients are different than in healthy humans. The authors took the microbes from human feces and transplanted it into the guts of the germ free α-syn mice. Amazingly, the germ free mice that got the bacteria from Parkinson’s patients had more severe motor impairments than the mice that got bacteria from the healthy humans. So there’s something going on in the microbiome of humans with PD that enhances the symptoms.

The authors raise the point that two things were needed for these mice to have the symptoms of Parkinson disease:
1) Overexpression of α-syn (genetics)
2) Disordered microbiome, also known as dysbiosis (environment)

This is a great example of a complex disease that is caused by the interplay of genetics and environment. Perhaps this information can be used to come up with new treatments to correct the dysbiosis and slow down the progression of Parkinson disease.