As you know, I’ve been following the developing story of the bacterial microbiomes relationship to the development of Parkinson’s Disease (PD) for years now. This past week, science took another step forward: Brazilian researchers published a paper in Scientific Reports that suggest, yet again, that alterations in gut bacteria may be at the heart of the development of the disease.
The lead author, Dr. Fonseca, points out the specific cells (enteroendocrine cells) in the epithelial lining of the gut have many neuron-like properties and they also express the protein alpha-synuclein (aSyn), abnormalities of which have been implicated in the development of the disease. These cells are connected to the nervous system of the gut (the enteric nervous system). There is already existing research that has demonstrated that it appears aSyn migrates to the brain via the enteric nervous system, eventually causing an immune response in the brain that leads to the destruction of dopamine producing cells in the substantia nigra.I’ve written about this process many times on this blog.
I have also written frequently about the benefits of certain probiotic species, like Akkermansia municiphila – but have also written countless times about how too much of a good thing is equally as bad as too little. Some research has shown that Akkermansia has been found at excessive levels in those with PD. (See here.) Thus, Dr. Fonseca and colleagues wanted to see if these bacteria secrete anything that might trigger the abnormal aggregation of aSyn. They cultured the proteins produced by these bacteria and found that indeed, they did lead to aggregation of aSyn. More than that, they also determined that aSyn can be transferred from enteroendocrine cells to the cells of the enteric nervous system. The paper concludes by stating that, “This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies by shifting the focus of PD etiology to the peripheral nervous system…”[i]
What does the cascade look like? Proteins excreted by Akkermansia lead to a calcium overload, intracellularly, in the enteroendocrine cells. This in turn, stresses their mitochondria, which are the energy-producing centers of the cell. This leads to the production of reactive oxygen species (i.e. oxidative stress) which damage the intracellular structures and that, finally, leads to abnormalities in, and aggregation of, the protein, aSyn. While no one yet knows for certain all the functions of aSyn, at this time it is believed to have, at least in part, a function in the immune system.
Says Dr. Fonseca, “The cascade of reactions can start in the gut and move up into the brain. People predisposed to sporadic [non-genetic] Parkinson’s usually suffer from recurring constipation many years before they manifest the disease. In our study with animal models, we found a direct correlation between gut dysbiosis and Parkinson’s.”[ii]
So where does this leave us? The recognition that the disease almost certainly starts with alterations of the bacterial microbiome may soon lead to preventative strategies: dietary changes, fecal transplants, and so forth. One big problem though seems to be the contradictory research. I also wrote, in the not-very-distant-past, about research that shows that Akkermansia seems to alleviate symptoms of PD. See here
Of course, it is possible that both scenerios are true. That is – just making up a suppose to illustrate my point – excess Akkermansia is a cause of the development of the disease but after the disease is present, the microbiome shifts (perhaps due to the increased constipation symptoms????) and Akkermansia levels drop. I will, of course, continue to follow this ever-developing story!
[i] Rodrigues, P.V., de Godoy, J.V.P., Bosque, B.P. et al. Transcellular propagation of fibrillar α-synuclein from enteroendocrine to neuronal cells requires cell-to-cell contact and is Rab35-dependent. Sci Rep 12, 4168 (2022). https://doi.org/10.1038/s41598-022-08076-5.