Parkinson’s and the Bacterial Microbiome: An Early 2021 Update

Two new pieces of Parkinson’s Disease (PD) research for me to share with you.You’ll remember that more and more research is showing that bacterial microbiome alterations are associated with the misfolding of the protein alpha-synuclein, which then makes it’s way into the brain causing a damaging immune response.  Researchers took tissue samples from the appendix, the ileum (part of the small intestine) and the liver (where bile is produced) of 12 people with PD and 16 healthy people who served as the control group.  The appendix used to be thought a vestigial organ, but we know now that in fact, it is a reservoir for gut microbes.[i]

They found that the appendixes of those with PD had higher levels of 3 kinds of bacteria: Peptostreptococcaceae, Lachnospiraceae, and Burkholderiales.  Bukholderia has been associated with brain infection, and it also alters the ability of the microbiomes to produce the enzyme necessary to metabolize bile acids, turning them into secondary bile acids.  I’ve written now several times (look here and here for example) about how critically important bile acids are to health of the both the host and their microbiome.  Thus, those with PD ended up with higher levels of secondary bile acids.  The scientists found an almost 19-fold increase in lithocholic acid, and a 5.6-fold increase in deoxycholic acid, both of which are toxic to cells in elevated amounts.  The researchers write that they found, “…changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism.  Microbially derived toxic bile acids are heightened in PD, which suggest biliary abnormalities may play a role in PD pathogenesis.”

Upon discovering this dysregulated bile metabolism, the scientists looked to see whether or not proteins involved in these metabolic pathways were also altered in the small intestine (the ileum) and the appendix.  They found that indeed, there was a decrease in proteins affecting lipid metabolism as well as impairments in the pathways involved in a variety of cellular activities including immune activity.

By the way, these scientists also found lower levels of 5 different kinds of bacteria in the appendixes of those with PD:  Methanobacteriales, Odoribacter. Clostridium, unclassified Sutterellaceae and Escherichia.  Alterations to the gut bacteria were pervasive.

The results were robust enough for the authors to suggest that research should begin to pursue treatments involving bile acids and the appendix microbiome for those with PD:  “Targeting the appendix microbiome and bile acids may be an innovative approach for future therapeutics. Our results support microbiome transplantation as a potential treatment for PD.”

The second article is somewhat similar.   scientists looked at the fecal microbiomes and metabolomes of 104 patients with PD and found significant differences between these samples and those from 96 healthy controls.  They found several metabolites that are associated with cognitive impairment, constipation and postural-instability/gait disorder severity.  The study included information on disease severity, medications, BMI, diet, exercise, cognitive function, gastrointestinal symptoms and weight.  No real differences were found in lifestyle factor between the PD patients and the controls, but the microbial composition found in the fecal samples were very different.  Those with PD had markedly higher levels of Akkermansia muciniphila, Lactobacillus acidophilus, Bifidobacterium bifidum, and Bacteroides fragilis.  However, various studies in the literature have found differing results so there is  no consensus on this as yet:  this is likely the result of differences in the populations used in the studies.  (For example, the degree of frailty does seem to affect the microbiome composition, as do demographics and other factors.)

As found in previous studies (look here for example), the researchers found that those with PD had significantly lower levels of the short-chain fatty acid, butyrate, in their feces and the lower the level, the worse their cognitive function and postural instability.  Says the lead researchers, “…these findings suggest that alterations of gut SCFA levels may play an important role in the neurodegenerative process of PD, possibly through disruption of gut barrier integrity and inflammatory mechanisms. There is hope that these may represent novel therapeutic targets for PD.”[ii]

One great mystery:  Akkermansia, as you know, as well as Lactobacillus acidophilus and Bifidobacterium bifidum generally have beneficial effects on the immune system and gut health.  High levels of Akkermansia though has also been associated with neurological disorders like Alzheimer’s and multiple sclerosis.  Further research is definitely needed.

In the meantime, probiotics are being explored in clinical trials to manipulate the gut biome in those with PD.  In fact, recently a double-blind, placebo-controlled, randomized trial with a multi-strain probiotic (given for 4 weeks) was tested and patients with PD showed an improvement in constipation – which is a hallmark symptom of PD. [iii]

So, probiotic trials are happening.  The bile acid, ursodeoxycholic acid, is being tested to see if it can slow the progression of PD.  Perhaps some new treatments for PD are not that far away.[iv]

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[i] Li P, Killinger BA, Ensink E, Beddows I, Yilmaz A, Lubben N, Lamp J, Schilthuis M, Vega IE, Woltjer R, Pospisilik JA, Brundin P, Brundin L, Graham SF, Labrie V. Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease. Metabolites. 2021; 11(1):29. https://doi.org/10.3390/metabo11010029

[ii]https://journals.lww.com/neurotodayonline/Fulltext/2021/02040/Why_Researchers_Look_to_Gut_Microbial_Metabolites.2.aspx

[iii] https://www.mdlinx.com/journal-summary/probiotics-for-constipation-in-parkinson-disease-a-randomized-placebo-controlled-study/2wJeiKqH1nEuHPffYsBy6Y

[iv] https://www.medicalnewstoday.com/articles/can-the-microbiome-predict-parkinsons#Potential-Parkinsons-treatments

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