Neurodegenerative Diseases and Gut Bacteria: Zeroing in on the Culprits (and the Solution)

My regular readers know that there is a (rapidly) growing body of evidence linking alterations in the bacterial microbiome to neurodegenerative diseases like Parkinson’s, (PD), Alzheimer’s and ALS.  (I have provided you links to just 3 of many previous posts on these topics.)  No one knows as yet what particular species of bacteria may be the culprits, but Researchers at the University of Florida are attempting to figure it out.[i]

Neurodegenerative diseases are linked to the production of abnormal (“folded”) proteins in the body.  When these proteins are misfolded, they can accumulate in tissues (including the brain) and these aggregates interfere with normal cell communications and functioning.  What causes misfolded proteins though remains a mystery.  We know that those with neurodegenerative diseases have abnormal bacterial microbiomes, including low levels of good bacteria (for example, in PD, we know there is low levels of bacteria which produce the anti-inflammatory short-chain fatty acid, butyrate).  So the question becomes – are these linked?  If so, what “bad” bacteria may induce the misfolding of proteins?  And do any gut bacteria ameliorate this issue?

Using the tiny worm, Caenorhabditis elegans (C.elegans are commonly used in this kind of research, and are particularly useful because they are simple organisms and thus, can provide clarity on complex questions), the scientists introduced specific pathogenic species of bacteria (ones frequently found in humans) to see if they would cause protein aggregation.  Short answer:  yes, they did indeed.  The misfolded protein aggregates could be seen throughout the worms, not just in the intestines.  Not only that, but the worms also lost mobility, which is a common symptom of these diseases:  “We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity.” In other words, probiotic bacteria that produce butyrate prevented aggregates from forming.  Prevotella species were among the best performers in terms of preventing aggregation, with P. corporis almost completely doing so.  (I have written several times, including here, about the relationship of butyrate to PD.)

So what bacteria were the biggest culprits in causing protein misfolding? Many species were tested: “Escherichia, Klebsiella, Proteus, Citrobacter, Shigella, and Salmonella, as well as additional pathogenic bacteria that are associated with gut microbiota; these include gram-negative Pseudomonas and Acinetobacter.” The winners in terms of causing issues included  Klebsiella pneumoniae and Pseudomonas aeruginosa and research has already linked these species to diseases like Parkinson’s.  The scientists also noted that these two species are also known to be particularly antibiotic resistant, leading them to hypothesize that antibiotic treatments may actually encourage the growth of these pathogenic and resistant species, while decreasing the abundance of good (butyrate producing) bacteria.  In fact, a recent meta-analysis found that a history of antibiotic therapy is associated with an increased risk of Parkinson’s disease.[ii]

What really rocked the scientists’ world is that increased protein aggregation was also seen in the offspring of these worms, even though the babies had not been exposed to the bacteria.  The lead researcher of the study says that, “This is very interesting because it suggests that these bacteria generate some sort of a signal that can be passed along to the next generation…”[iii]

The authors state in their discussion that, “Our results demonstrate that butyrate, a common metabolite produced by commensal microbiota, can suppress aggregation and the associated toxicity when supplied exogenously or produced by intestinal bacteria.”  Thus, butyrate should be considered as a therapeutic treatment for these diseases and clinical trials should be conducted.

Interesting, right?  I bet we see clinical trials in the not-terribly-distant future.

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[i] Walker AC, Bhargava R, Vaziriyan-Sani AS, Pourciau C, Donahue ET, et al. (2021) Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. PLOS Pathogens 17(5): e1009510. https://doi.org/10.1371/journal.ppat.1009510

[ii] https://www.medicalnewstoday.com/articles/dementia-parkinsons-do-gut-bacteria-trigger-protein-clumping

[iii] https://medicalxpress.com/news/2021-05-evidence-links-gut-bacteria-neurodegenerative.html