Is the gut microbiome a new frontier for diagnostics and therapeutics?
Event reportsOur seventh Parkinson's Cutting Edge Science conference took place on 19th March 2024 in Birmingham and was chaired by Prof Emily Henderson and Dr Neil Archibald. You can read an overview of the entire event here.
This write up is one of a series covering each session in detail for those who were unable to attend, or want to reflect on what they heard. Read more session write ups here.
The gut microbiome plays a critical role in human health, and there is growing evidence to suggest gut dysbiosis plays a role in Parkinson’s disease.
Such findings have raised the possibility of biome-related approaches for the diagnosis and treatment of the condition, said Professor Ai Huey Tan, associate professor and consultant neurologist at the University of Malaya in Kuala Lumpur, Malaysia.
The gut microbiome
Each of us plays host to somewhere between 2 million and 20 million bacterial genes, the majority of which are in gut.[1]
“Throughout our life, the gut microbiome plays critical roles in our anatomical, physiological, and immunological development,” said Prof Huey Tan, adding that bacterial diversity reduces as we age, resulting in a reduction in the microbiome’s functional capacity, and empathising that what constitutes normal “remains elusive”.
The gut/brain axis
The gut microbiome is an essential part of the gut barrier defence system, and gut dysbiosis has been associated with increased gut permeability and inflammation. This, Prof Huey Tan said, may enable pathogens and toxins to access the systemic circulation, or so-called leaky gut syndrome.
“The endings of the vagus nerve in the gut submucosa are micrometres away from the gut lumen. This raises the possibility that exposure to a toxin or infectious agent that leaks through the gut barrier could be spread through the vagus nerve to the brain,” she explained.
Indeed, several pre-clinical studies have demonstrated that gut microbes and their products can promote gut permeability and inflammation. This can lead to systemic inflammation, neuroinflammation, and increased α-synuclein pathology in the gut and brain.
As of 2022, there were more than 50 faecal microbiome case control cohort studies in Parkinson's disease, she said. Prof Huey Tan said: “Almost all of them found an altered gut microbiome in Parkinson’s patients, compared to controls. However, the findings on specific microbial changes were heterogeneous due to differences in study populations and methodology.”
In addition, two meta-analyses found that Parkinson’s status explained just 0.04% of the variances, she went on. [2],[3] “This is no surprise. We know that many intrinsic and extrinsic factors can influence the human gut microbiome, including age, frailty, comorbidities, slow transit time, diet, physical activity, and medications,” she said.
Possible biomarkers
Studies have found increased levels of Akkermansia bacteria among people with Parkinson’s, multiple system atrophy, progressive supranuclear palsy, Alzheimer’s disease, and amyotrophic lateral sclerosis.[4] “This suggests changes may be a non-specific, shared response to disease,” said Prof Huey Tan.
While the available evidence shows a high degree of variation in gut microbiome composition, the gut functional capacity is “quite consistent among healthy people”. This suggests that markers of gut function, such as gut metabolites, may be a more promising approach.
Numerous studies have integrated fecal metabolites using various platforms. “The most consistent metabolite signature lies in the reduction of short chain fatty acids (SCFA), butyrate, acetate, and propionate in Parkinson’s disease,” she said.[5]
Clinical studies have also demonstrated that a lower abundance of SCFA-producing bacteria and lower fecal SCFA is associated with worse Parkinson’s progression and cognition, and higher motor severity and depressive symptoms.[5]
“This is potentially a promising target, and we hope to see more studies looking at SCFA as a potential biomarker.”
Possible therapeutics
There are a variety of possible avenues in terms of using microbiome modulation to treat Parkinson’s.
Early studies investigating the hypothesis that eradicating Helicobacter pylori could increase levodopa absorption yielded conflicting results. A double-blind placebo controlled randomised trial did not record any improvement in clinical measures, including MDS-Unified Parkinson's Disease Rating Scale part III or timed motor tests, at weeks 12 or 52. A post-hoc analysis did not reveal any improvement in motor fluctuations.[6] “However, the disease modifying effect in the longer term is not excluded. We are currently still tabulating our five-year follow-up data,” said Prof Huey Tan.
Tyrosine decarboxylase (tdc) and a α-fluoromethyl-tyrosine (AFMT), which both play a role in the conversion of levodopa to dopamine in the small bowel, are both worthy of future investigation, she added.
More data on whether microbiome modification can be used to treat the motor and non-motor symptoms of Parkinson’s is also needed.
“We are now seeing an increasing number of studies using dietary supplementation to increase SCFA levels. It will be very exciting to see the findings,” said Prof Huey Tan.
While there is now class I evidence for the use of probiotics as a treatment for constipation in Parkinson’s, she went on, their efficacy in terms of motor and non-motor symptoms, as well as their long-term safety “require further investigation”.
“Probiotics are widely sold as food supplements without requirements for manufacturers to provide pre-clinical or clinical evidence of efficacy. To regulate the use of live microorganisms as medicinal products, FDA and the European Pharmacopeia have created a drug class called ‘live biotherapeutics’,” said Prof Huey Tan.
She also highlighted a small open label study of Parkinson’s patients that recorded an improvement in surrogate markers of intestinal permeability, intestinal inflammation, and neurodegeneration following a prebiotic fiber intervention.[7]
Fecal microbiota transplantation (FMT), or the transfer of fecal material from a donor into the GI tract of a recipient to directly change the gut microbial composition, is another promising area. Clinical trials have shown it is effective in inflammatory bowel disease, multi-drug resistant infection, and metabolic syndrome.[8] Data in Parkinson’s is currently limited to constipation, but trials are ongoing.
Emerging therapeutics
While many advances are in the pipelines, the advent of some innovative microbial-related approaches could be imminent.
One is symbiotic microbial consortia, or the design of well-characterised microbial strains which work synergistically towards specific microbial functions. Gut-103, which is composed of 17 bacterial strains, for example, has been shown to be a promising therapy for a range of conditions affected by dysbiosis-mediated intestinal inflammation and hyperpermeability, including Parkinson’s.[9]
In addition, two live biotherapeutics, MRX0005 and MRX0029, both of which have potent anti-inflammatory and antioxidant effects, have recently entered phase I Parkinson’s clinical trials.
Summing up, Prof Huey Tan said it was an exciting time for the field.
References
Gilbert, J. A., Blaser, M. J., et al. (2018). Current understanding of the human microbiome. Nature medicine, 24(4), 392-400.
Romano, S., Savva, G. M., et al. (2021). Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. npj Parkinson's Disease, 7(1), 27.
Toh, T. S., Chong, C. W., et al. (2022). Gut microbiome in Parkinson's disease: New insights from meta-analysis. Parkinsonism & related disorders, 94, 1-9.
Li, Z., Liang, H., et al. (2023). Gut bacterial profiles in Parkinson's disease: A systematic review. CNS neuroscience & therapeutics, 29(1), 140-157.
Duan, W. X., Wang, F., et al. (2023). Relationship between short-chain fatty acids and Parkinson’s disease: a review from pathology to clinic. Neuroscience Bulletin, 1-17.
Tan, A. H., Lim, S. Y., et al. (2020). Helicobacter pylori eradication in Parkinson's disease: a randomized placebo‐controlled trial. Movement Disorders, 35(12), 2250-2260.
Hall, D. A., Voigt, R. M., et al. (2023). An open label, non-randomized study assessing a prebiotic fiber intervention in a small cohort of Parkinson’s disease participants. Nature Communications, 14(1), 926.
Sorbara, M. T., & Pamer, E. G. (2022). Microbiome-based therapeutics. Nature Reviews Microbiology, 20(6), 365-380.
van der Lelie, D., Oka, A., et al. (2021). Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nature communications, 12(1), 3105.
This meeting is designed and delivered by the Parkinson’s Academy and sponsored by BIAL Pharma. The sponsor has had no input into the educational content of this meeting.
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