Introduction Parkinson's disease (PD) is a neurodegenerative disorder affecting millions globally. Though not as common as Alzheimer's disease, it presents a significant challenge, with estimates suggesting 1 in 100 people over 60 will develop it [1]. While the exact cause remains elusive, PD's signature symptoms – tremors, stiffness, and balance problems – significantly impact daily life. The initial diagnosis often relies on a neurological examination. Observing tremors, rigidity, slowness of movement (bradykinesia), poor balance and coordination, and speech difficulties paints a strong clinical picture [2]. In some cases, dopamine replacement therapy can provide a diagnostic clue – marked improvement following the introduction of levodopa, a dopamine precursor, strengthens the PD diagnosis. The culprit behind these motor issues lies deep within the brain. In the substantia nigra, a specific area involved in motor control, dopamine-producing neurons degenerate. Dopamine acts as a chemical messenger, facilitating smooth communication between brain regions responsible for movement. This breakdown in communication disrupts our ability to control movement freely [3]. While the exact cause is unknown, genetic predisposition and environmental factors play a role. Mutations in specific genes have been linked to PD, though they represent a small minority of cases. Exposure to toxins like herbicides and certain medications might also contribute. Accordingly, the common risk factors include age, genetics, environmental triggers, medications, and head injuries [4,5]. Currently, there is no cure for PD. Treatment focuses on managing symptoms and improving quality of life. Levodopa remains the mainstay of therapy, but its effectiveness can decline over time. Other medications, surgery in some cases, and physical therapy all contribute to symptom management. The relentless march of research offers a glimmer of hope. Scientists are actively exploring various avenues. Gene therapy holds promise for replacing or repairing faulty genes. Cell-based therapies involve the transplant of dopaminergic pluripotent stem cells. Deep brain stimulation, where electrodes deliver electrical pulses to specific brain regions, is another area of ongoing investigation [6]. Yet, another emerging area of research that has gained significant attention lately is the gut microbiome of Parkinson’s patients and the potential use of fecal microbiota transplant (FMT) for disease treatment. References [1] Who has Parkinson’s? [2] Getting diagnosed [3] Diagnosis & treatment of Parkinson’s disease [4] Parkinson’s disease risk factors and causes [5] 5 risk factors for Parkinson’s diseases [6] Parkinson’s Disease-Clinical Research Parkinson's Microbiome Microbiome definition re-visited: old concepts and new challenges. Berg G. et al. Microbiome (2020) 8:103 Figure 2 Over the last few years many studies have described dysbiosis in the microbiome of PD patients compared to healthy controls albeit with variations in results from one study to another due to variations in sampling and study designs. Recent meta-analysis [1,2] and metagenomics studies [3] have resulted in a more robust and coherent picture, which we will now attempt to summarize without overinterpretations. The overall dysbiosis is confirmed and characterized by a decrease in the most abundant species of the normal flora and an increase in the rare ones. The species that are depleted are from genera (e.g. Roseburia, Fusicatenibacter, Blautia, Anaerostipes (Lachnospiraceae family), and Faecalibacterium (Ruminococcaceae family) or from the Butyricicoccaceae family, which are known to secrete short chain fatty acids (SCFAs) and butyrate critical for gut health including the enteric nervous system. Depletion of these species was also noted in the gut microbiomes of patients suffering from gastrointestinal dysfunctions, and other neuroinflammatory or neurodegenerative diseases. Bacterial species that tend to increase in abundance in the gut microbiome of PD patients include those that belong to the following genera: Lactobacillus, Akkermansia, Hungatella, and Bifidobacterium. The enrichment in Lactobacillus and Bifidobacterium is not well understood as these taxa are generally known to be beneficial. Whether they contribute to PD or just prefer the pro-inflammatory gut environment remains to be determined. Likewise, there are conflicting evidence about the role of Akkermansia spp whose association with PD is not uniform and appears geographically specific [3]. They are considered beneficial and used as probiotics for treatment of metabolic diseases [4]. On the other hand, some Akkermansia species readily degrade mucin and could contribute to decrease intestinal peristalsis and constipation, a hallmark of PD. The Christensenellaceae family of bacteria also tends towards more abundance in PD. They are hydrogen producers and support the growth of the archeon methanobrevibacter, a major hydrogenotrophic methane producer in the human gut. The abundance of the latter is also known to contribute to constipation in PD. Besides the effect on SCFAs depletion on gut integrity and health, at the functional level the PD microbiota is also characterized by an overall state of altered production of inflammatory species (e.g. increased lipopolysaccharides (LPS), lipoteichoic acid (LTA) and murein/bacterial lipoprotein (BLP)), altered proteolytic and amino acid degradation pathways, and dysregulation in synthesis and metabolism of neurotransmitters (dopamine, glutamate, gamma amino butyric acid and serotonin). In addition, it was reported that there is an upregulation in the pathways involved in the degradation of nicotinamide and trehalose, two neuroprotective agents. The metabolic pathways to produce the bacterial amyloidogenic protein curli were upregulated, likewise for the pathways involved in the production of trimethylamine, a toxic metabolite linked to cardiovascular diseases and stroke [3]. On the overall these changes in metabolic profiles favor an intestinal inflammatory and neurodegenerative state and indicate that dysbiosis could play a significant role in the development of PD together with genetic predisposition, environmental factors and aging. The progress achieved to date has provided the impetus not only for deeper research delving into causes and effects, but also for the development of biomarkers and manipulation of the microbiome to prevent or mitigate the progression of PD. The use of probiotics was investigated resulting in modest successes [5,6]. More importantly, the application of fecal microbiota transplantation (FMT) for treatment has seen significant progress and the results of the latest clinical trials are promising. References [1] Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. Romano S, Savva GM, Bedarf JR, Charles IG, Hildebrand F and Narbad A. npj Parkinson’s Disease (2021) 7:27; https://doi.org/10.1038/s41531-021-00156-z. [2] Inflammatory microbes and genes as potential biomarkers of Parkinson’s disease. Nie S, Wang J, Deng Y, Ye Z and Ge Y. npj Biofilms and Microbiomes (2022) 8:101; https://doi.org/10.1038/s41522-022-00367-z. [3] Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Wallen ZD, Demirkan A, Twa G, Cohen G, Dean MN, Standaert DG, Sampson TR & Payami H. Nature Communications (2022) 13:6958. [4] A Critical Perspective on the Supplementation of Akkermansia muciniphila: Benefits and Harms. Chiantera, V.; Laganà, A.S.; Basciani, S.; Nordio, M.; Bizzarri, M. Life (2023) 13, 1247. https://doi.org/10.3390/life13061247 [5] Probiotics and Parkinson’s Disease: What You Need To Know. Emily Wagner, M.S. August 17, 2023 [6] Probiotics and the Treatment of Parkinson's Disease: An Update. Mirzaei, H., Sedighi, S., Kouchaki, E. et al. Cell Mol. Neurobiol (2022) 42, 2449–2457. https://doi.org/10.1007/s10571-021-01128-w Fecal Microbiota Transplant (FMT) in PD The concept of FMT involves transferring fecal microbiota from a healthy donor to a recipient to restore microbial balance. In 2019, the first case report by Huang et al. [1] demonstrated symptomatic improvement in a 71-year-old PD patient following FMT, sparking interest in its therapeutic potential. Subsequent observational studies and initial clinical trials further explored the safety and efficacy of FMT in PD patients. Notably, a small pilot study by Kuai et al. in 2021 [2] with 11 PD patients reported not only constipation relief but also significant improvements in motor symptoms and quality of life after a single transplant via nasoduodenal tube. These findings were corroborated by two additional studies: a small randomized, placebo-controlled study with 12 PD patients dosed with FMT orally twice weekly for 12 weeks [3], the other with 56 PD patients dosed orally once a week for 3 weeks [4]. Both studies used lyophilized encapsulated FMT for oral administration. Together the results of the three studies indicate a promising therapeutic effect of FMT on PD symptoms. Despite encouraging results, these early studies faced methodological limitations, including small sample sizes, lack of standardized protocols, and heterogeneous patient populations. The variability in donor selection, fecal preparation, and administration routes also contributed to inconsistencies in outcomes. Moreover, the long-term effects and optimal dosing regimen of FMT remain uncertain, necessitating further investigation [5]. The field of FMT for PD is currently undergoing a paradigm shift towards more rigorous randomized controlled trials (RCTs) to establish its efficacy and safety. Notably, a single-center randomised, double-blind, placebo-controlled trial (GUT-PARFECT) with 46 early-stage PD patients was recently reported [6]. It demonstrated superior motor improvement in PD patients receiving a single FMT via nasojejunal administration compared to placebo, supporting its therapeutic potential. This finding marks another significant milestone in the clinical validation of FMT for PD. Notable advancements notwithstanding, several challenges lie ahead in establishing FMT as a mainstream treatment for PD. Large-scale RCTs with long-term follow-up are needed to confirm the efficacy, safety, and durability of FMT across diverse patient populations. Standardization of protocols, including donor screening, preparation methods, and administration routes, is essential to ensure reproducibility and minimize variability. Moreover, mechanistic studies elucidating the underlying pathways linking gut dysbiosis to PD pathology will provide valuable insights for targeted interventions. In conclusion, FMT holds promise as a novel therapeutic approach for alleviating motor and non-motor symptoms of Parkinson's disease. From its humble beginnings in case reports to the recent milestone RCTs, the journey of FMT in PD underscores the transformative potential of microbiome-based therapies. While challenges persist, concerted efforts towards rigorous research and clinical validation are essential to harness the full therapeutic benefits of FMT and improve the quality of life for PD patients worldwide. References [1] Fecal microbiota transplantation to treat Parkinson's disease with constipation: A case report. Huang H et al. Medicine (2019) 98(26): p e16163. DOI: 10.1097/MD.0000000000016163 [2] Evaluation of fecal microbiota transplantation in Parkinson's disease patients with constipation. Kuai X et al. Microb. Cell Fact. (2021) 20, 98. https://doi.org/10.1186/s12934-021-01589-0 [3] Fecal microbiota transplantation in Parkinson's disease—A randomized repeat-dose, placebo-controlled clinical pilot study. DuPont HL et al. Front. Neurol. (2023) 14:1104759. doi: 10.3389/fneu r.2023.1104759 [4] Efficacy of fecal microbiota transplantation in patients with Parkinson’s disease: clinical trial results from a randomized, placebo-controlled design. Cheng Y et al. Gut Microbes (2023), 15(2), 2284247. https://doi.org/10.1080/19490976.2023.2284247 [5] The Potential Role of Fecal Microbiota Transplantation in Parkinson’s Disease: A Systematic Literature Review. Vongsavath T et al. Appl. Microbiol. (2023) 3, 993–1002. https://doi.org/10.3390/applmicrobiol3030067 [6] Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson’s disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial. Bruggerman A et al. eClinical Medicine (2024) 71: 102563. https://doi.org/10. 1016/j.eclinm.2024. 102563 Looking forward Living with Parkinson's disease presents a daily challenge. However, with ongoing research and the combined efforts of medical professionals and patients, including private sector investments, the future holds promise for improved management and potentially, a cure for this debilitating disease.
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AuthorHung V. Le PhD Archives
June 2024
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Preventive medicine plays a crucial role in enhancing public health by focusing on proactive measures to avoid illness. By promoting healthy lifestyles, vaccinations, and early screenings, it significantly reduces the burden on healthcare systems and improves overall quality of life. It empowers individuals to take charge of their well-being and fosters a healthier, more sustainable society.
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