Parkinson Disease and the Gut: Treatment Potential Abounds

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Current evidence highlights the potential role of cross-talk between the enteric and central nervous systems and the pathogenesis of Parkinson disease.
Current evidence highlights the potential role of cross-talk between the enteric and central nervous systems and the pathogenesis of Parkinson disease.

Primarily recognized for its motor symptoms, Parkinson disease (PD) can also be associated with a range of non-motor features, including gastrointestinal (GI) dysfunction1 and constipation,2 both of which are key symptoms of inflammatory bowel disease (IBD). Constipation is reported to be one of the most prevalent symptoms of PD and may precede the onset of motor symptoms by up to 2 decades.3 So, what exactly is the link between PD and IBD, and what treatment options are available?

The Parkinson's-Gut Link

A recent study showed a statistically significant increase in the risk for developing PD in patients with IBD.4 Current evidence highlights the potential role of cross-talk between the enteric and central nervous systems and the pathogenesis of PD.5 Thus, initial intestinal inflammation resulting from poorly controlled IBD may eventually result in neuroinflammation and lead to neurodegeneration.

The major biologic marker of PD, α-synuclein, is expressed in the enteric neurons prior to being detected in the brain, suggesting a "prion-like" development of the disease from the gut to the brain.6

The gut microbiota of a group of patients with PD has been successfully sequenced.7 Findings showed that the composition of the gut microbiome is altered in PD and that this is associated with motor symptoms. Implanting gut microbiota derived from patients with PD into α-synuclein overexpressing mice resulted in motor impairments, which were not seen in mice implanted with control-derived microbiota.8 This result indicates that PD-associated motor dysfunction can be induced via changes in microbiota composition. Alterations in the composition of the gut microbiota may in a similar fashion play a role in the pathogenesis of IBD.9

Potential Treatments Targeting the Gut

Given what is known about the role of GI disturbance in the pathogenesis of both PD and IBD, therapies targeting the dysbiosis of the gut microbiota may present a viable treatment option in both conditions. One such therapy is fecal microbiota transplantation (FMT), which is commonly used in the treatment of Clostridium difficile infection of the gut.10 According to senior neurologist Rajshekher Garikapati, MD, of University Hospital Sharjah in the United Arab Emirates, “FMT for the treatment of symptoms related to Parkinson disease is an evolving field with great potential.”

FMT is the process of transferring liquid filtrate feces from a healthy, screened individual into a diseased recipient. This solution can be infused into the recipient via various routes, including a nasogastric or nasoduodenal tube, enema, or colonoscope. The aim of FMT is to restore symbiosis of the gut microbiome. In support of this treatment, research shows that 2 weeks following FMT for C difficile infection, the gut bacteria composition of a recipient closely resembles that of their healthy donor.11

While there is limited evidence regarding the effectiveness of FMT, it is being used experimentally to treat a wide range of conditions, including multiple sclerosis, PD, chronic fatigue syndrome, IBD, and autism. Given the clinical potential of FMT, ongoing research is being conducted to further characterize its effectiveness. Risks associated with FMT are rare and usually mild; the most commonly reported adverse effects are transient GI disturbances such as bloating, diarrhea, and constipation.12

While more research is needed to assess the efficacy of FMT in the treatment of PD, current research findings are positive and individual case studies show promise for this treatment. Professor Thomas Borody, MD, PhD, of the Centre for Digestive Diseases in Sydney, Australia, who is renowned for his innovative clinical work in this area, successfully uses FMT to treat C difficile infection and chronic constipation and has noted an improvement in the symptoms of PD and other diseases in his treated patients.13 In addition, FMT in PD-affected mice has been shown to have a neuroprotective effect via suppression of neuroinflammation and a reduction in TLR4/TNF-α signaling — the signaling pathway between the gut and the brain.14

Similar Alternative Treatments

Other treatment methods that target the gut-brain axis may also be viable options for PD in the future. Antibiotic therapy may prevent the formation of α-synuclein aggregates and neuroinflammation.15 In one study, a patient with PD who was treated with antibiotics for chronic constipation reported a complete disappearance of their neurologic symptoms.13

Given that the gut microbiome is altered in patients with PD and that this plays a role in the development of symptoms,7 supplementing the diet with probiotics to encourage a more balanced gut microbiome may also help to ease both motor and non-motor PD symptoms. Research is currently being conducted to study the effect of probiotic treatment on PD.16

An area of great interest is immunotherapy approaches. It has been proposed that immunization therapies targeting α-synuclein may be used in the future to prevent their "prion-like" spread from the gut to the brain and thus reduce pathology.17 Finally, anle138b, a novel oligomer modulator that acts as an inhibitor of aggregation been described. This presents a potential barrier to the formation of α-synuclein aggregates and their associated pathology.18 Drugs using this mode of action are entirely novel in the clinical setting and need to be carefully researched.

Where Are We Headed?

Clearly, more research is needed to better understand the interaction between the gut microbiome and the pathogenesis of PD. Inga Peter, PhD, of the department of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York City, told Neurology Advisor: “There are several recent papers that have shown the link between Parkinson disease and the gut microbiome. However, it is still largely unknown if dysbiosis is a risk or consequence of the disease.”

“In terms of future therapies,” Dr Peter continued, “I think that preventive measures are capturing the attention now. Our paper has shown that exposure to TNF-alpha inhibitors earlier in life significantly reduced the risk of Parkinson's in patients with IBD[by 78%], otherwise at an [approximately] 30% higher risk of Parkinson disease compared to the general population.19 We suspect that reduction in systemic inflammation could be one of the potential targets for prevention.”

Links between the gut microbiome and PD also present the potential use of microbiome sequencing as a novel diagnostic marker for PD. This is another key area that needs to be further explored. While many questions remain, the links between PD and IBD have introduced some novel and promising approaches to the more effective treatment of PD.

References

  1. Fasano A, Visanji NP, Liu LWC, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's Disease. Lancet Neurol. 2015;14(6):625-639.
  2. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73(21):1752-1758.
  3. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73(21):1752-1758.
  4. Villumsen M, Aznar S, Pakkenberg B, Jess T, Brudek T. Inflammatory bowel disease increases the risk of Parkinson's disease: a Danish nationwide cohort study [published online May 21, 2018]. Gut. doi:10.1136/gutjnl-2017-315666
  5. Houser MC, Tansey M. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis? NPJ Parkinsons Dis. 2017;3:3.
  6. Felice VD, Quigley EM, Sullivan AM, O'Keeffe GW, O'Mahony SM. Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms. Parkinsonism Relat Disord. 2016;27:1-8.
  7. Scheperjans F, Aho V, Pereira PAB, et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015;30(3):350-358.
  8. Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell. 2016;167(6):1469-1480.
  9. Cammarota G, Ianiro G, Cianci R, Bibbò S, Gabarrini A, Currò D. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther. 2015;149:191-212.
  10. Evrensel A, Ceylan ME. Fecal microbiota transplantation and its usage in neuropsychiatric disorders. Clin Psychopharmacol Neurosci. 2016;14(3):231-237.
  11. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2009;44(5):354-360.
  12. Choi HH, Cho YS. Fecal microbiota transplantation: current applications, effectiveness, and future perspectives. Clin Endosc. 2016;49(3):257-265.
  13. Ananthaswamy, A. Bugs from your gut to mine. New Scientist. 2011;209(2796):8-9.
  14. Sun MF, Zhu YL, Zhou ZL, et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun. 2018;70:48-60.
  15. Reglodi D, Renaud J, Tamas A, et al. Novel tactics for neuroprotection in Parkinson's disease: Role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol 2017;155: 120-148.
  16. Machado D,  Honeycutt L. Effects of probiotics on constipation, neurological symptoms, and quality of life associated with Parkinson's disease. Neurology. 2018;90(15 Supplement):P2.037.
  17. Schneeberger A, Tierney L,  Mandler M. Active immunization therapies for Parkinson's disease and multiple system atrophy. Mov Disord. 2016;31(2):214-224.
  18. Wagner J, Ryazanov S, Leonov A, et al. Anle138b: A novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013;125(6):795-813.
  19. Peter I, Dubinsky M, Bressman S, et al. Anti–tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 2018;75(8):939-946.

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