Constipation preceding Parkinson's disease: a systematic review and meta-analysis

Adams-Carr, Kerala L.; Bestwick, Jonathan P.; Shribman, Samuel; Lees, Andrew J.; Schrag, Anette; Noyce, Alastair J.

doi:10.1136/jnnp-2015-311680

Cited by 164 publications

(143 citation statements)

References 24 publications

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“…This hypothesis is supported by the observation that truncal vagotomy is associated with a lower risk of PD . Also, several gastrointestinal disorders, such as constipation, irritable bowel syndrome (IBS), and inflammatory bowel disease are associated with a higher risk of PD. Lewy‐type pathology has been detected in the gastrointestinal tract up to 20 years prior to PD diagnosis, and prominent denervation of the gut in prodromal and established PD has been demonstrated …”

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confidence: 89%

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

2019

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Background Gut microbiota alterations have been found in prodromal and established Parkinson's disease (PD). Antibiotic exposure can have long‐term effects on the composition of human intestinal microbiota, but a potential connection between antibiotic exposure and risk of PD has not been studied previously. Objective To evaluate the impact of antibiotic exposure on the risk of PD in a nationwide, register‐based, case‐control study. Methods We identified all patients who were diagnosed with PD in Finland during the years 1998 to 2014. Information was obtained on individual purchases of orally administered antibiotics during the years 1993 to 2014. We assessed the association between prior antibiotic exposure and PD using conditional logistic regression. Results The study population consisted of 13,976 PD cases and 40,697 controls. The strongest connection with PD risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416; 95% confidence interval, 1.053–1.904). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10 to 15 years before the index date, sulfonamides and trimethoprim 1 to 5 years before the index date, and antifungal medications 1 to 5 years before the index date were positively associated with PD risk. In post hoc analyses, further positive associations were found for broad‐spectrum antibiotics. Conclusions Exposure to certain types of oral antibiotics seems to be associated with an elevated risk of PD with a delay that is consistent with the proposed duration of a prodromal period. The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to PD, but further studies are needed to confirm this. © 2019 International Parkinson and Movement Disorder Society

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confidence: 89%

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

2019

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“…82 Meta-analyses reveal that constipation is more than 2 times common in people who develop PD compared to normal people, 83 and individuals with constipation have 2 times the chance to have PD within 10 years of their evaluation. 84 The time duration over which constipation indicates the development of PD is remarkable. After prospective and retrospective studies, it has been found that constipation becomes apparent at an average of 15.6-24.0 years before PD is diagnosed.…”

Section: Constipationmentioning

confidence: 99%

Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson's Disease: A Critical Review

Nair

Ramachandran

Joghee

et al. 2018

J Neurogastroenterol Motil

118

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Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson’s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson’s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson’s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson’s disease patients.

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“…For this reason, much attention has been focused on the GI tract, which is heavily burdened by Lewy pathology (13) and commonly expresses symptoms including dysphagia, bloating and constipation (14). Of these, constipation has been reported to manifest as early as 10 years prior to motor symptoms (15). Curiously, accumulation of α-synuclein can occur in the gut up to 10 years prior to diagnosis (16).…”

Section: Introductionmentioning

confidence: 99%

Rotenone and elevated extracellular potassium concentration induce cell‐specific fibrillation of α‐synuclein in axons of cholinergic enteric neurons in the guinea‐pig ileum

Sharrad

Chen

Gai

et al. 2016

Neurogastroenterology Motil

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Background Parkinson's disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson's disease are Lewy bodies and neurites, of which α‐synuclein fibrils are the major component. α‐Synuclein aggregation has been reported in the gut of Parkinson's disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease. However, unlike the central nervous system, the nature of α‐synuclein species that form these aggregates and the classes of neurons affected in the gut are unclear. We have previously reported selective expression of α‐synuclein in cholinergic neurons in the gut (J Comp Neurol. 2013; 521:657), suggesting they may be particularly vulnerable to degeneration in Parkinson's disease. Methods In this study, we used immunohistochemistry to detect α‐synuclein oligomers and fibrils via conformation‐specific antibodies after rotenone treatment or prolonged exposure to high [K+] in ex vivo segments of guinea‐pig ileum maintained in organotypic culture. Key Results Rotenone and prolonged raising of [K+] caused accumulation of α‐synuclein fibrils in the axons of cholinergic enteric neurons. This took place in a time‐ and, in the case of rotenone, concentration‐dependent manner. Rotenone also caused selective necrosis, indicated by increased cellular autofluorescence, of cholinergic enteric neurons, labeled by ChAT‐immunoreactivity, also in a concentration‐dependent manner. Conclusions & Inferences To our knowledge, this is the first report of rotenone causing selective loss of a neurochemical class in the enteric nervous system. Cholinergic enteric neurons may be particularly susceptible to Lewy pathology and degeneration in Parkinson's disease.

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Constipation preceding Parkinson's disease: a systematic review and meta-analysis

Abstract: This systematic review and meta-analysis demonstrates that people with constipation are at a higher risk of developing Parkinson's disease compared with those without and that constipation can predate Parkinson's diagnosis by over a decade.

Cited by 164 publications

References 24 publications

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson's Disease: A Critical Review

Rotenone and elevated extracellular potassium concentration induce cell‐specific fibrillation of α‐synuclein in axons of cholinergic enteric neurons in the guinea‐pig ileum

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