Constipation is a common prodromal symptom of PD; and in some patients can be a very troublesome symptom throughout their disease course. But the truly groundbreaking recent finding is that the gut-brain axis may be centrally involved in PD pathogenesis. Inflammation may also play a major part in the etiology of the disease.
Constipation is present in up to 80% of patients with PD, and around 30% have fewer than three bowel movements per week.1 This may be associated with abdominal pain, a sensation of incomplete emptying, nausea or bloating. These symptoms generally do not correlate with treatment but do correlate with disease severity, suggesting that the primary disease process is directly involved.
Constipation precedes PD
Furthermore, longitudinal studies demonstrate an association between constipation and later development of PD. The Honolulu Heart Program collected information on the frequency of bowel movements of almost seven thousand men without PD and followed them for over twenty years. Ninety-six developed PD an average of 12 years into follow-up. After adjustment for age and other relevant variables, men with fewer than one bowel movement per day at baseline had almost three times the risk of developing PD when compared with men with at least one bowel movement per day.2
At autopsy, alpha-synuclein is found in the GI tract of PD patients. Does it spread prion-like from gut to brain?
The association between infrequent bowel movements and subsequent PD is supported by more recent but retrospective data from a case-control study carried out in a primary care setting in the UK. Ten years before diagnosis, constipation was twice as common among people who went on to develop PD as it was among those who did not. Tremor, which conferred a 7.6 fold relative risk, was the only other factor significantly associated with diagnosis of PD ten years later.3 Taken together, these studies suggest that constipation is a common prodromalsymptom of PD.
Apart from the discomfort involved, gastroparesis (impaired gastric emptying without mechanical outlet obstruction) present before treatment but exacerbated by L-dopa or dopamine agonists can interfere with the absorption of oral PD drugs, increasing the likelihood of disabling motor fluctuations. This is because levodopa needs to reach the small intestine in order to be absorbed.
Gastroparesisinterfering with the effectiveness of oral PD medications
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Does alpha-synuclein spread from gut to brain?
However, the truly groundbreaking recent research is evidence - reviewed by Fasano et al4 and Klingelhoeffer and Reichmann5 - suggesting that the gut-brain axis may be centrally involved in the pathogenesis of PD. Lewy pathology involves not only nigral dopaminergic neurons but extra-nigral structures in the CNS (in many parts of the brain, and also in the spinal cord) and in the peripheral autonomic nervous system.6 This is associated with a host of neurotransmitter derangements in both the central and peripheral nervous systems.
Along with Lewy pathology, alpha-synuclein, which is the main constituent of Lewy bodies and central to the pathogenesis of PD, has been reported in autopsy studies as being present in the gastrointestinal (GI) tract of PD patients in both the myenteric and submucosal plexus.7 In submucosal samples obtained by endoscopic biopsy, Lewy pathology was present in 72% of PD patients and in none of the controls.8
In 2006, Braak et al reported that Lewy pathology was found in the GI tract of patients who had not yet developed motor symptoms and postulated that the enteric nervous system might be affected before the CNS.9 Clinical details were limited, but the suggestion was that the vagus nerve might be the route by which neuropathology spreads via prion-like trans-synaptic transmission from neuron to neuron, from gut to brain. Enteric neurons synapse with both afferent and efferent vagal neurons, and the terminals of the vagus nerve in the submucosa of the GI tract are only millimeters from the lumen. All of this raised the possibility that exposure to a toxin or infectious agent in the gut might initiate aggregation of alpha-synuclein.
In 2017, Chandra et al10 described a hypothetical pathway in which the apical surface of enteroendocrine cells is exposed to toxins that are ingested or derived from gut microbes. The enteroendocrine cells produce hormones and have neuron-like characteristics, such as producing alpha-synuclein. Toxin-induced aggregation of this protein and its migration to the enteric nerves could set off a pathogenic cascade involving the brainstem (medulla, pons and substantia nigra), leading eventually to the motor deficits characteristic of the synucleinopathies.
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The microbiome and Parkinson’s Disease(Adapted from Chandra et al. JCI Insight. 2017)
Enteric nerves do not have direct contact with luminal contents
EECs /enteroendocrine cells) are sensory cells in the gut and produce hormones
They have neuronal-like characteristics, including expression of alpha-synuclein
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Full truncal vagotomy was associated with a decreased risk of PD over twenty years when compared to the general population
This hypothesis gained support from epidemiological data – derived from a Danish registry of patients undergoing vagotomy over the period 1977-95 – showing that full truncal vagotomy was associated with a decreased risk of PD over the next twenty years when compared to people in the general population.11 Patients having superselective (partial) vagotomy had a risk similar to that of controls.
The hypothesis that pathological alpha-synuclein spreads like a prion from gut to brain along the vagus nerve is compatible with Braak staging and supported by evidence of host-to-graft transmission.
It was also supported by experimental evidence. In 2008, Li et al found evidence of host-to-graft transmission of pathological alpha-synuclein: Lewy body-like inclusions developed in fetal dopaminergic neurons grafted into the striatum of PD patients.12 It was also reported that inoculation of alpha-synuclein fibrils into the striatum of non-transgenic mice results in cell-to-cell propagation and initiates Parkinsonian neurodegeneration.13
Also compelling is evidence from the Dresden PD Model.5 Chronic intragastric administration of the pesticide rotenone in wild-type mice induces alpha-synuclein release from enteric neurons. This propagates via sympathetic and parasympathetic nerves to the CNS, leading eventually to motor symptoms corresponding to the Braak stages. Resection of nerves connecting the gut to the CNS halts this pathological process.14
There is also direct evidence from rats that Parkinsonian pathology spreads from the GI tract to the brain.15 Holmqvist et alinjected human PD brain lysate containing alpha-synuclein and recombinant alpha-synuclein into the intestinal wall of animals and found that both forms were transported via the vagal nerve to the brainstem. Three days after injection, alpha-synuclein was detected in the dorsal motor nucleus of the vagus, and death of dopaminergic neurons could be seen at ninety days.
Inflammation in PD
There is growing evidence that chronic inflammation plays a role in the etiology of various neurodegenerative disorders including PD. Dopamine biosynthesis involves production of reactive oxygen species (ROS) by mitochondria, thereby establishing a pro-oxidative state.16 The midbrain contains a high density of microglia. Further, nigral dopaminergic neurons are highly sensitive to systemic toxins and inflammatory mediators such as Tumor Necrosis Factor and lipopolysaccharide.
Nigral dopaminergic neurons are highly sensitive to inflammatory mediators; and increased intestinal permeability may allow the systemic translocation of bacterial toxins.
Evidence from the gastrointestinal tract suggests the presence of inflammation in PD.17 There is, for example, an increase in the stools of immune factors such as IL-1alpha and beta, CXCL8 and CRP. Increased inflammation and permeability of the large intestine have been suggested as playing a permissive role in the systemic translocation of bacteria and their endotoxins, and aggregation of alpha-synuclein in the gut. Houser and Tansey (2017) describe these factors and their role in gut-to-brain spread of pathology in a vulnerable individual exposed to inflammatory triggers, leading ultimately to neuroinflammation and degenerative changes.18
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The gut may be at the origin of the inflammation-driven PD pathogenesis (adapted from Houser & Tansey. Npj PD. 2017)
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Infection with Helicobacter pylori is associated with more severe PD
Relevant to this is a study by Tan et al showing that infection with Helicobacter pylori is associated with more severe PD.19 The study included 102 consecutive PD patients whose motor function was blindly assessed. Thirty-two percent were positive for H. pylori. On multivariate analysis, patients who were H. pylori-positive had worse scores on the UPDRS Part III (ie motor examination) and slower gait.
However, the adverse effect of H. pylori infection may be due at least in part to the fact that it reduces absorption of Levodopa. In a double-blind, placebo-controlled study in PD patients with motor fluctuations who were positive for H. pylori, eradication of the bacterium increased drug availability by around 20% and increased ON time.20
Gut dysmotility, common in PD, may favor Small Intestinal Bacterial Overgrowth (SIBO), which Gabrielli et al found was present in 54% of 48 consecutive PD patients and in only 8% of matched controls.21 Fasano et al subsequently reported that eradication of SIBO reduced motor fluctuations without affecting the pharmacokinetics of L-dopa.22 However, it should be noted that the number of patients involved in the study was small: only 18 patients received antibiotic treatment for SIBO, and there was a high SIBO relapse rate of 43% at six months.
Due to the fact that treatment trials have involved relatively small samples of patients, further confirmatory studies are needed before eradication of H. pylori and/or SIBO can be advocated on a routine clinical basis.
We thank Lundbeck Institute Campus Editorial Board member Professor Shen-Yang Lim MBBS MD FRACP, Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, for sharing his expertise and insights surrounding gastrointestinal dysfunction in Parkinson’s disease.
Edwards LL, Pfeiffer RF, Quigley EM, et al. Gastrointestinal symptoms in Parkinson's disease. Mov Disord. 1991;6(2):151-6.
Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology. 2001;57(3):456-62.
Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet Neurol. 2015;14(1):57-64.
Fasano A, Visanji J, Liu WJC, et al. Gastrointestinal function in Parkinson’s Disease. Lancet Neurol. 2015; 14(6):625-39.
Klingelhoeffer L, Reichmann H. Pathogenesis of Parkinson’s Disease – the gut-brain axis and environmental factors. Nat Rev Neurology. 2015; 11(11):625-36.
Goedert M, Spillantini MG, del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013; 9(1):13-24.
Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010;119(6):689-702.
Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS One. 2010;5(9):e12728.
Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. 2006;396(1):67-72.
Chandra R, Hiniker A, Kuo Y-M, et al. α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease. JCI Insight. 2017; Jun 15;2(12). pii: 92295.
Svensson E, Horvath-Puo E, Thomsen RW, et al.Vagotomy and subsequent risk of Parkinson’s Disease. Ann Neurol. 2015; 78(4):522-529.
Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501-03.
Luk KC1, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949-53.
Pan-Montojo F1, Schwarz M, Winkler C, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2:898. doi: 10.1038/srep00898.
Holmqvist S, Chutna O, Bousset L, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014 Dec;128(6):805-20.
Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol. 2007;208(1):1-25.
Houser MC, Chang J, Factor SA, et al. Stool immune profiles evince gastrointestinal inflammation in Parkinson's Disease. Mov Disord. 2018;33(5):793-804.
Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis? NPJ Parkinson’s Dis. 2017;3:3. doi: 10.1038/s41531-016-0002-0.
Tan AH, Mahadeva S, Marras C, et al. Helicobacter pyloriinfection is associated with worse severity of Parkinson’s disease. Parkinsonism and Related Disorders. 2015;21:221-225.
Pierantozzi M, Pietroiusti A, Brusa L, et al. Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology. 2006;66(12):1824-49.
Gabrielli M, Bonazzi P, Scarpellini E, et al. Prevalence of small intestinal bacterial overgrowth in Parkinson’s Disease. Mov Disord. 2011; 26(5):889-92.
Fasano A, Bove F, Gabrielli M, et al. The role of small intestinal bacterial overgrowth in Parkinson's disease.Mov Disord. 2013;28(9):1241-49.