A Critical Analysis of Intestinal Enteric Neuron Loss and Constipation in Parkinson’s Disease

Abstract

Constipation afflicts many patients with Parkinson’s disease (PD) and significantly impacts on patient quality of life. PD-related constipation is caused by intestinal dysfunction, but the etiology of this dysfunction in patients is unknown. One possible cause is neuron loss within the enteric nervous system (ENS) of the intestine. This review aims to 1) Critically evaluate the evidence for and against intestinal enteric neuron loss in PD patients, 2) Justify why PD-related constipation must be objectively measured, 3) Explore the potential link between loss of enteric neurons in the intestine and constipation in PD, 4) Provide potential explanations for disparities in the literature, and 5) Outline data and study design considerations to improve future research. Before the connection between intestinal enteric neuron loss and PD-related constipation can be confidently described, future research must use sufficiently large samples representative of the patient population (majority diagnosed with idiopathic PD for at least 5 years), implement a consistent neuronal quantification method and study design, including standardized patient recruitment criteria, objectively quantify intestinal dysfunctions, publish with a high degree of data transparency and account for potential PD heterogeneity. Further investigation into other potential influencers of PD-related constipation is also required, including changes in the function, connectivity, mitochondria and/or α-synuclein proteins of enteric neurons and their extrinsic innervation. The connection between enteric neuron loss and other PD-related gastrointestinal (GI) issues, including gastroparesis and dysphagia, as well as changes in nutrient absorption and the microbiome, should be explored in future research.

Constipation in Parkinson's Disease

“…67,68 The clinical significance of this finding is unclear, however, since the presence of αsynuclein does not correlate with the occurrence of constipation. 67,68 That the CNS might also contribute to constipation in PD was suggested by the demonstration of differences in regional neuronal activity and functional activity in the brain between PD patients with and without constipation. 69 Further studies are needed to confirm if dopamine and other neurotransmitters are actually depleted in the ENS and to define their relationships to symptoms and motor dysfunction in affected PD patients.…”

“…66 Of late, the focus has shifted to the role of α-synuclein, with more recent studies consistently identifying α-synuclein in the ENS and muscularis propria in the colon. 67,68 The clinical significance of this finding is unclear, however, since the presence of αsynuclein does not correlate with the occurrence of constipation. 67,68 That the CNS might also contribute to constipation in PD was suggested by the demonstration of differences in regional neuronal activity and functional activity in the brain between PD patients with and without constipation.…”

Management of Gastrointestinal Symptoms in Parkinson’s Disease

“…Indeed, increasing severity of constipation is associated with a likelihood of later developing PD (hazard ratio: 10.47 [9.46-11.58] for severe constipation) 75 . As in other segments of the GI tract, several studies have noted the presence of alpha-synuclein deposition, in the colon, predominantly examining the submucosal plexus, although a handful have also examined the myenteric plexus 76 . Because of small sample sizes and heterogeneity in study design, there remains inadequate data to draw concrete correlations between constipation symptom severity and the extent or precise location of abnormal alpha-synuclein depositions as well as with neuronal loss.…”

“…75 As in other segments of the GI tract, several studies have noted the presence of alpha-synuclein deposition, in the colon, predominantly examining the submucosal plexus, although a handful have also examined the myenteric plexus. 76 Because of small sample sizes and heterogeneity in study design, there remains inadequate data to draw concrete correlations between constipation symptom severity and the extent or precise location of abnormal alpha-synuclein depositions as well as with neuronal loss. However, it has been proposed that Lewy body pathology in the ENS is linked to vagal neurodegeneration, reduced peristalsis, dysregulation of intestinal secretions, and dysbiosis as well as inflammation-all of which contribute to constipation.…”

Parkinson's disease constipation effect of electroacupuncture at ST25 through colonic motility and enteric neuropathology

“…All these findings support Braak's proposed pathophysiological model of α-syn aggregates in Parkinson's disease, which is the early pathological involvement of the enteric nervous system (ENS) and the dorsal motor nucleus vagus ( 4 , 5 ). The ENS plays a crucial role in the neurodegenerative process leading to PD ( 6 ). The ENS determines the motor patterns of the gastrointestinal tract, processes sensory input from mechanical and chemical receptors in the gut wall, and integrates sympathetic and parasympathetic inputs, interacting with the immune and endocrine systems of the gut to produce coordinated effects ( 7 ).…”