When Digestive Symptoms Signal Parkinson's Disease

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak's hypothesis suggests that the digestive tract could be the starting point for Parkinson's disease. The fact that nearly all patients with Parkinson's disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson's disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer's disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.

Large Combined Study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson's disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer's disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson's disease, Alzheimer's disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson's disease (vs NC, Alzheimer's disease, and CVD) in both case-controls (odds ratios [OR] all P < .0001) and cohort analyses (relative risks [RR] all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson's disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson's disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson's disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson's disease.

A 'Second Brain'

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson's disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer's disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson's disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson's disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson's disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson's disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak's hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson's disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson's disease, as is suggested by Braak's hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson's, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

Medscape Medical News © 2023 

Cite this: When Digestive Symptoms Signal Parkinson's Disease - Medscape - Oct 20, 2023.