Damage to the Gut Mucosa May Almost Double Parkinson's Risk

Most people with ulcers and other gastrointestinal symptoms never develop neurological problems. But some 80 percent of people with Parkinson's disease have GI problems, such as acid reflux, irritable bowel syndrome, and constipation, which often emerge decades before motor difficulties do. This link has led many researchers to ask if problems in the gastrointestinal tract can trigger the neurodegenerative disease.

  • A history of gut mucosal damage from any cause is a risk factor for Parkinson's disease 14 years later, on average.
  • Inflammation, gastrointestinal α-synuclein, or lack of dopamine might explain the link.
  • The finding supports the “gut-first” theory of PD.

Now, scientists led by Trisha Pasricha, Beth Israel Deaconess Medical Center, Boston, report that damage to the upper gastrointestinal mucosa almost doubles a person’s risk of developing Parkinson’s within about 14 years, on average, after controlling for factors such as bacterial infection. The findings lend support to the “gut-first” hypothesis, which posits that toxic aggregates of α-synuclein produced by enteric neurons, or other toxic proteins produced by intestinal flora can aggregate and travel to the brain (Jul 2019 news; Dec 2016 news). The new study was published September 5 in JAMA Network Open.

First author Jocelyn Chang and colleagues had initially set out to find biomarkers of Parkinson's disease that appear in the gut before motor symptoms set in. “The hope is we can find a way to diagnose and treat Parkinson's earlier,” said Chang, a medical student at Tufts University Medical Center, Boston.

Pasricha and her collaborators turned to health records of 9,350 predominantly white people with no history of PD who were enrolled in a Boston medical registry. All had undergone upper intestinal tract endoscopies and biopsies for gastrointestinal issues. The scientists found mucosal damage, such as ulcers and esophageal lesions, in 2,338 of them. Many were infected with Helicobacter pylori—the bacterium that causes ulcers. This infection is common in Parkinson's patients and believed to be linked to the disease—a few studies have even hinted that treating H. pylori with antibiotics improves motor abilities and the efficacy of L-dopa treatment (Liu et al., 2017; Nyholm et al., 2021). 

Looking at follow-up medical records, Chang determined that among the 2,338 people with a history of mucosal damage, 52 went on to develop Parkinson's, compared to 48 out of 8,995 individuals who’d had healthy mucosa. Overall, the GI issues bumped up PD incidence fourfold. On average, people developed PD around 14 years after the intestinal damage was first diagnosed (image below).

Lasting legacy. Survival curves show the chances of a Parkinson's diagnosis develop sooner in people with a history of mucosal damage.

Controlling for other risk variables such as H. pylori infection, chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), and smoking, people with mucosal damage were still 1.8 times more likely to get Parkinson’s.

The authors are not sure why upper GI mucosal damage might lead to Parkinson’s. Chang thinks it possible that it triggers α-synuclein production or inflammatory pathways in the gut that impact the brain, perhaps through the vagus nerve. Alternatively, small drops in dopamine production due to Parkinson's that isn’t yet clinically apparent might spark problems in the intestinal mucosa. Enteric nerves modulate peristalsis and gut health and respond to dopamine and other CNS neurotransmitters. Dopamine agonists have even been used to treat gastrointestinal diseases (for a review see Kurnik-Łucka, 2021).

Malú Tansey, University of Florida, Gainesville, told Alzforum that the study fits with previous literature on gut- or body-first Parkinson's. “Timely detection of H. pylori and other inflammatory conditions may help us reduce risk and progression of PD in body-first cases,” she said. She noted that genetic or environmental risks could modulate the association between GI damage and PD.

Although the evidence supports the gut-first hypothesis, Chang said it doesn’t exclude “brain-first” disease progression in some people with mucosal damage. “Determining the different pathways will help us better understand the disease and create more personalized treatment methods,” she said.

In that vein, the group plans to study the biopsy tissue to try to determine how mucosal damage triggers PD at the molecular level. They are particularly interested in longitudinal studies that analyze the roles of gut α-synuclein and the vagus nerve, which connects the gut to the brain.—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

News Citations

  1. In PD Model, α-Synuclein Spreads from Intestine to Brain

Paper Citations

  1. Liu H, Su W, Li S, Du W, Ma X, Jin Y, Li K, Chen H. Eradication of Helicobacter pylori infection might improve clinical status of patients with Parkinson's disease, especially on bradykinesia. Clin Neurol Neurosurg. 2017 Sep;160:101-104. Epub 2017 Jul 5 PubMed.
  2. Nyholm D, Hellström PM. Effects of Helicobacter pylori on Levodopa Pharmacokinetics. J Parkinsons Dis. 2021;11(1):61-69. PubMed.
  3. Kurnik-Łucka M, Pasieka P, Łączak P, Wojnarski M, Jurczyk M, Gil K. Gastrointestinal Dopamine in Inflammatory Bowel Diseases: A Systematic Review. Int J Mol Sci. 2021 Nov 29;22(23) PubMed.

Further Reading

Primary Papers

  1. Chang JJ, Kulkarni S, Pasricha TS. Upper Gastrointestinal Mucosal Damage and Subsequent Risk of Parkinson Disease. JAMA Netw Open. 2024 Sep 3;7(9):e2431949. PubMed.

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