Most people with ulcers and other gastrointestinal symptoms never develop neurological problems. However, about 80 percent of Parkinson's disease patients have gastrointestinal problems, such as acid reflux, irritable bowel syndrome, and constipation, that often appear decades before the motility disorder appears. This association has led many researchers to question whether gastrointestinal problems could cause neurodegenerative diseases.

  • A history of intestinal mucosal injury from any cause is a risk factor for developing Parkinson's disease, on average, 14 years later.
  • Inflammation, gastrointestinal alpha-synuclein, or dopamine deficiency may explain the association.
  • This finding supports the “gut first” theory of Parkinson's disease.

Now scientists led by Trisha Pasricha at Beth Israel Deaconess Medical Center in Boston report that damage to the upper gastrointestinal mucosa nearly doubles the risk of developing Parkinson's disease within about 14 years, on average, after taking into account factors such as bacterial infection. The findings support the “gut-first” hypothesis, which hypothesizes that toxic aggregates of α-synuclein produced by enteric neurons, or other toxic proteins produced by the gut microbiota, can aggregate and travel to the brain (News for July 2019(News, December 2016). The new study was published September 5 in JAMA Network Open..

Lead author Jocelyn Chan and colleagues initially aimed to find biomarkers of Parkinson's that would appear in the gut before motor symptoms set in. “We're hopeful that we might find ways to diagnose and treat Parkinson's earlier,” said Chan, a medical student at Tufts University Medical Center in Boston.

Pasricha and her colleagues looked at the health records of 9,350 people, mostly white, with no history of Parkinson's disease, enrolled in a Boston medical registry. All had undergone upper intestinal endoscopy and biopsy for gastrointestinal problems. The scientists found mucosal damage, such as ulcers and esophageal lesions, in 2,338 of them. Many Helicobacter pylori— a bacterium that causes ulcers. This infection is common in Parkinson's patients and is thought to be linked to the disease. Some studies have shown that treatment Helicobacter pylori Combined use with antibiotics improves exercise capacity and improves the effectiveness of L-dopa treatment (Liu et al., 2017; Nyholm et al., 2021).

After examining follow-up medical records, Chan concluded that 52 of 2,338 people with a history of mucosal damage developed Parkinson's disease, compared with 48 of 8,995 people with healthy mucosa. Overall, gastrointestinal problems increased the incidence of Parkinson's disease fourfold. On average, people developed Parkinson's disease about 14 years after their intestinal damage was first diagnosed (image below).

A lasting legacy. Survival curves indicate that individuals with a history of mucosal injury are more likely to have an early diagnosis of Parkinson's disease.

Controlling for other risk variables, Helicobacter pylori Despite prevalent infections, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), and smoking, people with mucosal damage were 1.8 times more likely to develop Parkinson's disease.

The authors are not sure why damage to the upper gastrointestinal mucosa leads to Parkinson's. Chan thinks it may trigger alpha-synuclein production or inflammatory pathways in the gut that affect the brain, perhaps via the vagus nerve. Alternatively, a slight decrease in dopamine production due to Parkinson's that is not yet clinically evident could lead to problems in the gut mucosa. Enteric nerves regulate peristalsis and gut health, and respond to dopamine and other central nervous system neurotransmitters. Dopamine agonists are also used to treat gastrointestinal disorders (for a review, see Kurnik Tuka, 2021).

Mal Tansey of the University of Florida in Gainesville told AlzForum that the study is consistent with previous literature on Parkinson's disease originating in the gut or body. Helicobacter pylori “Other inflammatory diseases may help reduce the risk and progression of Parkinson's disease in somatic cases,” she said, noting that genetic or environmental risks may modulate the association between gut damage and Parkinson's disease.

Although the evidence supports the gut-first hypothesis, it does not exclude a “brain-first” disease progression in some people with mucosal damage, Chan said. “Identifying the different pathways will help us understand the disease better and develop more personalized treatments,” Chan said.

The research group plans to study biopsies to understand how mucosal damage causes Parkinson's disease at a molecular level. They are particularly interested in long-term studies analyzing the role of intestinal alpha-synuclein and the vagus nerve, which connects the gut to the brain. —Sarah Reardon

Sarah Reardon is a freelance writer living in Bozeman, Montana.

News Quotes

  1. α-Synuclein spreads from the gut to the brain in PD models

Citation

  1. Liu H, Su W, Li S, Du W, Ma X, Jin Y, Li K, Chen H.
    Eradication of Helicobacter pylori infection may improve the clinical status, especially bradykinesia, of Parkinson's disease patients..
    Clinical Neurology Neurosurgery2017 September;160:101-104. Electronic publication July 5, 2017
    Publisher.
  2. Nyholm D, Hellstrom PM.
    Effect of Helicobacter pylori on the pharmacokinetics of levodopa.
    J. Parkinson Dis2021;11(1):61-69.
    Publisher.
  3. Kurnik-Utka M, Pasieka P, Uczak P, Wojnarski M, Jurczyk M, Gill K.
    Gut dopamine in inflammatory bowel disease: a systematic review.
    International Journal of Molecular ScienceNovember 29, 2021;22(23)
    Publisher.