Researchers addressed the gut-first hypothesis of Parkinson disease by identifying how mucosal damage impacts risk of development.
Patients with a history of upper gastrointestinal (GI) mucosal damage experienced an increased risk of developing clinical Parkinson disease (PD), according to a cohort study published in JAMA Network Open.1 Researchers’ findings warranted a recommendation for providers to express increased vigilance when treating patients with MD to minimize the risk of future PD.
“The Braak hypothesis, rooted in neuropathological staging of PD, outlines a consistent progression pattern from specific induction sites,” wrote authors of the study.1 “Additionally, accumulating evidence indicates a prolonged prodromal phase of PD, lasting years and characterized by significant [GI] dysfunction. The convergence of these factors suggests a gut-first hypothesis, proposing that in a subset of individuals, pathology may originate in the gut and travel to the brain through the vagus nerve.”
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PD is the second most common neurodegenerative disorder in the US, affecting at least 500,000 patients, but with significant rates of undiagnosed individuals suspected, experts believe the number is much higher. Furthermore, most PD diagnoses are seen in patients over the age of 60 years, but data show that 5% to 10% of cases are reported before the age of 50 years.2 Globally, however, PD impacts nearly 8.5 million individuals.1
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With evidence of a gut-originated pathology in animals, researchers believed there was a relationship between gut health and PD. When previous literature showed no association between inflammatory bowel disease and risk of PD, they decided to focus on mucosal damage (MD), “suggesting that MD in the distal GI tract where pelvic rather than vagal innervation is the hallmark may play a less important role in pathogenesis,” they wrote.
Subsequently, this led researchers to focus on a specific infection of the gut known as Helicobacter pylori, which is a common risk factor for the development of upper GI tract ulcers. Identifying H pylori as a point of focus for MD’s potential association with PD, researchers defined MD as erosions, esophagitis, ulcers, or peptic injury observed in upper endoscopy or pathology reports.1
In their retrospective cohort study, researchers gathered 9350 patients (mean age, 52.3 years; 55.4% male; 73.7% White) who underwent an upper endoscopy between January 2000 and December 2005. The final follow-up assessments were conducted by July 31, 2023. Each patient with MD included in the study was matched with 3 participants without MD. At the time of receiving endoscopy, a majority (30.4%) of patients were aged 50 to 64 years old.
“Of the 2338 patients with MD, 52 patients (2.2%) were later diagnosed with PD, while of the 8955 patients without MD, 48 (0.5%) were later diagnosed with PD. In other words, of the 100 patients who were diagnosed with PD in this cohort, 52 had MD on initial biopsy (52%),” wrote the authors.1
In results supporting the Braak hypothesis, more patients with MD subsequently developed PD than those without MD, despite 3 times more participants in the non-MD group. Furthermore, PD incidence within the researchers’ MD cohort (16 per 100,000 person-years) was similar to the commonly known incidence rate of PD globally at 17 per 100,000 person-years.
“The findings of our investigation corroborate our hypothesis that upper [GI] MD would be associated with clinical PD development, reinforcing the theory of a gut-first progression in PD in a subset of patients,” wrote authors of the study. Their findings regarding MD gave researchers 2 possibilities regarding the pathways of PD and its relationship with the gut.
“First, MD may serve as an inciting event that could precipitate pathologic alpha-synuclein misfolding in the gut. Second, as dopamine is known to play a key gastroprotective role, it may be that patients with subclinical dopaminergic signaling reduction are at higher risk of MD and that alpha-synuclein pathology preceded this event,” they wrote.1
The study results showed researchers and experts alike that there may be more of a relationship between gut and mental health than was once previously understood. Keith Scharf, DO, FACS, FASMBS, director of bariatric surgery at Loma Linda University Health, is sure of a connection between the gut and the brain.
“The brain and the gut are intimately connected and send signals back and forth. Emerging evidence suggests that imbalances in the gut microbiota can disrupt this communication, potentially leading to mental health disorders such as anxiety, depression, and even neurodevelopmental conditions,” he said.3
Furthermore, addressing the gut’s relationship with the brain, researchers of a Nurtrients study said that the gut microbiota “could play an important role in mental health through the microbiota–gut–brain axis” and is associated with mental health disorders like anxiety, depression, bipolar disorder, and schizophrenia.4
“With [peptic ulcer disease] globally affecting upwards of 8.09 million people and H pylori infection even more widespread, timely detection and treatment of H pylori infection, along with MD management, may prove crucial to early recognition of risk of and potentially intervention against PD,” concluded authors of the study.1
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