Gut conditions could be warning for Parkinson’s disease

Some gut problems, such as constipation, difficulty swallowing and irritable bowel syndrome, could be early warning signs of Parkinson’s disease, according to new studies.

New research published in today’s edition of Gut looked at Braak’s hypothesis, which suggests that as gastrointestinal symptoms are thought to precede the development of cerebrovascular disease, such as stroke, brain aneurysm or Alzheimer’s disease, gut conditions may precede the development of Parkinson’s disease.

The research team used data from TriNetX, a US nationwide medical record network, to compare 24,624 people who had been diagnosed with Parkinson’s disease of unknown cause with those who had been diagnosed with other neurological conditions. These comprised 19,046 with Alzheimer’s disease, 23,942 with cerebrovascular disease and 24,624 for whom had no neurological disease.

Those with Parkinson’s disease were matched with people in the other groups for age, sex, race, ethnicity and length of diagnosis to compare the frequency of gut conditions included in their electronic health record for an average of six years before they were diagnosed with Parkinson’s disease.

The researchers then tested the same hypothesis by dividing all the adults in the network who had been diagnosed with any of 18 gut conditions into separate groups, one for each condition of interest.

People in these groups were matched with individuals without a particular gut condition and were monitored via their medical records for five years to see how many of them developed Parkinson’s disease or other neurological disorders.

Both analyses indicated that four gut conditions were associated with a higher risk of a Parkinson’s disease diagnosis: gastroparesis, dysphagia and constipation were all associated with a more than doubling in risk of Parkinson’s disease in the five years preceding the diagnosis, while irritable bowel syndrome (IBS) without diarrhoea was associated with a 17% higher risk.

Some other gut issues, including functional dyspepsia; IBS with diarrhoea; and diarrhoea plus faecal incontinence, were also more prevalent among people who developed Parkinson’s disease.

But these conditions were also more prevalent before the onset of Alzheimer’s disease or cerebrovascular disease.

The researchers add that appendix removal seemed to be protective, prompting questions about its potential role in the disease processes leading to Parkinson’s disease.

Neither inflammatory bowel disease nor vagotomy were associated with a heightened risk.

This is an observational study, and as such, cannot establish cause. The researchers also highlight several limitations to their findings, including that the monitoring period was relatively short and that the diagnostic information captured in electronic health records might have been incomplete.

Nevertheless, they conclude: “This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation, but also dysphagia, gastroparesis and irritable bowel syndrome without diarrhoea might specifically predict the development of Parkinson’s disease.”

They add: “These findings warrant alertness for [gastrointestinal] syndromes in patients at higher risk for Parkinson’s disease and highlight the need for further investigation of [gastrointestinal] precedents in Alzheimer’s disease and cerebrovascular disease.”

Meanwhile a study published in Neuron by a team at Columbia University, NYC, USA, found that initial gastrointestinal changes in Parkinson’s could be a misdirected immune attack.

Dr David Sulzer said: “If this is the beginning of Parkinson’s in many people, we could potentially identify who has the disease before it ever reaches the brain and hopefully stop it in its tracks.”

In Parkinson’s, the alpha-synuclein protein becomes misfolded, accumulates inside neurons and slowly poisons the cells. Now Dr Sulzer and his team have shown that small portions of the misfolded alpha-synuclein also can appear on the outside of neurons. This makes the neurons vulnerable to attack from the immune system.

They created a mouse capable of displaying pieces of misfolded alpha-synuclein on cell surfaces and injected them with alpha-synuclein and monitored what happened in the brain and the gut.

While they did not see any signs of Parkinson’s disease in the brain, they saw that an immune attack on neurons in the gut produced constipation and other gastrointestinal effects resembling those seen in most Parkinson’s patients years before they are diagnosed with the disease.

“This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s and is strong support that Parkinson’s is in part an autoimmune disease,” Dr Sulzer said.

The findings also raise the possibility that early detection and then interruption of an immune response in the gut could prevent a later attack on the brain’s neurons and stop Parkinson’s before it develops.

“Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the human disease process, which doesn’t exist right now,” said Dr Sulzer. “That will be critical in answering questions about the disease that we can’t explore in people and eventually developing better therapies.”

Konings B, Villatoro L, Van den Eynde J et al. Gastrointestinal syndromes preceding a diagnosis of Parkinson’s disease: testing Braak’s hypothesis using a nationwide database for comparison with Alzheimer’s disease and cerebrovascular diseases. Gut 25 August 2023; doi 10.1136/gutjnl-2023-329685


Garretti F, Monahan C, Sloan N et al. Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease. Neuron 18 August 2023; doi: 10.1016/j.neuron.2023.07.015


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