Researchers at the Indiana University School of Medicine have uncovered new biological evidence that shows Parkinson’s disease and inflammatory bowel disease share similar gut microbiome dysfunction at the cellular level. This discovery suggests chronic inflammation in the gut may contribute to the onset and progression of Parkinson’s disease.
“Our findings, along with many other recent reports, strongly suggest that Parkinson’s disease is partly an immune-mediated disease that affects other organs and not just the brain,” said Malú Tansey, PhD, the James A. Caplin, MD Chair in Alzheimer's Research. “This opens up novel avenues for intervention, such as restoring gut barrier integrity, modulating the gut microbiome and reducing peripheral inflammation to slow or delay progression of Parkinson’s.”
More than 10 million people worldwide are living with Parkinson’s disease, a degenerative brain condition that causes movement issues and worsens over time. While the disease predominately affects a person’s brain and nervous system, there’s growing evidence that it may develop in the gut microbiome decades earlier, before it reaches the brain.
Up to 80% of people living with Parkinson’s disease have gastrointestinal dysfunction, namely constipation, years before motor impairments, Tansey said. Likewise, people diagnosed with inflammatory bowel disease — the most common gastrointestinal condition — such as Crohn’s disease and ulcerative colitis, have a nearly 30% increased risk for Parkinson’s disease.
The study, published in npj Parkinson’s Disease, revealed that gut epithelial dysfunction, iron mishandling and impaired immune signaling form a shared peripheral mechanism linking inflammatory bowel disorder and Parkinson’s disease. Tansey, who leads a neuroimmunology research group at the Stark Neurosciences Research Institute, is a co-author on the study, along with Kelly Menees, PhD, assistant research professor of neurology.
Researchers examined biopsies of tissue collected after sigmoidoscopies of people with Parkinson’s disease or no neurological impairments, or after routine colonoscopies of people with inflammatory bowel disease in collaboration with Nikolaus McFarland, MD, and Christopher Forsmark, MD, at the University of Florida College of Medicine.
The biopsies from Parkinson’s disease and inflammatory bowel disease patients both showed parallel molecular dysregulation at the cellular level in the gut epithelium — the cell layer that forms the lining of the large intestine, also called the colon.
“This supports a model where chronic gut inflammation primes systemic immune dysfunction that may directly contribute to Parkinson’s disease onset and progression because the support cells don’t do their job properly to support and protect neurons.” Tansey said.
The team identified inflammatory injury in epithelial cells, even when inflammatory bowel disease patients are in remission, of which all participants were in the study.
“Individuals with inflammatory bowel disease appear to still display immune dysfunction in the gut and signs of chronic inflammation during remission or in-between flare-ups which could still put the brain at risk decades later,” Tansey said. “We hope that our findings spark new ideas that could lead to development of preventative strategies to lower their lifetime risk of Parkinson’s disease.”
The research team also found that iron mishandling in the gut likely contributes to systemic inflammation that may increase the risk of Parkinson’s disease for people living with inflammatory bowel disease. Tansey said key iron-related genes in the body were disrupted in both diseases, raising the possibility that iron may be deficient in epithelial cells of the colon but trapped within immune cells in the colon.
“Surprisingly, while it’s been reported that, at autopsy, Parkinson’s disease brains appear to be iron loaded,” Tansey said, “in our findings, the Parkinson’s disease gut appears to be iron poor — the latter is consistent with the fact that people living with Parkinson’s are often anemic and require iron supplements.”
Additionally, they saw evidence of dysfunctional immune signaling between cells and systemic immune dysfunction along the gut-brain axis, Tansey said.
Tansey said her team will next investigate how iron dysregulation in the gut affects cells that are part of the enteric nervous system — sometimes called the “second brain” — and whether gut immune cells travel to the brain and dump iron, which may hasten onset and/or progression of Parkinson’s disease.
They will also study how chronic gut inflammation contributes to the accumulation of alpha-synuclein proteins — a hallmark characteristic of Parkinson’s disease — in the enteric nervous system and perhaps be the nexus of pathology spread to the brain, as described in the “gut-first” hypothesis of Parkinson’s disease.
This work was supported by grants from the National Institutes of Health, the Parkinson’s Foundation Research Center of Excellence, the Michael J. Fox Foundation for Parkinson’s Research and the Aligning Science Across Parkinson’s initiative.
