A team of scientists from the University of Coimbra (UC) has discovered new gut biomarkers – signals that indicate the onset of disease - which could be used in future strategies for the early diagnosis of Parkinson's disease. These biomarkers offer potential for new diagnostic approaches aimed at preventing the progression of the disease from the gut to the brain.
 

In the article Gut-first Parkinson's disease is encoded by gut dysbiome, published in the journal Molecular Neurodegeneration, the team led by Sandra Morais Cardoso, professor at the UC Faculty of Medicine (FMUC) and researcher at the Center for Neuroscience and Cell Biology (CNC-UC) and the Centre for Innovative Biomedicine and Biotechnology (CiBB), and by Nuno Empadinhas, researcher at CNC-UC and CiBB, demonstrated that the gut microbiome - population of microorganisms that inhabit the intestine  - often altered in patients with Parkinson's disease, has the properties to trigger intestinal and systemic changes that lead to the emergence of neuropathological marks of the disease.
 

In previous studies, the researchers and their teams had demonstrated mechanisms indicating that some cases of Parkinson's disease may originate in the gut due to a dysfunctional microbiome elicited by chronic exposure to a microbial toxin found in foods of aquatic origin. In Parkinson’s, gastrointestinal alterations like chronic constipation are common non-motor symptoms that often emerge years before the onset of motor symptoms.
 

In this new study, the researchers not only confirmed that Parkinson's disease can be triggered in the intestine, but also identified “the presence of inflammatory markers and aggregates of the alpha-synuclein protein - the classic brain histopathological marker of the disease - in the ileum (a region of the small intestine), which can serve as biomarkers for the prodromal phase of the disease, appearing in the intestine before the pathology progresses to the brain” explains Sandra Morais Cardoso.
 

The researchers examined the effects of chronic transfer of gut microbiome samples from Parkinson's patients to mice. This exposure triggered inflammation and the formation of alpha-synuclein aggregates in the mice's intestines, leading to a loss of intestinal barrier integrity. This dysfunction resulted in chronic systemic inflammation, and ultimately neuroinflammation. Both neuroinflammation and the buildup of alpha-synuclein in the brain contribute to neuronal loss.
 

The scientists believe that by understanding this early process, it may be possible to prevent intestinal changes from reaching and affecting the brain, thereby arresting the disease progression. “Early detection of inflammatory markers and alpha-synuclein aggregates in the gut will enable intervention before significant brain damage occurs,” the scientists explain. “This proactive approach not only supports new clinical trials aimed at testing interventions to halt disease progression, but also offers hope of delaying or even preventing neurological symptoms, improving patients’ quality of life and reducing the social and economic burden of this health condition,” they add.
 

The research team also examined terminal ileum samples collected by colonoscopy from patients and identified the same biomarkers, revealing promising results. This analysis enabled the detection of early signs of Parkinson's disease in the intestine. Based on this findings, Sandra Morais Cardoso and Nuno Empadinhas suggest that “while the combinations of microbes or their metabolites driving intestinal dysfunction remain unknown, detecting inflammatory markers and alpha-synuclein aggregates in the terminal ileum through colonoscopy with biopsy, ideally between the ages of 50 and 55, could help identify individuals at higher risk of developing the disease. This approach would enable early intervention, potentially preventing the progression of some forms of this currently incurable neurodegenerative disease to the brain,” they explain.
 

According to the World Health Organization, over 10 million people will be living with Parkinson’s disease worldwide in 2024, a significant rise from the 6.1 million cases reported in 2016. “The alarming increase in new cases has led to Parkinson’s being classified as a pandemic. Projections estimate that by 2040, annual new cases could surpass 17 million,” notes Sandra Morais Cardoso. In Portugal, approximately 20,000 people are currently living with the disease.
 

“This discovery of new biomarkers could play a crucial role in advancing prevention strategies, ultimately benefiting both patients and society at large,” the scientists emphasize. “It paves the way for innovative diagnostic approaches, enabling the early detection of Parkinson's disease - a tangible goal achievable through the collective effort and collaboration across multiple medical disciplines. This interdisciplinary study, which brought together neuroscientists, microbiologists, neurologists and gastroenterologists from the University of Coimbra, the Coimbra Hospital and University Center (CHUC), Coimbra Local Health Unit (ULS Coimbra), highlights the essential synergy that made this breakthrough possible,” underscore Sandra Morais Cardoso and Nuno Empadinhas.
 

Building on the findings from this study, the scientists are already pursuing new lines of investigation “focused on neutralizing the inflammatory process in the gut before the disease progresses to the brain”, they explain. The preliminary results “are promising, suggesting that early-stage interventions aimed at neutralizing or modulating the inflammation onset could significantly help preserve the integrity of the intestinal barrier, and prevent the disease from spreading to the brain,” they report.
 

The research was funded by the Portuguese Foundation for Science and Technology (FCT) and by Cure Parkinson's, a UK charity dedicated to finding a cure for Parkinson's disease. The study involved a collaborative team of researchers from CNC-UC, FMUC, the UC Functional Ecology Center, as well as the Neurology and Gastroenterology Services of CHUC - ULS Coimbra.
 

The scientific article can be accessed here.

Catarina Ribeiro w/CNC-UC