New research in mice suggests Parkinson’s disease may spread from the gut to the brain with help from the immune system. Targeting gut immune cells could open the door to earlier diagnosis and new treatments.
Parkinson’s disease may begin in the gut and spread to the brain with help from the body’s own immune cells, according to new research that could reshape how doctors detect and treat the condition.
In a study in mice, scientists from the UK Dementia Research Institute at University College London (UCL) traced how a toxic protein linked to Parkinson’s travels from the intestines to the brain. They found that specialized immune cells in the gut, called macrophages, help carry that harmful cargo along the so‑called gut-brain axis.
When the researchers reduced the number of these gut macrophages, the toxic protein spread less and movement problems in the mice improved. The findings, published in the journal Nature, point to a new potential strategy: targeting the gut’s immune system to intervene in Parkinson’s long before classic motor symptoms appear.
Parkinson’s is best known for tremors, stiffness and slowed movement, but many people experience digestive problems years or even decades before diagnosis. Previous studies have shown that between half and nearly all people with Parkinson’s report gut symptoms such as chronic constipation long before they develop movement issues.
That pattern has led scientists to suspect that, in many patients, the disease starts in the body rather than the brain. One of the first brain regions affected in Parkinson’s is the dorsal motor nucleus of the vagus nerve, which connects directly to the gut. Patients are sometimes grouped into “body-first” and “brain-first” types, with body-first cases thought to make up around two-thirds of people with Parkinson’s.
What has been missing is a clear explanation of how the disease might move from the gut into the brain.
To probe that question, the UCL team focused on alpha-synuclein, a protein that can misfold and clump together in the brains of people with Parkinson’s. These clumps are toxic to nerve cells and are considered a hallmark of the disease.
The researchers first isolated misfolded alpha-synuclein from the brains of people who had died with Parkinson’s. They then inserted tiny amounts of this patient-derived protein into the small intestines of mice and tracked what happened next.
In the gut, macrophages normally act as first responders, engulfing and destroying harmful invaders such as bacteria. In this study, the team found that gut macrophages also engulfed the misfolded alpha-synuclein. But instead of successfully breaking it down, the cells began to show signs of trouble in their lysosomes, the compartments responsible for digesting cellular waste.
With their waste-disposal systems faltering, the macrophages did not simply neutralize the toxic protein. Instead, they appeared to help set off a chain reaction involving other parts of the immune system.
The researchers discovered that the dysfunctional macrophages sent signals to T cells, a type of white blood cell involved in the body’s adaptive immune response. These T cells, shaped by what they encountered in the gut, then traveled from the intestines to the brain. The team described them as “gut-instructed” T cells.
Once in the brain, these immune cells were associated with the spread of toxic alpha-synuclein and the development of Parkinson’s-like changes in the mice.
To test whether gut macrophages were truly key players in this process, the scientists depleted these cells in some mice before introducing alpha-synuclein into the small intestine. Those animals showed lower levels of toxic protein in the brain compared with control mice, and their motor symptoms were less severe.
Co-lead author Soyon Hong, a group leader at UCL’s UK Dementia Research Institute, noted the results challenge the idea that the immune system is just a passive observer in Parkinson’s.
“Our study shows that immune cells are not bystanders in Parkinson’s; these gut macrophages are responding, albeit in a dysfunctional way. This presents an opportunity to think about how we can boost the function of the immune system and these cells, so that they respond in the correct manner and help to slow or stop the spread of disease,” she said in a news release.
Because the work was done in mice, more research is needed to confirm whether the same mechanisms operate in people. But the study adds weight to the view that Parkinson’s often has a long, slow buildup outside the brain, potentially offering a wider window for early detection and prevention.
Neurodegenerative diseases such as Parkinson’s typically develop over many years before symptoms become obvious. By the time tremors and movement problems appear, significant damage has usually already occurred in the brain.
Co-lead author Tim Bartels, also a group leader at UCL’s UK Dementia Research Institute, noted that understanding the earliest steps of the disease could transform care.
“Neurodegenerative diseases have slow trajectories over decades. Understanding how Parkinson’s begins in the body could allow us to develop simple blood tests to screen for it, enabling diagnosis long before damage to the brain starts. Having the ability to detect and manage Parkinson’s before it even reaches the brain could have a huge impact for those affected,” he said in the news release.
The new findings suggest several possible paths forward.
One is to develop drugs that modulate gut macrophages or the signals they send to T cells, with the goal of stopping or slowing the spread of toxic alpha-synuclein along the gut-brain axis. Another is to use markers of inflammation or immune activity in the blood as early warning signs of Parkinson’s in people who have digestive symptoms or a family history of the disease.
The UCL team plans to study in more detail how the body’s immune system can influence the brain in harmful ways, and how that knowledge might be turned into new treatments. They also intend to investigate whether specific inflammatory markers in blood samples could serve as early diagnostic tools.
For patients and families, the work offers a hopeful message: Parkinson’s may not be an inevitable, unstoppable process that only becomes visible once the brain is already badly damaged. If scientists can learn to read the early signals in the gut and the immune system, and intervene there, it may one day be possible to delay, lessen or even prevent the disease’s most devastating effects.
Source: University College London