What if part of the answer to Parkinson’s disease was in our intestines? A team from the UK Dementia Research Institute describes, in a study published in the journal Naturehow cells of the intestinal immune system help a toxic protein travel from the gut to the brain in the very early stages.
Parkinson’s and the intestine: unsuspected links
Previous research has found that 50 to 90 percent of people with Parkinson’s disease have bowel problems long before their motor symptoms appear, such as chronic constipation occurring years before diagnosis. Patients are divided into two categories: those whose symptoms begin with bodily manifestations and those whose symptoms begin with brain damage. The first group makes up about two-thirds of people with the disease.
Indeed, the dorsal motor nucleus of the vagus nerve, which is directly connected to the intestine, is one of the first brain regions affected by this disease. However, until recently, researchers did not understand how the disease spreads to the brain.
When local immunity gets involved
The study begins with a particular material: misfolded alpha-synuclein, this protein which accumulates in the brains of people who die from Parkinson’s. Small amounts of this protein were injected into the small intestine of mice, then the researchers followed its progression along the vagus nerve, from the intestinal wall to the affected brain structures.
In this model, the key players are macrophages installed in the wall of the intestine, real “garbage collectors” of the immune system. These cells engulf alpha-synuclein but their internal recycling systems, lysosomes, show signs of dysfunction. Instead of eliminating the toxic protein, they seem to retain fragments capable of fueling the spread of the pathology.
Macrophages and T lymphocytes: an intestinal-brain highway
The researchers found that the macrophages then signaled to T cells, which are part of the body’s adaptive immune response. These T lymphocytes, “activated by the intestine”, leave the wall of the digestive tract, join the circulation then are found in brain regions affected by the disease, such as the dorsal motor nucleus of the vagus nerve.
Crucially, when the team reduced the number of these intestinal macrophages before injecting alpha-synuclein, the mice had fewer toxic deposits in the brain than control animals and better motor skills scores. This experience suggests a new therapeutic strategy: preventing these cells, or the T lymphocytes they recruit, from reaching the brain could slow down the neurodegenerative cascade at the origin of the disease.
A path to act earlier and detect Parkinson’s earlier
These preclinical results redraw the possible targets. “Our study shows that immune cells are not mere spectators in Parkinson’s disease; these intestinal macrophages respond, even if it is in a dysfunctional way. This gives us an opportunity to think about how to strengthen the functioning of the immune system and these cells, so that they respond correctly and help slow or stop the spread of disease.“, explained Soyon Hong, co-senior author and group leader at the UK Institute of Dementia Research (UCL).
His colleague Tim Bartels insists on screening. “Neurodegenerative diseases progress slowly over decades. Understanding how Parkinson’s disease begins in the body could allow us to develop simple blood tests to detect it, and make a diagnosis long before brain damage begins. Being able to detect and treat Parkinson’s disease before it even reaches the brain could have an immense impact for those affected“.