Does parkinson’s disease start in the intestine

Begins Parkinson's in the gut?

Parkinson's disease could spread from the gastrointestinal tract to the brain. (Image: Eraxion/ istock)

Increasingly, it is becoming apparent that the stomach and the brain are surprisingly closely linked to each other. This connection could also play a role in diseases such as Parkinson's disease. Some doctors suspect that misfolded proteins typical of the disease may be formed in the gastrointestinal tract and then spread from there to the brain. Now, for the first time, there is evidence for this pathway: researchers have injected mice with the harmful proteins in the abdomen. Weeks later, these were also detectable in the rodents' brains – with noticeable health consequences.

Pathological deposits of the protein alpha-synuclein appear to play a key role in Parkinson's disease. Interestingly, these deposits are not only found in the brains of affected patients, but sometimes also in the nerve cells of their digestive tract. This observation is supported by the fact that Parkinson's disease is often accompanied by gastrointestinal complaints. Often, these non-specific symptoms appear years before the neurodegenerative disease can be diagnosed on the basis of its typical features, such as shaky hands and slowed movements. In this context, neuroanatomist Heiko Braak and his research group published an exciting hypothesis as early as 2003: Parkinson's, according to their idea, may even start in the abdomen and travel upward from there to the brain. According to Braak's theory, harmful environmental influences can act on local nerve cells via the mucous membrane of the digestive tract. Trigger pathological changes in the alpha-synuclein proteins present there. These then spread like a germ via the vagus nerve – a large nerve pathway that runs from the gastrointestinal tract to the base of the brain. Analyses of brain tie from deceased persons also led the physician to describe the exact sequence in which the misfolded alpha-synuclein proteins appear in the different regions of the thinking organ. Until now, however, there has been no solid evidence for this route of spread. But this has now changed.

From the belly to the head

Scientists led by Sangjune Kim of Johns Hopkins University in Baltimore have shown for the first time in an animal model that misfolded alpha-synuclein can actually travel via the vagus nerve into the brain – and spread there in a similar way to that postulated by Braak. To prove this, the researchers injected protein fibrils of defective alpha-synuclein proteins into the muscle tie of the small intestine and stomach outlet in mice. If they injected the rodents with relatively high doses of 25 micrograms, the first effects were seen after just one month. A look into the brain revealed that after four weeks, the misfolded proteins had reached the lower part of the brain stem.

After three months, alpha-synuclein was also detected in the caeruleus locus of the hindbrain and in the substantia nigra – the part of the brain typically affected by cell death in Parkinson's disease. After seven months, the scientists even found alpha-synuclein deposits in additional brain regions such as the hippocampus. In addition, the characteristic loss of dopamine-producing nerve cells was now also evident in the substantia nigra. A second experiment confirmed that the fatal spread of the proteins really took place via the vagus nerve: In mice with a severed vagus nerve, nothing happened in the brain after the protein was injected into the intestine.

Symptoms typical of Parkinson's

As the researchers report, the changes in the brains of affected mice triggered many of the symptoms typical of Parkinson's disease. It was revealed that rodents had motor difficulties in nest building, for example. In addition, many of them showed signs of anxiety disorders, depression, cognitive impairment and olfactory disorders – features that are also characteristic of Parkinson's patients. "These findings provide further evidence for the role of the gastrointestinal tract in Parkinson's and give us a model to study the onset and development of the disease in more detail in the future," states Kim's colleague Ted Dawson.

But what do the findings now presented mean in practice?? "It remains unclear whether and what can be derived from this basic paper for patients," comments Anja Schneider of the University Hospital of Bonn, Germany. "Of course, one can imagine that food, inflammatory processes or the gut microbiome can lead to local aggregation of alpha-synuclein fibrils in the digestive tract, and then there can be spread from there. This hypothesis has been discussed for some time and remains a possible pathway, which is now confirmed in the current mouse model." As Walter Schulz-Schaeffer of Saarland University Hospital emphasizes, the results do not mean that Parkinson's must necessarily develop in the gastrointestinal tract: "But they do show that the disease can involve the gastrointestinal tract."

Transferable to humans?

If further studies succeed in more precisely understanding the role of the abdominal cavity in Parkinson's disease in humans, this could lead to better possibilities for therapy and early diagnosis in the future. Researchers are already investigating how reliably Parkinson's can be diagnosed using biopsies of nerves in the gut. Kim's team now plans to conduct studies with primates. They will show whether the observations can be repeated with other animals – and whether the spread of alpha-synuclein via the vagus nerve can possibly be prevented with the help of special treatment methods.

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