The earliest evidence that the gut might be involved in Parkinson’s emerged more than 200 years ago. In 1817, the English surgeon James Parkinson reported that some patients with a condition he termed “shaking palsy” experienced constipation. In one of the six cases he described, treating the gastrointestinal complaints appeared to alleviate the movement-related problems associated with the disease.
Since then, physicians have noted that constipation is one of the most common symptoms of Parkinson’s, appearing in around half the individuals diagnosed with the condition and often preceding the onset of movement-related impairments. Still, for many decades, the research into the disease has focused on the brain. Scientists initially concentrated on the loss of neurons producing dopamine, a molecule involved in many functions including movement. More recently, they have also focused on the aggregation of alpha synuclein, a protein that twists into an aberrant shape in Parkinson’s patients. A shift came in 2003, when Heiko Braak, a neuroanatomist at the University of Ulm in Germany, and his colleagues proposed that Parkinson’s may actually originate in the gut rather than the brain.
Braak’s theory was grounded in the observation that in post-mortem samples of Parkinson’s patients, Lewy bodies, clumps of alpha synuclein, appeared in both the brain and the gastrointestinal nervous system that controls the functioning of the gut. The work by Braak and his colleagues also suggested that the pathological changes in patients typically developed in predictable stages that starts in the gut and ends in the brain. At the time, the researchers speculated that this process was linked to a “yet unidentified pathogen” that travels through the vagus nerve—a bundle of fibers connecting major bodily organs to the brainstem, which joins the spinal cord to the brain.
The idea that the earliest stages of Parkinson’s disease may occur in the gastrointestinal tract has been gaining traction. A growing body of evidence supports this hypothesis, but the question of how changes in the intestines drive neurodegeneration in the brain remains an active area of investigation. Some studies propose that aggregates of alpha synuclein move from the intestines to the brain through the vagus nerve. Others suggest that molecules such as bacterial breakdown products stimulate activity along this channel, or that that the gut influences the brain through other mechanisms, such as inflammation. Together, however, these findings add to the growing consensus that “even if the pathology [of Parkinson’s] is very much driven by brain abnormalities, it doesn’t mean that the process starts in the brain,” says Michael Schlossmacher, a physician-scientist at the Ottawa Hospital Research Institute.
THE GUT-BRAIN HIGHWAY
The vagus nerve, a bundle of fibers that originates in the brain stem and innervates major organs, including the gut, may be the primary route through which pathological triggers of Parkinson’s travel from the gastrointestinal tract to the brain. Recent epidemiological examinationsof vagotomy patients whose vagus nerves were severed show that they have a lower risk of developing Parkinson’s. Researchers have also demonstrated that alpha-synuclein fibers, injected into the gastrointestinal tracts of rodents, can traverse through the vagus into the brain.
If alpha-synuclein does travel from the intestines to the brain, the question still arises: Why does the protein accumulate in the gut in the first place? One possibility is that alpha-synuclein produced in the gastrointestinal nervous system helps fight off pathogens. Last year, Michael Zasloff, a professor at Georgetown University, and his colleagues reported that the protein appeared in the guts of otherwise healthy children after norovirus infections, and that, at least in a lab dish, alpha-synuclein could attract and activate immune cells.
Microbes themselves are another potential trigger for promoting the build-up of intestinal alpha-synuclein. Researchers have found that, in mice, bacterial proteins could trigger the aggregation of the alpha-synuclein in the gut and the brain. Some proteins made by bacteria may form small, tough fibers, whose shape could cause nearby proteins to misfold and aggregate in a manner akin to the prions responsible for mad cow disease, explains Robert Friedland, a neurologist at the University of Louisville who coauthored that study.