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scientificamerican.com

Does Parkinson's Begin in the Gut?

Diana Kwon
10-12 minutos

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.

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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

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route through which pathological triggers of Parkinson’s travel from

the gastrointestinal tract to the brain. Recent epidemiological
examinations of 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.

The microbiome, the totality of microorganisms in the human body,

has spurred intense interest among Parkinson’s researchers. A
number of reports have noted that individuals with the disease
harbor a unique composition of gut microbes, and scientists have

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also found that transplanting fecal microbes from patients into

rodents predisposed to develop Parkinson’s can worsen motor
symptoms of the disease and increase alpha-synuclein aggregation
in the brain.

But rather than bacterial proteins triggering misfolding, Sarkis

Mazmanian, a Caltech microbiologist, believes that these microbes
could be acting through the metabolites they produce, such as
short-chain fatty acids. Mouse experiments from his lab have
shown that these molecules appear to activate microglia, the
immune cells of the brain. The metabolites, Mazmanian adds, may
send a signal through the vagus nerve or bypass it completely
through another pathway such as the bloodstream. Because
epidemiological studies find that vagus nerve removal does not
completely eliminate the risk of Parkinson’s, other brain-gut routes
may also be involved. “We’re currently testing [that] question,”
Mazmanian says.

A Role for Inflammation?

Yet another idea holds that that intestinal inflammation, possibly

from gut microbes, could give rise to Parkinson’s disease. The
latest evidence supporting this idea comes from a large
epidemiological study, in which Inga Peter, a genetic epidemiologist
at the Icahn School of Medicine at Mount Sinai, and her colleagues
scanned through two large U.S. medical databases to investigate
the overlap between inflammatory bowel diseases and Parkinson’s.

Their analysis compared 144,018 individuals with Crohn’s or

ulcerative colitis and 720,090 healthy controls. It revealed that the
prevalence of Parkinson’s was 28 percent higher in individuals with

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the inflammatory bowel diseases than in those in the control group,

supporting prior findings from the same researchers that the two
disorders share genetic links. In addition, the research team
discovered that in people who received drugs used to reduce
inflammation—tumor necrosis factor (TNF) inhibitors—the
incidence of the neurodegenerative disease dropped 78 percent.

This study further validates the theory that gut inflammation could
drive Parkinson’s pathogenesis, says Madelyn Houser, a graduate
student in neuroscientist Malú Tansey’s lab at Emory University.
The anti-TNF finding in particular, she adds, suggests that the
“overlap between the two diseases might be primarily mediated by
inflammation.”

Intestinal inflammation might give rise to Parkinson’s in several

ways, Houser explains. One possibility is that a chronically inflamed
gut might elevate alpha-synuclein levels locally—as Zasloff’s
investigation in children suggests—or else it may give rise to
inflammation throughout the body, which in itself could increase the
permeability of the gut and blood-brain barriers. Or else it could
increasecirculating cytokines, molecules that that can promote
inflammation. Tansey adds that changes in the microbiome could
also be influencing gut inflammation.

“There’s probably multiple pathways that lead the gut to the brain,”
Peter says, explaining that it is too early to rule out any hypotheses.
For now, her team is focused on determining whether the protective
effect of anti-TNF compounds is due to the lowering of inflammation
throughout the body, which could result from other conditions, or
whether they only benefit individuals with bowel disorders. Peter
plans to investigate the prevalence of Parkinson’s in other patients
who take these drugs, such as those with psoriasis or rheumatoid

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arthritis.

Because not all Parkinson’s patients will have inflammatory bowel

disorders, findings from the investigations into the co-occurrence of
the two conditions might not generalize to everyone with the
neurodegenerative disease, Mazmanian says. Still, these studies
and many others that have emerged in recent years support the
idea that the gut is involved in Parkinson’s is correct, he adds. “If
this is indeed true, it allows us to now devise interventions that
target the gut instead of the brain.”

Already, some researchers have started to test such interventions.

In 2015, Zasloff and his colleagues launched a company, Enterin,
that is currently testing a compound that slows alpha-synuclein
aggregation in the gut. Although the treatment is intended to reduce
non-motor symptoms of Parkinson’s, such as constipation, the
researchers hope that by targeting early gut pathology, they will be
able to restore—or prevent—the disease’s effects on the central
nervous system.

While many lines of evidence support the gut origins of Parkinson’s,

the question of how early the gastrointestinal changes occur
remains, Tansey says. In addition, other scientists have suggested
that it is still possible that the disease begins elsewhere in the body.
In fact, Braak and his colleagues also found Lewy bodies in the
olfactory bulb, which led them to propose the nose as another
potential place of initiation. “I think there’s likely multiple sites of
origin for Parkinson’s disease,” says Viviane Labrie, a
neuroscientist at the Van Andel Research Institute in Michigan. “For
some individuals, it might be the gut, for others it might be the
olfactory system—or it might just be something that occurs in the
brain.”

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Diana Kwon

Diana Kwon is a journalist with a master's degree in neuroscience

from McGill University. She writes about health and the life sciences
from Berlin.

Credit: Nick Higgins

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