Caltech scientists have discovered for the first
time a functional link between bacteria in the
intestines and Parkinson's disease (PD). The
researchers show that changes in the composition of
gut bacterial populations—or possibly gut bacteria
themselves—are actively contributing to and may even
cause the deterioration of motor skills that is the
hallmark of this disease.
The work—which has profound implications for the
treatment of PD—was performed in the laboratory of
Sarkis Mazmanian, the Luis B. and Nelly Soux
Professor of Microbiology and Heritage Medical
Research Institute Investigator, and appears in the
December 1 issue of Cell.
Characteristic features of Parkinson's disease
include symptoms such as tremors and difficulty
walking, aggregation of a protein called alpha-synuclein
(aSyn) within cells in the brain and gut, and the
presence of inflammatory molecules called cytokines
within the brain. In addition, 75 percent of people
with PD have gastrointestinal (GI) abnormalities,
primarily constipation.
"The gut is a permanent home to a diverse community
of beneficial and sometimes harmful bacteria, known
as the microbiome, that is important for the
development and function of the immune and nervous
systems," Mazmanian says. "Remarkably, 70 percent of
all neurons in the peripheral nervous system—that
is, not the brain or spinal cord—are in the
intestines, and the gut's nervous system is directly
connected to the central nervous system through the
vagus nerve.
Because gastrointestinal problems often precede the
motor symptoms by many years, and because most
Parkinson's disease cases are caused by
environmental factors, we hypothesized that bacteria
in the gut may contribute to PD."
To test this, the researchers utilized mice that
overproduce aSyn and display symptoms of
Parkinson's.
One group of mice had a complex consortium of gut
bacteria;
the others, called germ-free mice, were bred in a
completely sterile environment at Caltech and thus
lacked gut bacteria.
The researchers had both groups of mice perform
several tasks to measure their motor skills, such as
running on treadmills, crossing a beam, and
descending from a pole. The germ-free mice performed
significantly better than the mice with a complete
microbiome.
"This was the eureka moment," says Timothy Sampson,
a postdoctoral scholar in biology and biological
engineering and first author on the paper. "The mice
were genetically identical; both groups were making
too much aSyn. The only difference was the presence
or absence of gut microbiota. Once you remove the
microbiome, the mice have normal motor skills even
with the overproduction of aSyn."
"All three of the hallmark traits of Parkinson's
were gone in the germ-free models," Sampson says.
"Now we were quite confident that gut bacteria
regulate, and are even required for, the symptoms of
PD. So, we wanted to know how this happens."
When gut bacteria break down dietary fiber, they
produce molecules called short-chain fatty acids (SCFAs),
such as acetate and butyrate.
Previous research has shown that these molecules
also can activate immune responses in the brain.
Thus, Mazmanian's group hypothesized that an
imbalance in the levels of SCFAs regulates brain
inflammation and other symptoms of PD. Indeed, when
germ-free mice were fed SCFAs, cells called
microglia—which are immune cells residing in the
brain—became activated. Such inflammatory processes
can cause neurons to malfunction or even die.
In fact, germ-free mice fed SCFAs now showed motor
disabilities and aSyn aggregation in regions of the
brain linked to PD.
In a final set of experiments, Mazmanian and his
group collaborated with Ali Keshavarzian, a
gastroenterologist at Rush University in Chicago, to
obtain fecal samples from patients with PD and from
healthy controls.
The human microbiome samples were transplanted into
germ-free mice, which then remarkably began to
exhibit symptoms of PD. These mice also showed
higher levels of SCFAs in their feces. Transplanted
fecal samples from healthy individuals, in contrast,
did not trigger PD symptoms, unlike mice harboring
gut bacteria from PD patients.
For more information
Cell
Gut Microbiota Regulate Motor Deficits and
Neuroinflammation in a Model of Parkinson’s Disease
Link...
California Institute of Technology
Link...
MDN |