For clues to Parkinson’s brain symptoms, a gut check is in order.
Intestinal microbes send signals that set off the disease’s characteristic brain inflammation and motor problems in mice, researchers report December 1 in Cell. Doctors might someday be able to treat Parkinson’s by fixing this bacterial imbalance.
“It’s quite an exciting piece of work,” says John Cryan, a neuroscientist at University College Cork in Ireland who wasn’t involved in the study. “The relationship between the brain and gut for Parkinson’s has been bubbling up for many years.” The new research, he says, “brings the microbiome really into the forefront for the first time.”
Parkinson’s affects more than 10 million people worldwide, and roughly 70 percent of those patients also have gastrointestinal issues like constipation. Sometimes the GI symptoms show up years before the muscle weakness and other neurological problems. Several recent studies in humans have suggested a link between gut microbes and Parkinson’s. But it wasn’t clear whether intestinal microbes were actually causing the disease, says study coauthor Sarkis Mazmanian, a microbiologist at Caltech. “What our study adds is a functional, mechanistic role for the microbiome.”
Mazmanian’s team studied mice that produced too much alpha-synuclein, the protein that’s believed to cause Parkinson’s when it clumps in the brain. Mice with extra alpha-synuclein acted like they had Parkinson’s: They traversed a narrow beam more slowly, they couldn’t grip as well to a pole and they struggled to pull stickers off their noses. Their brains showed signs of inflammation, too. But when the researchers raised the same type of mice to be germ-free —that is, to not have any gut microbes — the animals acted less sick.
Those mice were still producing boatloads of alpha-synuclein, but the protein wasn’t clumping in their brains. And without the clumps, the mice didn’t have the unsteady gait and muscle weakness typical of Parkinson’s.
In another experiment, the researchers transferred gut microbes from Parkinson’s patients into germ-free mice making too much alpha-synuclein. Those mice developed motor problems when tested 6 or 7 weeks after the transfer, but mice who got microbes from healthy humans were fine.
“Even though the mice that received the healthy microbiota received hundreds of bacteria, they didn’t get the disease,” says Mazmanian. That suggests it’s not the presence or absence of bacteria that triggers Parkinson’s, but the specific composition of the microbial cocktail.
Alpha-synuclein clumps can move from the gut to the brain, a recent study showed. Now, it seems that gut bacteria themselves are also sending important signals.
Researchers are now trying to figure out which signals — and which microbes —are throwing off the balance.
Fecal samples from the mice implanted with bacteria from Parkinson’s patients had higher than normal levels of certain intestinal bacteria. That could be sparking symptoms, says Caltech microbiologist Tim Sampson, who also worked on the study. “I’m interested in trying to understand if there are potential pathogenic microbes that might be individually driving the disease,” he says. “Once we’ve figured that out we’ll be able to understand whether we can remove that group of organisms or block them.”
Abnormally low levels of other bacteria could also factor in. The analyses aren’t large enough to firmly conclude which microbes are particularly important players. But if scientists can figure out what those missing beneficial bacteria are, Mazmanian says, targeted probiotic therapy might be a treatment option in the future.
Aging-associated diseases like Parkinson’s are tricky to study in mice, cautions Stanford University microbiologist Justin Sonnenburg. “They’re typically the result of decades of accumulations of problems,” whereas the mice in the current study were just a couple months old. So the findings will need to be validated in human studies before influencing treatments. Still, he says, “it’s a really important contribution to the growing list of ways that gut microbes can alter our health.”