A new study in mice demonstrates that manipulating the microbiome can influence the extent of brain damage caused by a stroke
The bacteria that inhabit our guts have become key players for neuroscientists. A growing body of research links them to a wide array of mental and neurological disorders—from anxiety and depression to schizophrenia and Alzheimer’s disease. Now a study in mice published this week in Nature Medicine suggests that striking the right microbial balance could cause changes in the immune system that significantly reduce brain damage after a stroke—the second leading cause of both death and disability for people around the globe.
Experts have known for some time that stroke severity is influenced by the presence of two types of cell, found abundantly within the intestine, that calibrate immune responses: Regulatory T cells have a beneficial inflammatory effect, protecting an individual from stroke. But gamma delta T cells produce a cytokine that causes harmful inflammation after a stroke.
A team of researchers at Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center set about investigating whether they could tilt the balance of these cells in the favor of beneficial cells by tinkering with the body’s bacterial residents. To do so, they bred two colonies of mice: One group’s intestinal flora was resistant to antibiotics whereas the other’s gut bacteria was vulnerable to treatment. As a result, when given a combination of antibiotics over the course of two weeks, only the latter’s microbiota underwent change. The researchers then obstructed the cerebral arteries of the mice, inducing an ischemic stroke (the most common type). They found that subsequent brain damage was 60 percent smaller in the drug-susceptible mice than it was in the other group.
To confirm that this result could truly be attributed to the change in intestinal flora, the researchers performed fecal transplants. That is, they took the contents of the colons of mice that had experienced reduced stroke and gave this material to new mice. This time, however, the team did not administer antibiotics, thus creating a group of mice with altered gut bacteria but no drug exposure. By inducing an ischemic attack in this group, the researchers discovered that these mice had also acquired protection against stroke.
The researchers found that by altering intestinal flora they had indirectly pushed the ratio between immune cells in favor of the “good” regulatory T cells while suppressing the more harmful gamma delta T cells. The team tracked both kinds of cells as they left the gut and traveled to the brain, where they settled on the meninges and, the researchers suspect, conditioned how the brain responded to the stroke. This so-called systemic inflammatory response—supported by T cells—can be beneficial, clearing the brain of dead cells, or debilitating, causing brain swelling and further damage. “These cells determine what kind of inflammatory immune response the brain is going to experience after stroke,” says neurologist Constantino Iadecola, director of the Brain and Mind Research Institute at Weill Cornell and one of the study’s authors. By changing the bacterial landscape of the gut, he explains, “immune cells end up helping out instead of contributing to the damage that occurs.”
“Now the microbiome is another element in this equation—it’s not just diabetes, high blood pressure and obesity,” Iadecola notes. “There are also other factors which we need to know in order to tailor treatment.” The study suggests that such treatment may involve antibiotics, probiotics, dietary changes or other interventions that would change the gut’s microbiota to be supportive of regulatory T cells and reduce delta gamma T cells. For example, patients undergoing heart surgery, many of whom end up suffering a stroke, might go on a special preemptive diet, he says.
Such interventions remain a long way off, however. A mouse’s microbiome is very different from that of a human; researchers will need clinical data. Right now they are working on identifying the specific bacteria involved in their findings as well as the molecular mechanism—how exactly the gut and brain interact and communicate—that underlies the immune responses observed in this study. Both avenues of research are important for developing targeted therapeutic approaches down the line. “This is just the beginning,” says Ulrich Dirnagl, a neurologist at the Center for Stroke Research Berlin who did not participate in this research. “The study links the microbiota and the immune system and the brain in stroke—an acute brain disorder—in one story. That’s really novel. But this is not a therapy.” He adds, “In a different future you could argue that maybe what this means is there are certain kinds of microbiota that make humans more susceptible to having larger or smaller strokes. But saying that now would be premature.”
Studying the link between intestinal composition and stroke risk would be a very complicated endeavor, as the human microbiome is influenced by a huge range of factors, including diet, living conditions and antibiotics. Still, the researchers are optimistic. “This emphasis on the microbiome, and sequencing it, is a young field,” says Weill Cornell neuroscientist and study author Josef Anrather. “Obviously it takes time. But the implications are there.”