A new study in mice found that gut bacteria affect the behavior of immune cells throughout the body, including ones in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer’s disease.
The study, “ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy,” published in Science, may lead to potentially reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
“We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III distinguished professor of neurology. “What’s exciting is that manipulating the gut microbiome could be a way to have an effect on the brain without putting anything directly into the brain.”
The researchers altered the gut microbiomes of mice predisposed to develop Alzheimer’s-like brain damage and cognitive impairment. The mice were genetically modified to express a mutant form of the human brain protein tau. They also carried a variant of the human APOE gene.
The genetically modified mice that were raised under sterile conditions from birth, did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice harboring normal mouse microbiomes.
When such mice were raised under normal, nonsterile conditions, they developed normal microbiomes. A course of antibiotics at 2 weeks of age, however, permanently changed the composition of bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age. Antibiotic treatment had no significant effect on neurodegeneration in female mice.
“We already know, from studies of brain tumors, normal brain development, and related topics, that immune cells in male and female brains respond very differently to stimuli,” Holtzman said. “So it’s not terribly surprising that when we manipulated the microbiome we saw a sex difference in response, although it is hard to say what exactly this means for men and women living with Alzheimer’s disease and related disorders.”
“This study may offer important insights into how the microbiome influences tau-mediated neurodegeneration, and suggests therapies that alter gut microbes may affect the onset or progression of neurodegenerative disorders,” said Linda McGavern, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided some of the funding for the study.
The findings suggest a new approach to preventing and treating neurodegenerative diseases by modifying the gut microbiome with antibiotics, probiotics, specialized diets, or other means.
“What I want to know is, if you took mice genetically destined to develop neurodegenerative disease, and you manipulated the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?” Holtzman asked. “That would be the equivalent of starting treatment in a person in late middle age who is still cognitively normal but on the verge of developing impairments. If we could start a treatment in these types of genetically sensitized adult animal models before neurodegeneration first becomes apparent, and show that it worked, that could be the kind of thing we could test in people.”
