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Summary: Gut bacteria affect the behavior of immune cells throughout the body and in the brain, including those involved in neurodegenerative disorders such as Alzheimer’s disease. The findings open up the possibility of altering the microbiome to prevent or treat neurodegeneration.
A growing body of evidence suggests that the tens of trillions of microbes that normally live in our gut—the so-called gut microbiome—have profound effects on how our bodies function. Members of this microbial community produce vitamins, help us digest food, prevent the overgrowth of harmful bacteria, and regulate the immune system, among other benefits.
Now, a new study suggests that the gut microbiome also plays a key role in the health of our brains, according to researchers at Washington University School of Medicine in St. Louis.
The study in mice found that gut bacteria — in part by producing compounds such as short-chain fatty acids — influence the behavior of immune cells throughout the body, including those in the brain, which can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer’s disease disease.
The findings, published Jan. 13 in the journal Sciencediscover the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
“We gave young mice antibiotics for just one week and saw a permanent change in their gut microbiomes, their immune responses and how much neurodegeneration associated with a protein called tau they experienced with age,” said senior author David M. Holtzman, MD, Barbara Burton and Reuben M. Morris III Professor Emeritus of Neurology.
“What’s exciting is that manipulating the gut microbiome could be a way to affect the brain without putting anything directly into the brain.”
Evidence is accumulating that the gut microbiomes of people with Alzheimer’s disease may differ from those of healthy people. But it’s unclear whether these differences are a cause or a result of the disease — or both — and what effect the change in the microbiome might have on the course of the disease.
To determine whether the gut microbiome might play a causal role, the researchers altered the gut microbiome of mice predisposed to developing Alzheimer’s-like brain damage and cognitive impairment.
The mice were genetically engineered to express a mutant form of the human brain protein tau, which accumulates and causes neuronal damage and atrophy in their brains by 9 months of age.
They also carried a human variant APOE gene, a major genetic risk factor for Alzheimer’s. People with one copy of APOE4 variant are three to four times more likely to develop the disease than people with the more common variant APOE3option.
Along with Holtzman, the research team includes gut microbiome expert and co-author Jeffrey I. Gordon, MD, Robert J. Glazer, university professor emeritus and director of the Edison Family Center for Genome Sciences and Systems Biology; first author Dong-Oh Seo, PhD, instructor of neurology; and co-author Sangram S. Sisodia, PhD, professor of neurobiology at the University of Chicago.
When such genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice containing normal mouse microbiomes.
When such mice were raised under normal, non-sterile conditions, they developed normal microbiomes. However, a course of antibiotics at 2 weeks of age permanently changes the composition of bacteria in their microbiomes. In male mice, it also reduced the amount of brain damage seen at 40 weeks of age.
The protective effects of microbiome changes were more pronounced in male carrier mice APOE3 variant than in those at high risk APOE4variant, possibly due to the deleterious effects of APOE4nullifies some of the protection, the researchers said. 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 too surprising that when we manipulated the microbiome, we saw a gender difference in response, although it’s hard to say exactly what that means for men and women living with Alzheimer’s and related disorders.”
Additional experiments linked three specific short-chain fatty acids—compounds produced by certain types of gut bacteria as products of their metabolism—to neurodegeneration. All three of these fatty acids were scarce in mice with gut microbiomes altered by antibiotic treatment and undetectable in mice without gut microbiomes.
These short-chain fatty acids appear to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activates immune cells in the brain to damage brain tissue. When middle-aged mice with no microbiomes were fed the three short-chain fatty acids, their brain immune cells became more reactive and their brains showed more signs of tau-related damage.
“This study may offer important insights into how the microbiome influences tau-mediated neurodegeneration and suggest therapies that alter gut microbes may affect the onset or progression of neurodegenerative disorders,” said Linda McGovern, PhD, program director at the National Institute on Neurological Diseases and Stroke (NINDS), which provided part 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 predisposed to develop a neurodegenerative disease, and you manipulated the microbiome just before the animals started to show signs of damage, could you delay or prevent the neurodegeneration?” Holtzman asked.
“This would be equivalent to starting treatment on a person in late middle age who is still cognitively normal but on the verge of developing disability.” If we can start a treatment in these types of genetically susceptible adult animal models before the neurodegeneration first becomes apparent and show that it works, that could be something we could test in humans.
About this microbiome and neuroscience research news
Original Research: The findings will appear in Science
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