Overview: Gut bacteria influence 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 indicates that the tens of trillions of microbes that normally live in our gut – the so-called gut microbiome – have far-reaching implications for how our bodies function. Members of this microbial community produce vitamins, help digest our food, prevent the overgrowth of harmful bacteria, and regulate the immune system, among other things.
Now, a new study suggests that the gut microbiome also plays a key role in our brain health, 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 that can damage brain tissue and exacerbate neurodegeneration in conditions such as the disease. from Alzheimer’s. disease.
The findings, published Jan. 13 in the journal Scienceopen 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 we saw a permanent change in their gut microbiome, their immune response and how much neurodegeneration was related to a protein called tau that they experienced as they got older,” 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.”
Evidence is mounting that the gut microbiomes in people with Alzheimer’s disease may differ from those of healthy people. But it’s not clear whether these differences are the cause or the consequence of the disease – or both – and what effect altering the microbiome might have on the course of the disease.
To determine whether the gut microbiome might play a causative role, the researchers altered the gut microbiomes of mice prone to developing Alzheimer’s-like brain damage and cognitive impairment.
The mice were genetically modified to express a mutated form of the human brain protein tau, which builds up and causes damage to neurons and atrophy of their brains by 9 months old.
They also wore a variant of man APOE gene, an important genetic risk factor for Alzheimer’s disease. People with a copy of the APOE4 variant are three to four times more likely to develop the disease than people with the most common APOE3variant.
Along with Holtzman, the research team included gut microbiome expert and co-author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and Director of the Edison Family Center for Genome Sciences & Systems Biology; first author Dong-Oh Seo, PhD, an instructor in neurology; and co-author Sangram S. Sisodia, PhD, a professor of neurobiology at the University of Chicago.
When such genetically modified mice were raised under sterile conditions from birth, they lacked a gut microbiome and at 40 weeks of age their brains showed much less damage than the brains of mice with 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 changed the composition of bacteria in their microbiome. For male mice, it also reduced the amount of brain damage apparent at 40 weeks of age.
The protective effects of the microbiome shifts were more pronounced in male mice receiving the APOE3 variant than in those at high risk APOE4variant, possibly due to the harmful effects of APOE4canceled part 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 very surprising that when we manipulated the microbiome, we saw a gender difference in response, although it’s hard to say exactly what this means for men and women living with Alzheimer’s disease and related conditions.”
Further 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 seemed to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice with no microbiome were given the three short-chain fatty acids, their brain immune cells became more reactive and their brains showed more signs of tau-linked damage.
“This study may provide important insights into how the microbiome affects tau-mediated neurodegeneration, suggesting that therapies that alter gut microbes may influence 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 take mice that are genetically predisposed to develop neurodegenerative diseases, and you manipulate the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?” asked Holtzmann.
“That would be the equivalent of starting treatment in a late middle-aged person who is still cognitively normal but on the verge of developing impairment. If we could start treatment in these types of genetically sensitized adult animal models before neurodegeneration becomes clear for the first time, and we could show that it worked, then we could test things like that in humans.
About this microbiome and neuroscience research news
Writer: Judy Martin Finch
Contact: Judy Martin Finch – WUSTL
Image: The image is in the public domain
Original research: The findings appear in Science