Summary: Gut bacteria affect the behavior of immune cells throughout the body and in the brain, including those implicated in neurodegenerative diseases such as Alzheimer’s disease. The results open up the possibility of modifying the microbiome to prevent or treat neurodegeneration.
Source: WUSTL
A growing pile of evidence indicates that the tens of trillions of microbes that normally live in our guts – the so-called gut microbiome – have far-reaching effects on how our bodies function. Members of this microbial community produce vitamins, help us digest food, prevent the growth 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 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 – affect 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 Alzheimer’s disease. illness.
The results, published on January 13 in the journal Scienceopen up the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
“We gave the young mice antibiotics for just one week, and we saw a permanent change in their gut microbiomes, their immune responses, and the amount of neurodegeneration related to a protein called tau that they suffered with age.” said lead author David M. Holtzman, MD, Barbara Burton Emeritus Professor and Reuben M. Morriss III Professor of Neurology.
“What’s exciting is that manipulating the gut microbiota 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 of people with Alzheimer’s disease may differ from those of healthy people. But it’s unclear whether these differences are the cause or result of the disease — or both — and what effect changing the microbiome might have on the course of the disease.
To determine if the gut microbiome may play a causal role, the researchers altered the gut microbiomes 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 tau protein, which accumulates and causes neuron damage and brain atrophy by the age of 9 months.
They also wore a variant of the human APOE genetics, a major genetic risk factor for Alzheimer’s disease. Persons with a copy of the APOE4 variant are three to four times more likely to develop the disease than people with the more common APOE3variant.
Along with Holtzman, the research team included gut microbiome expert and co-author Jeffrey I. Gordon, MD; 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, neurology instructor; and co-author Sangram S. Sisodia, PhD, professor of neurobiology at the University of Chicago.
When these genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes and their brains showed significantly less damage at 40 weeks than the brains of mice harboring normal mouse microbiomes.
When these mice were reared under normal, non-sterile conditions, they developed normal microbiomes. However, a course of antibiotics at 2 weeks of age permanently changed the makeup of the bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age.
The protective effects of microbiome changes were more pronounced in male mice bearing the APOE3 variant than in those at high risk APOE4variant, perhaps because the deleterious effects of APOE4voided 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 terribly surprising that when we manipulated the microbiome, we found a gender difference in response, although it’s hard to say exactly what this means for men and women living with the condition. Alzheimer’s disease and related disorders.
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Other experiments have linked three specific short-chain fatty acids — compounds produced by certain types of gut bacteria as products of their metabolism — to neurodegeneration. These three fatty acids were rare in mice with gut microbiomes altered by antibiotic treatment, and undetectable in mice without gut microbiomes.
These short-chain fatty acids appeared to trigger neurodegeneration by activating immune cells in the blood, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice without microbiomes were fed all three short-chain fatty acids, their brain immune cells became more responsive 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 suggests therapies that modify gut microbes may affect the onset or progression of neurodegenerative disorders,” said Linda McGavern, PhD, Director program at the National Institute of Neurological Disorders. and Stroke (NINDS), which provided some funding for the study.
The results 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 that if you took mice that were genetically destined to develop a neurodegenerative disease and manipulated the microbiome just before the animals started showing signs of damage, could you slow down or prevent the neurodegeneration? Holtzman asked.
“It would be the equivalent of starting treatment in a late middle-aged person who is still cognitively normal but on the verge of developing impairments. If we could start treatment in these kinds of genetically sensitized adult animal models before neurodegeneration became apparent, and show that it worked, that might be the kind of thing we could test in humans.
About this microbiome and current neuroscience research
Author: Judy Martin Finch
Source: WUSTL
Contact: Judy Martin Finch – WUSTL
Picture: Image is in public domain
Original research: The findings will appear in Science