A Study in Mice Shows Gut Bacteria Affects Brain Health – Washington University School of Medicine in St. Louis

Visit the news center

The findings point to a new approach to treating Alzheimer’s and other neurodegenerative diseases

Getty Images

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 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 indicates that the gut microbiome also plays a major role in the health of our brains, according to researchers from 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 cells in the brain that can damage brain tissue and worsen degeneration. Neuropathy in conditions such as Alzheimer’s disease. Illness. The findings, published Jan. 13 in the journal Science, open up 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 lasting change in their gut microbes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced as they aged,” said study senior author David Holtzman. MD, Barbara Burton and Robin M. Morris III Distinguished Professor of Neurology. “What’s exciting is that manipulating the gut microbiome could be a way to influence the brain without putting anything directly into the brain.”

Evidence is accumulating that the gut microbiomes of people with Alzheimer’s disease can differ from those of healthy people. But it is not clear whether these differences are the cause or consequence of the disease — or both — and what effect an altered microbiome might have on the course of the disease.

To determine whether the gut microbiome plays a causal role, the researchers altered the gut microbiomes of mice predisposed to Alzheimer’s disease-like brain damage and cognitive impairment. Mice were genetically engineered to express a mutated 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 kind of humanoid APOE The gene, which is a major genetic risk factor for Alzheimer’s disease. People who have one copy of APOE4 The variant is three to four times more likely to develop the disease than the more common people APOE3 alternative.

Along with Holtzmann, the research team included gut microbiome expert and co-author Jeffrey I. Gordon, MD, Distinguished University Professor Dr. Robert Glaser and director of the Edison Family Center for Genomics and Systems Biology. First author Dong-Oh Seo, Ph.D., instructor in neuroscience; and co-author Sangram S. Sisodia, PhD, professor of neuroscience at the University of Chicago.

When such transgenic mice were raised under sterile conditions from birth, their gut microbes did not gain, and their brains showed significantly less damage at 40 weeks of age than the brains of mice harboring the microbiota of normal mice.

When raised in natural, non-sterile conditions, these mice developed a normal microbiome. However, a course of antibiotics at 2 weeks of age permanently changed the bacterial composition of his microbiome. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age. The protective effects of microbiome shifts were most pronounced in male carrier mice APOE3 variant of those with high risk APOE4 variable, possibly due to adverse effects of APOE4 The researchers said some of the protections were revoked. Antibiotic treatment had no significant effect on neurodegeneration in female mice.

“We already know, from studies of brain tumors, normal brain development and related subjects, that immune cells in male and female brains respond very differently to stimuli,” said Holtzmann. “So it’s not terribly surprising that when we got to grips with the microbiome, we saw a gender difference in response, although it’s hard to say exactly what this means for men and women with Alzheimer’s disease and related disorders.”

Other experiments have linked three short-chain fatty acids — compounds produced by certain types of gut bacteria as products of metabolism — to neurodegeneration. All three of these fatty acids were rare in mice with gut microbes altered by antibiotic treatment, and undetectable in mice without gut microbes.

These short-chain fatty acids seem to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn activate immune cells in the brain in some way to destroy brain tissue. When middle-aged mice without microbiomes were fed the three short-chain fatty acids, their immune cells became more reactive, and their brains showed more signs of tau-related damage.

“This study may provide important insights into how the microbiome affects tau-mediated neurodegeneration, and suggests therapies that alter the gut microbiota may influence the onset or progression of neurodegenerative disorders,” said Linda McGovern, PhD, program director at the National Institute of Neurological Disorders. and Stroke (NINDS), which provided some 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 a neurodegenerative disease, and manipulate their microbiomes before the animals start to show signs of damage, can you slow or prevent neurodegeneration?” Holtzmann asked. “This would be the equivalent of starting treatment in a middle-aged person who is still cognitively normal but on the verge of developing disabilities. If we could start treatment in these types of genetically sensitive adult animal models before neurodegeneration becomes apparent for the first time, and show that it works.” This might be something we can test in people.”

Seo D, O’Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, Bao X, Franke E, Karlsson M, Meier M, Deng S, Desai C, Dodiya H, Lelwala-Guruge J, Handley SA, Kipnis J, Sisodia SS, Gordon JI, Holtzman DM. “ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of taupathy.” Sciences. January 13, 2023. DOI: 10.1126/science.add1236

This study was supported by Good Ventures and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH), grant number NS090934.

About the University of Washington School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care, and educational programs with 2,700 faculty members. The National Institutes of Health’s (NIH) research funding portfolio is the fourth-largest among U.S. medical schools, and has grown 54% in the past five years. Combined with institutional investment, WashU Medicine commits more than $1 billion annually for basic research, clinical innovation, and training. Its faculty practice is consistently in the top five in the nation, with more than 1,790 physicians working on the faculty at more than 60 locations who are also the medical staff at Barnes-Jews and St. Louis Children’s Hospitals at BJC HealthCare. WashU Medicine has a strong history of MD/PhD training, recently committed $100 million to scholarships and curriculum renewals for medical students, and is home to first-class training programs in every medical subspecialty as well as physical therapy, occupational therapy, audiology, and communication sciences.

Leave a Comment