A growing body of evidence indicates that the tens of trillions of microbes that normally inhabit our gut, the so-called gut microbiome, have far-reaching effects on how our bodies function. Members of the microbial community produce vitamins, help digest food, prevent the overgrowth of harmful bacteria, regulate the immune system, and more. A new study suggests that the gut microbiome also plays an important role in brain health.
This study in mice found that gut bacteria influence the behavior of immune cells throughout the body by producing compounds such as short-chain fatty acids. This includes things in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer’s disease. disease. Findings published in the journal on January 13 chemistryopens up the possibility of reshaping the gut microbiota as a way to prevent or treat neurodegeneration.
“After as little as one week of antibiotics in young mice, we saw permanent changes in the gut microbiome, immune response, and the degree of neurodegeneration associated with a protein called tau experienced with age,” he said. Author David M. Holtzman says: MD, Barbara Burton and Reuben M. Morris III Distinguished Professor of Neurology. “What’s interesting is that by manipulating the gut microbiome, you can affect the brain without putting anything directly into it.”
Evidence is accumulating that the gut microbiota of patients with Alzheimer’s disease may differ from those of healthy individuals. It is not clear how changes in
To determine whether the gut microbiome may have a causative role, researchers altered the gut microbiota in mice prone to develop Alzheimer’s-like brain damage and cognitive deficits. Did. Mice have been genetically engineered to express a mutant form of the human brain protein tau, which accumulates and damages neurons by 9 months of age, causing brain atrophy.They also carried human variants appointment gene, the major genetic risk factor for Alzheimer’s disease.who has one copy of APOE4 Variants are three to four times more likely to develop the disease than people with more common variants. APOE3Mutant.
Along with Holzmann, the research team includes gut microbiome experts and co-authors Jeffrey I. Gordon, MD, and Robert J. Glazer, MD, directors of the Edison Family Center for Genome Science and Systems Biology. I was. Dr. Dong-Oh Seo, First Author, Neurology Instructor. Co-author Sangram S. Sisodia, Ph.D., is professor of neurobiology at the University of Chicago.
Such transgenic mice do not acquire a gut microbiota when housed in germ-free conditions from birth, and brain damage at 40 weeks of age is more pronounced than that of mice with normal mouse microbiota. was also shown to be much lower.
When such mice were housed under normal non-sterile conditions, they developed a normal microbiome. However, administration of antibiotics at 2 weeks of age permanently altered the composition of bacteria within the microbiome. The amount of overt brain damage was also reduced in male mice at 40 weeks of age. The protective effect of microbiome alterations was more pronounced in virus-carrying male mice. APOE3 Variants over high-risk individuals APOE4variant, possibly due to the detrimental effects of APOE4Some of the protections have been revoked, researchers say. 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 stimulation,” Holtzman said. “Thus, it’s hard to say exactly what this means for men and women living with Alzheimer’s disease and related disorders, but it’s so surprising that we saw gender differences in responses when we manipulated the microbiome. It’s not that.”
Further experiments linked three specific short-chain fatty acids, compounds produced as metabolites by certain types of gut bacteria, to neurodegeneration. All three of these fatty acids were deficient in mice with altered gut microbiota by antibiotic treatment and were undetectable in mice without gut microbiota.
These short-chain fatty acids caused neurodegeneration by activating immune cells in the bloodstream, which somehow appeared to activate immune cells in the brain to damage brain tissue. When middle-aged mice with no microbiome were given three short-chain fatty acids, immune cells in the brain became more responsive and the brain showed more signs of tau-related damage.
“This study may provide important insights into how the microbiome influences tau-mediated neurodegeneration, suggesting that therapeutics that alter the gut microbiome may contribute to the development or progression of neurodegenerative diseases.” It suggests that it may have an impact.” Stroke (NINDS) provided some of the research funding.
This finding suggests new approaches to prevent and treat neurodegenerative diseases by altering the gut microbiota with antibiotics, probiotics, specialized diets, or other means.
“What I would like to know is that if we take a mouse that is genetically destined to develop a neurodegenerative disease and manipulate the microbiome just before the animal begins to show signs of damage, we can slow or prevent neurodegeneration. Or is it?” asked Holzmann. “It’s the same as starting treatment in late middle-aged people who are still cognitively normal but are on the verge of developing the disorder. These types of neurodegeneration can be treated before neurodegeneration is first apparent.” If we can start a treatment in a genetically sensitized adult animal model and show it works, it could be something that can be tested in humans.
ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy.
Article publication date
January 13, 2023
DMH is a co-founder of C2N Diagnostics, LLC and participates on the scientific advisory boards and/or consulting of Genentech, Denali, C2N Diagnostics, Cajal Neurosciences, and Alector. DMH is the inventor of a patent licensed by the University of Washington to his C2N Diagnostics for the therapeutic use of anti-tau antibodies and a patent licensed by the University of Washington to Eli Lilly for humanized anti-Ab antibodies. The Holzmann Institute has received research grants from the National Institutes of Health, CURE Alzheimer’s Foundation, Rainwater Foundation, JPB Foundation, Good Ventures, Novartis, Eli Lilly, and NextCure. The authors declare no other competing interests.
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