The findings of this study point to a novel method for treating neurodegenerative diseases, including Alzheimer’s.
According to a growing body of data, tens of billions of microorganisms that normally reside in our intestines, or the so-called gut microbiome, have a significant impact on how our bodies work. Among other things, members of this microbial community help us digest food, generate vitamins, prevent the overgrowth of dangerous bacteria, and regulate the immune system. According to researchers from Washington University School of Medicine in St. Louis, a recent study reveals that the gut microbiome also has a significant impact in the health of our brains.
The study in mice discovered that the behavior of immune cells throughout the body, including those in the brain that can harm brain tissue and exacerbate neurodegeneration in conditions like Alzheimer’s disease, is influenced by gut bacteria, in part by producing substances like short chain fatty acids. Published in the journal Science, the research suggests that neurodegeneration may be prevented or treated by altering the gut flora.
“We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age,” 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.”
An increasing number of evidence suggest that the gut microbiomes of patients with Alzheimer’s disease and healthy individuals can vary. It is unclear, however, whether these variations are the cause or the result of the disease—or both—and what impact changing the microbiome would have on disease progression.
To ascertain whether the gut microbiome might be playing a causative role, the researchers changed the gut microbiomes of mice prone to develop brain damage and cognitive impairment similar to that seen in Alzheimer’s disease. The mice were genetically altered to exhibit a mutant form of the tau protein found in the human brain, which accumulates and damages neurons by the time the mice are nine months old. They also carried a variant of the human APOE gene, which is a major genetic risk factor for Alzheimer’s. Three to four times as many people with one copy of the APOE4 mutation will get the disease as compared to those with the more prevalent APOE3 variant.
When maintained in sterile environments, these genetically altered mice did not acquire gut microbiomes, and at 40 weeks of age, their brains displayed far less damage than those of mice with typical mouse microbiomes.
When raised in a typical, non-sterile environment, the mice developed normal microbiomes. However, a course of antibiotics given at 2 weeks of age irreversibly altered the bacterial makeup of their microbiomes. For male mice, it lessened the degree of brain damage evident at 40 weeks of age. The researchers hypothesised that the protective benefits of the microbiome alterations were more obvious in male mice with the low-risk APOE3 variant than in those with the high-risk APOE4 genotype, presumably because APOE4‘s negative impacts partially cancelled out the protection. In female mice, antibiotic therapy had no significant impact on neurodegeneration.
“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 saw a sex difference in response, although it is hard to say what exactly this means for men and women living with Alzheimer’s disease and related disorders.”
Additional research established a connection between neurodegeneration and three specific short-chain fatty acids. In mice whose gut microbiomes had been changed by antibiotic treatment, all three of these fatty acids were scarce, and they were undetectable in mice without gut microbiomes.
These short-chain fatty acids appeared to cause neurodegeneration by stimulating immune cells in the bloodstream, which in turn stimulated immune cells in the brain to cause brain tissue damage. When middle-aged mice without microbiomes were fed 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 offer important insights into how the microbiome influences tau-mediated neurodegeneration, and suggests therapies that alter gut microbes may affect 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, specialised diets or other means.
“What I want to know is, if you took mice genetically destined to develop neurodegenerative disease, and you manipulated the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?” Holtzman asked. “That would be the equivalent of starting treatment in a person in late middle age who is still cognitively normal but on the verge of developing impairments. If we could start a treatment in these types of genetically sensitized adult animal models before neurodegeneration first becomes apparent, and show that it worked, that could be the kind of thing we could test in people.” [APBN]
Source: Culibrk, R. A., & Hahn, M. S. (2020). The Role of Chronic Inflammatory Bone and Joint Disorders in the Pathogenesis and Progression of Alzheimer’s Disease. Frontiers in Aging Neuroscience, 12, 583884.