Summary: Modulating the gut’s microbiome by fecal implants induced behavioral and cognitive changes in mouse models of Alzheimer’s disease. Researchers say the findings could help develop therapies to stall dementia via probiotic use and fecal transplantation.
New research in mice for the first time draws a definitive causal connection between changes in the gut microbiome to behavioral and cognitive changes in an animal model of Alzheimer’s disease.
The study, published today in the journal Frontiers in Behavioral Neuroscience, suggests new avenues involving the use of probiotics to treat and potentially forestall symptoms of dementia associated with neurodegenerative diseases including Alzheimer’s.
The research was led by scientists at Oregon Health & Science University.
“We found that modulating the gut microbiome by fecal implants in germ-free mice induces behavioral and cognitive changes in an Alzheimer’s disease model,” said senior author Jacob Raber, Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine. “To the best of my knowledge, no one has shown that before in an Alzheimer’s disease model.”
The work follows on a previous OHSU study in mice, published last year, that revealed a correlation between the composition of the gut microbiome and the behavioral and cognitive performance of mice carrying genes associated with Alzheimer’s.
In the new study, researchers carefully manipulated the digestive tract of mice using fecal implants.
They found changes in measures of behavior and cognition among three different genotypes and between males and females. Two of the genotypes involved mirror those associated with a predisposition to Alzheimer’s in people.
Researchers found that changes in the gut microbiome clearly affected behavioral and cognitive changes measured in mice.
The study suggests possible avenues for forestalling dementia through targeted use of probiotics or fecal transplants, which already have been used to manipulate the gut microbiome in people. However, Raber said much more research needs to be conducted to ascertain the mechanism of these behavioral and cognitive effects, because the relationship between these effects and gut microbiome is influenced by genotype and sex.
“People can buy probiotics over the counter, but we want to make sure the right treatment is being used for each patient, and that it actually benefits them,” Raber said. “The gut microbiome is a complex environment. If you change one element, you’ll also change other elements, so you want to make sure to select a probiotic that promotes brain health and brain function for each patient, while limiting any negative side effects.”
In addition to Raber, co-authors include Payel Kundu, Ph.D., and Sarah Holden of OHSU; Keaton Stagaman, Ph.D., Kristin Kasschau, Ph.D., Natalia Shulzhenko, M.D., Ph.D., and Thomas Sharpton, Ph.D., of Oregon State University.
Funding: The research was supported by the National Institutes of Health, awards R56 AG057495-01, RF1 AG059088, R21 AG065914, T32 AG055378, T32 ES007060, and the Collins Medical Trust.
About this Alzheimer’s disease research news
Author: Erik Robinson Source: OHSU Contact: Erik Robinson – OHSU Image: The image is in the public domain
The gut microbiome and the gut brain axis are potential determinants of Alzheimer’s disease (AD) etiology or severity and gut microbiota might coordinate with the gut-brain axis to regulate behavioral phenotypes in AD mouse models.
Using 6-month-old human amyloid precursor protein (hAPP) knock-in (KI) mice, which contain the Swedish and Iberian mutations [APP NL-F (AppNL–F)] or the Arctic mutation as third mutation [APP NL-G-F (AppNL–G–F)], behavioral and cognitive performance is associated with the gut microbiome and APP genotype modulates this association.
In this study, we determined the feasibility of behavioral testing of mice in a biosafety cabinet and whether stool from 6-month-old AppNL–G–F mice or AppNL–G–F crossed with human apoE4 targeted replacement mice is sufficient to induce behavioral phenotypes in 4-5 month-old germ-free C57BL/6J mice 4 weeks following inoculation. We also compared the behavioral phenotypes of the recipient mice with that of the donor mice. Finally, we assessed cortical Aβ levels and analyzed the gut microbiome in the recipient mice.
These results show that it is feasible to behaviorally test germ-free mice inside a biosafety cabinet. However, the host genotype was critical in modulating the pattern of induced behavioral phenotypes as compared to those seen in the genotype- and sex-match donor mice.
Male mice that received stool from AppNL–G–F and AppNL–G–F/E4 donor genotypes tended to have lower body weight as compared to wild type, an effect not observed among donor mice. Additionally, AppNL–G–F/E4 recipient males, but not females, showed impaired object recognition. Insoluble Aβ40 levels were detected in AppNL–G–F and AppNL–G–F/E4 recipient mice.
Recipients of AppNL–G–F, but not AppNL–G–F/E4, donor mice carried cortical insoluble Aβ40 levels that positively correlated with activity levels on the first and second day of open field testing. For recipient mice, the interaction between donor genotype and several behavioral scores predicted gut microbiome alpha-diversity.
Similarly, two behavioral performance scores predicted microbiome composition in recipient mice, but this association was dependent on the donor genotype.
These data suggest that genotypes of the donor and recipient might need to be considered for developing novel therapeutic strategies targeting the gut microbiome in AD and other neurodegenerative disorders.