Summary: New research links variations in the gut microbiome with differences in behavior, cognition, and gene regulation in mice carrying Alzheimer’s-related genes.
Source: Oregon Health and Science University
New findings in mice, published in the journal Scientific Reports, add to growing evidence that the gut microbiome influences neurodegenerative processes relevant to Alzheimer’s disease.
Researchers at Oregon Health & Science University report a correlation between gut microbiome composition and both behavioral and cognitive outcomes in mice engineered to carry human amyloid precursor protein (App) genes with Alzheimer’s-associated mutations. These mice include knock-in models that contain combinations of the Swedish, Iberian and Arctic mutations.
Beyond behavioral links, the study identifies associations between specific gut microbes and epigenetic changes in the hippocampus—an essential brain region for memory that is affected early in Alzheimer’s. These hippocampal epigenetic alterations included differential DNA methylation in regions related to the Apoe and Tomm40 genes, both of which have been implicated in Alzheimer’s disease risk and progression.
“We often say, ‘You are what you eat,’” said senior author Jacob Raber, Ph.D., professor of behavioral neuroscience at the OHSU School of Medicine. “Although all mice received the same diet, their gut microbiomes varied by genotype, and those differences appeared to relate to brain function and behavior.”
This work is the first in an Alzheimer’s animal model to directly link gut microbiome composition with cognitive and behavioral changes while also showing concurrent epigenetic changes in neural tissue. Comparable experiments in humans are not feasible, which makes these animal results valuable for exploring mechanisms and potential interventions.
The investigators measured gut microbiome composition from fecal samples and compared wild-type mice with two App knock-in strains: AppNL-F (Swedish and Iberian mutations) and AppNL-G-F (Swedish, Iberian and Arctic mutations). They found that specific bacterial groups — notably members of the Lachnospiraceae and Ruminococcaceae families — correlated with performance on behavioral and cognitive tests, and that these relationships were modulated by genotype.
In a subset of female mice, the team examined DNA methylation patterns in the hippocampus and identified differentially methylated regions that distinguished AppNL-G-F mice from wild-type controls. One notable region overlapped the 3′ untranslated region of Tomm40 and the promoter region of Apoe, and showed greater methylation in the mutant mice.
Integrated analysis linked amplicon sequence variants (ASVs) within the Lachnospiraceae family to methylation changes at the Apoe gene. While the study demonstrates clear correlations, researchers emphasize that it does not establish causation: gut microbes may influence neural epigenetic states and behavior, or conversely, genotype-driven brain changes could alter intestinal physiology and thereby reshape the microbiome.
Raber noted the translational potential of these findings: “What makes this exciting is that the gut microbiome is modifiable. Dietary interventions, probiotics or other microbiome-targeted approaches could be tested to see whether altering gut communities reduces Alzheimer’s-like symptoms in genetically susceptible animals.”
The research team included postdoctoral fellow Payel Kundu, Ph.D., former graduate student Eileen Ruth S. Torres, Ph.D., and Sarah Holden from the Raber laboratory. Collaborators included microbiome specialist Thomas Sharpton, Ph.D., at Oregon State University, and Lucia Carbone, Ph.D., director of the Knight Cardiovascular Institute’s Epigenetics Consortium at OHSU, along with members of their laboratories. The App mutant mouse strains used in the study were generated by Takashi Saito, Ph.D., and Takaomi Saido, Ph.D., of Nagoya City University and the RIKEN Center for Integrative Medical Sciences, respectively.
Funding: This work was supported by the National Institutes of Health, grants R56AG057495-01, RF1AG059088, R01ES030226, R21AG065914, T32AG055378 and T32ES007060.
About this Alzheimer’s disease research news
Source: Oregon Health and Science University
Contact: Erik Robinson – Oregon Health and Science University
Image: The image is in the public domain
Original Research: Open access.
“Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice” by Payel Kundu, Eileen Ruth S. Torres, Keaton Stagaman, Kristin Kasschau, Mariam Okhovat, Sarah Holden, Samantha Ward, Kimberly A. Nevonen, Brett A. Davis, Takashi Saito, Takaomi C. Saido, Lucia Carbone, Thomas J. Sharpton & Jacob Raber. Scientific Reports
Abstract
Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice
Epigenetic mechanisms in the brain and alterations in gut microbiome composition may both contribute to Alzheimer’s disease (AD). Human amyloid precursor protein knock-in (KI) mice either carry the Swedish and Iberian mutations (AppNL-F) or those two plus the Arctic mutation (AppNL-G-F). This study assessed whether behavioral and cognitive performance in 6-month-old AppNL-F, AppNL-G-F, and C57BL/6J wild-type mice was associated with the gut microbiome, and whether genotype influenced those associations.
Genotype effects on behavior varied by the type of test. Biodiversity and composition of the gut microbiome were linked to multiple aspects of mouse behavior and cognition, and those links were modulated by genotype, including associations involving taxa in the Lachnospiraceae and Ruminococcaceae families. In a subset of female mice, hippocampal DNA methylation analysis identified differentially methylated regions, including a roughly 1 kb region overlapping the 3′UTR of Tomm40 and the promoter of Apoe, which was more methylated in AppNL-G-F mice than in wild-type animals.
Integrated analysis revealed a positive relationship between certain Lachnospiraceae ASVs and methylation at the Apoe locus. These results suggest that specific gut microbes may influence AD-relevant behavior and cognition via epigenetic modulation of susceptibility genes in the brain, or alternatively that genotype-driven epigenetic changes in the brain may alter intestinal physiology in ways that favor growth of particular microbial taxa.