AUTHOR=Parikh Ishita J. , Estus Janice L. , Zajac Diana J. , Malik Manasi , Maldonado Weng Juan , Tai Leon M. , Chlipala George E. , LaDu Mary Jo , Green Stefan J. , Estus Steven 

TITLE=Murine Gut Microbiome Association With APOE Alleles

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00200

DOI=10.3389/fimmu.2020.00200

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Since <italic>APOE</italic> alleles represent the most impactful genetic risk factors for Alzheimer's disease (AD), their differential mechanism(s) of action are under intense scrutiny. <italic>APOE4</italic> is robustly associated with increased AD risk compared to the neutral <italic>APOE3</italic> and protective <italic>APOE2</italic>. <italic>APOE</italic> alleles have also been associated with differential inflammation and gastrointestinal recovery after insult in human and murine studies, leading us to hypothesize that <italic>APOE</italic> alleles impact the gut microbiome.</p><p><bold>Methods:</bold> To assess this hypothesis, we compared 16S ribosomal RNA gene amplicon-based microbiome profiles in a cohort of mice that were homozygous for <italic>APOE2, APOE3, or APOE4</italic>, and included both males and females as well as carriers and non-carriers of five familial AD (5xFAD) mutations. Fecal samples were analyzed from mice at 4 and 6 months of age. <italic>APOE</italic> genotype, as well as sex and 5xFAD status, was then tested for influence on alpha diversity (Shannon H index) and beta diversity (principal coordinate analyses and PERMANOVA). A Random Forest analysis was used to identify features that predicted <italic>APOE</italic>, sex and 5xFAD status.</p><p><bold>Results:</bold> The richness and evenness (alpha diversity) of the fecal microbiome was not robustly associated with <italic>APOE</italic> genotype, 5xFAD status or sex. In contrast, microbial community composition (beta-diversity) was consistently and strongly associated with <italic>APOE</italic> genotype. The association between beta-diversity and sex or 5xFAD status was less consistent and more modest. Comparison of the differences underlying <italic>APOE</italic> effects showed that the relative abundance of multiple bacterial taxa was significantly different as a function of APOE genotype.</p><p><bold>Conclusions:</bold> The structure of the gut microbiome was strongly and significantly associated with <italic>APOE</italic> alleles in this murine model. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on AD-relevant phenotypes in murine models, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby <italic>APOE</italic> genotype impacts AD.</p>