Exploring the relationship between APOEε4 allele and gut microbiota composition and function in healthy adults.

The APOE ε4 allele (APOE4) is a known risk factor for neurodegenerative and cardiovascular diseases, but its link to body composition and metabolism remains debated. The gut microbiota influences host metabolism and immunity, yet its relationship with APOE genotype in healthy individuals is not well understood. The objective of this work was to examine associations between APOE genotype and gut microbiota composition and function in healthy adults, focusing on microbial and metabolic differences related to the APOE4 allele. Seventy-seven healthy Spanish adults were genotyped for APOE. Fecal microbiota profiles were assessed by 16 S rRNA gene sequencing, and predicted functions were inferred using PICRUSt2. Body composition (DEXA) and physical activity (accelerometry) were also measured. APOE4 carriers exhibited subtle shifts in microbiota composition, including a five-fold reduction in Megamonas and lower abundance of the Eubacterium brachy group-both linked to energy harvest and adiposity-compared to APOE3 homozygotes. An uncharacterized Puniceicoccaceae genus was enriched in APOE4 carriers. Although E. brachy group abundance correlated with adiposity, no significant differences in body composition were observed. Functional predictions showed APOE4-associated microbiota enriched in pathways for carotenoid biosynthesis and trehalose metabolism, and depleted in tryptophan biosynthesis, propionate production, and multidrug resistance mechanisms. APOE4 carriers harbor gut microbiota with distinct taxonomic and functional features, potentially reflecting adaptations to metabolic and oxidative challenges. These findings underscore the relevance of the gut microbiome in shaping APOE4-associated phenotypes and warrant further investigation into its mechanistic contributions to health and disease.