Gut microbial composition and diversity varies by <i>CREBRF</i> genotype among Samoan infants

Over 40% of Samoans have at least one copy of the minor A allele at rs373863828 in encoding CREB3 regulatory factor (<i>CREBRF</i>), which is associated with increased body mass index (BMI) but decreased odds of type 2 diabetes mellitus. The mechanisms underlying this paradoxical effect remain unknown. We hypothesized that gut microbiota may play a role and examined associations between <i>CREBRF</i> genotype and gut microbial diversity and composition among Samoan infants. Fecal samples were collected from Samoan infants aged 0 (<i>n</i> = 23), 4 (<i>n</i> = 20), and 21 (<i>n</i> = 27) mo. Microbiota community structure was analyzed using 16S rRNA bacterial gene sequencing. Both cross-sectional and longitudinal analyses revealed no associations between <i>CREBRF</i> genotype and overall microbiome composition or diversity at 0 or 4 mo. Cross-sectional analysis at 21 mo revealed a significant association between genotype and unweighted UniFrac distances (<i>F</i>_1,24 = 1.855, <i>R</i>² = 0.072, <i>P</i> = 0.015). Longitudinal differential abundance analysis also revealed several differentially abundant taxa at 21 mo. Notably, the AG genotype was associated with a lower relative abundance of <i>Escherichia-Shigella</i> (β = -6.741, SE = 2.243, <i>P</i> = 0.004, <i>q</i> = 0.042). Significant genotype differences in gut microbiome composition and diversity at 21 mo suggest that gut microbiota may be involved in relationships between <i>CREBRF</i> genotype and metabolic health. No genotype differences were observed at 0 or 4 mo, suggesting that environmental and/or maternal variables have a greater influence on the gut microbiome in early infancy, and genotype effects emerge later. Further research should examine whether genotype differences in gut microbiota are associated with functional differences in metabolic or immune signaling pathways or energy extraction.<b>NEW & NOTEWORTHY</b> Missense variant rs373863828 in <i>CREBRF</i> is associated with higher odds of obesity but lower odds of diabetes among Polynesians. We examined associations between <i>CREBRF</i> genotype and gut microbial diversity and composition among Samoan infants and identified significant differences at age 21 mo but not at age 0 or 4 mo. These results suggest that gut microbiota may contribute to the mechanisms through which <i>CREBRF</i> genotype impacts metabolic health.