Common genetic variants in vitamin D metabolism-related genes affect gut microbiota diversity in postmenopausal women

Recent studies have demonstrated that vitamin D (VD) influences gut microbiota (GM) by regulating epithelial barrier function and immune responses, thereby affecting microbial composition and diversity. Additionally, host genetic factors, particularly single-nucleotide variants (SNVs) in genes related to VD metabolism, may influence GM composition. Postmenopausal women are a particularly relevant population to assess the impact of these SNVs, as this group experiences reduced hormonal variability and a higher burden of vitamin D deficiency (VDD), enabling clearer evaluation of the association between vitamin D-related genetic variants and gut microbiota composition. To explore the relationship between SNVs in genes involved in VD metabolism and their impact on GM. We genotyped nine variants: rs10741657 (CYP2R1), rs6013897 (CYP24A1), rs10877012 (CYP27B1), rs10783219 and rs4516035 (VDR), rs4588 and rs7041 (GC), rs4944957 and rs3794060 (NADSYN1). GM was characterized by sequencing the V4 hypervariable region of the 16S rRNA gene. We compared taxon abundance at the genus level across host genotypes using the dominant model. Quantile regression was used to analyze non-mean diversity responses, and PICRUSt2 identified functional pathways. We also calculated the genetic risk score (GRS) using rs4516035, rs3794060, and rs4944957, which were associated with lower alpha diversity. Alpha microbial diversity differed significantly for the VDR (rs4516035) and NADSYN1 (rs3794060, rs4944957) variants, both for risk alleles and genotypes. Differential abundance analysis identified taxonomic disparities, notably in the genera DTU014, Fusobacterium, Negativibacillus, Pseudomonas, Peptococcus, and [Clostridium]_innocuum_group. PICRUSt2-predicted functional pathways for the rs4516035- C allele revealed significant glutamine-glutamate, folate, galactose, and fatty acid metabolism. A GRS was associated with lower alpha diversity indices and differences in the insulin signaling pathway and oxidative phosphorylation. These findings highlight the role of SNVs in GM modulation and suggest potential implications for VD metabolism and host health.