Causal relationship between gut microbiota and serum vitamin D: evidence from genetic correlation and Mendelian randomization study

Abstract

The gastrointestinal microbiota is emerging as an important mediator in intestinal metabolism, such as vitamin D absorption. To elucidate the causality of microbiota and vitamin D, we used linkage disequilibrium score (LDSC) regression and two-sample Mendelian randomization (MR) methods with largest genome-wide association study (GWAS) summary statistics to identify specific taxa that are linked to serum 25-hydroxyvitamin D (25(OH)D). We found that Ruminiclostridium9 was significantly genetically correlated with 25(OH)D at nominal significance (rg = 0.43, P = 0.04). Applying the inverse variance weighted (IVW) method, we identified that doubling the genetic liability of abundance of Erysipelotrichia, Erysipelotrichaceae and Erysipelotrichales reduced the concentration of 25(OH)D by 0.06 standard deviation (SD) (βIVW = -0.06, s.e. = 0.01, P = 1.48 × 10-6, PFDR = 1.93 × 10-4) and, in turn, one SD increment in genetically determined serum 25(OH)D caused a 0.16 SD decrease in the relative abundance of Phascolarctobacterium (βIVW = -0.16, s.e. = 0.04, P = 2.48 × 10-4, PFDR = 0.02) after removing pleiotropic instruments and outliers. Moreover, four MR methods were also used to evaluate causality, the results of which supported these findings. Leave-one-out analyses showed that the results were robust with regard to alterations in the single nucleotide polymorphisms (SNPs) we selected. In conclusion, our results support the hypothesis that the gut microbiota mediates the absorption of serum vitamin D supplementation and interacts with it closely. These microbiota are potential therapeutic targets for promoting serum vitamin D homeostasis.