Rosuvastatin alters the genetic composition of the human gut microbiome

Abstract

The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.

Figure 1

A trend towards increased gut microbial richness in participants receiving rosuvastatin. Participants on rosuvastatin treatment showed an increase in gut microbial richness (delta Chao1, paired t-test p = 0.04), but this increase was not statistically significant compared with the placebo group (P_GLM = 0.22). A similar trend was detected for Phylogenetic diversity, while the change in Shannon diversity index was similar in the rosuvastatin and the placebo group. Data shown as mean ±95% CI. Paired t-test from baseline and study-end within the same study group, denoted p. Comparison of change between the study groups using repeated measures ANOVA from baseline and study-end, denoted P_GLM. Values at 4 weeks missing for n = 1 in each group.

Figure 2

Functions (KEGG Orthologs) in the gut microbiota related to cellular transport and metabolism along the choline/betaine-trimethylamine (TMA) metabolic pathway are affected by rosuvastatin treatment. Data are shown as mean ±95% CI. Repeated measures ANOVA from baseline and study-end, denoted P_GLM. Values at four weeks missing for n = 1 in each group.

Figure 3

Changes in microbiome-related metabolites in peripheral blood during rosuvastatin treatment. (a) Rosuvastatin increase precursors of the microbiota dependent metabolite trimethylamine (TMA) in plasma. (b) TMA is metabolized to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) in the liver, which is not affected by rosuvastatin. (c) Participants with the least favorable treatment response (defined as below median change in high density to low density lipoprotein (HDL/LDL) ratio) show a marked increase in TMAO levels compared to those with a more favorable response. All randomized participants with serum samples available were included in the analysis, irrespective of the availability of microbiome data. TMAO values missing for n = 2 in panel C. Data shown as mean ±95% CI. Repeated measures ANOVA, denoted P_GLM.