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. Originally discovered for their anti-microbial properties 1 , statins primarily reduce cholesterol levels and are first-line agents in the management of coronary artery disease (CAD) 2. The use of statins has been increasing rapidly in recent decades, and they are now one of the most commonly prescribed group of drugs in Western countries 2,3. The primary mode of action is inhibition of hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the liver leading to decreased levels of low-density lipoprotein (LDL) cholesterol, but statins have other potential beneficial effects e.g., anti-inflammatory properties, inhibition of matrix metalloproteinases (MMPs) leading to plaque stabilization and inhibition of platelet aggregation 4. The mechanisms underlying these pleiotropic effects are not completely understood and may not necessarily be mediated through HMG-CoA reductase inhibition 5-7. Changes in the composition and function of gut microbiome have been implicated in the pathogenesis of a wide range of human conditions including various systemic disorders like cardiometabolic and autoimmune disorders 8,9. In cardiovascular disease (CVD), the gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) and related metabolites, has been associated cardiovascular risk 8,9. The large intra-individual variation

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

“…Participants with a poor treatment response to rosuvastatin also showed a significant increase in TMAO values compared to other participants treated with placebo [ 89 ]. Another study evaluated gut microbial communities in hypercholesterolemic patients treated with atorvastatin.…”

The Associations of Gut Microbiota Metabolites with Blood Lipids and the Effect of Rosuvastatin Therapy on Them

“…Previous studies found that drugs like proton pump inhibitors (PPIs) and statins could affect the gut microbiota compositions profoundly [30,31], but there was scarce information about the effect of drugs on the gut microbiota metabolites. Recently, a small cohort study found that rosuvastatin therapy not only affected the genetic compositions of gut microbiota, but also may affect the gut microbiota metabolites [13]. Patients in rosuvastatin therapy group had higher betaine and γBB levels than placebo group, and the TMAO and carnitine levels in rosuvastatin therapy group also tended to decrease and increase separately, although the differences were not signi cant [13].…”

“…Recently, a small cohort study found that rosuvastatin therapy not only affected the genetic compositions of gut microbiota, but also may affect the gut microbiota metabolites [13]. Patients in rosuvastatin therapy group had higher betaine and γBB levels than placebo group, and the TMAO and carnitine levels in rosuvastatin therapy group also tended to decrease and increase separately, although the differences were not signi cant [13]. In this study we found that, rosuvastatin therapy could decrease TMAO, but increase carnitine, betaine and γBB levels signi cantly while it lowering the blood lipids levels.…”

“…Studies had found that gut microbiota metabolites trimethylamine N-oxide (TMAO) and related precursors choline, carnitine, betaine or γbutyrobetaine (γBB) were associated with the development of CVD, the occurrence of stroke, and the risk of major adverse cardiovascular events (MACEs) [1,12]. Recent studies found that gut microbiota was associated with the variation of blood lipids [9], and statin therapy could in uence the compositions of gut microbiota [13,14]. However, there is little information about the relationships between gut microbiota metabolites and blood lipids.…”

Towards a mechanistic understanding of reciprocal drug–microbiome interactions

“…For host‐targeted drugs, increasing evidence suggests that they are associated with shifts in gut microbiome composition. Known examples span a broad range of therapeutic classes and include the antidiabetic metformin, proton‐pump inhibitors, antipsychotics, non‐steroidal anti‐inflammatory drugs, paracetamol, opioids, selective serotonin reuptake inhibitors, laxatives, and statins (Le Bastard et al , 2018; Jackson et al , 2018; Kummen et al , 2020; MetaCardis Consortium et al , 2020). These shifts are not necessarily unfavorable for the host.…”