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Varying microbiome composition may explain differences in statin efficacy

A new study’s mix of microbiome and genetic data yields fascinating new insights into possible precision medicine treatment techniques for cardiovascular disease.

According to researchers at the Institute for Systems Biology, the heterogeneity in the human microbiome might explain various patient reactions to statins. The findings suggest that taking this into account may help improve precision statin treatments for individuals.

The study’s results show that the makeup and variety of the gut microbiota are predictive of statin effectiveness and the extent of unfavorable side effects.

The study’s first author Dr. Tomasz Wilmanski, told ISB Science, “Specifically, we found that a Bacteroides enriched microbiome with lower levels of diversity was associated with the strongest LDL-lowering response to statins, but also coincided with the greatest disruption to blood glucose levels.”

Individuals with a Ruminococcaceae-rich biome were similarly shielded against the deleterious effects of statins on insulin sensitivity while simultaneously displaying a clear LDL-lowering response, according to the researchers.

Wimanski and his team created predictive methods using data from an American cohort of over 1,800 people’s microbiome, metabolome, human genome, and clinical records, and produced their first discoveries concerning varying statin effects on cholesterol and blood glucose indicators. They next tested these findings on a nearly 1,000-person independent European sample.

In the clinic, a patient’s genetic profile has already been used to drive tailored statin therapy regimens, which incorporates known genetic indicators of statin drug efficacy. The scientists discovered that the variance in statin responses described by the microbiome was fully independent of the heterogeneity reflected by the genome in this investigation.

Dr. Wilmanksi added, “It’s a completely different axis of variability, so we’re able to build models including both genetics and the gut microbiome to improve our statin response predictions. The genome and the microbiome, together, appear to provide a more comprehensive and complementary picture of personalized drug responses.”

Dr. Sean Gibbons, co-author of the paper added his thoughts, saying, “It would be great to take this knowledge about the genome and the microbiome and predict personalized dosing regimens for a cohort of patients, and then follow these patients forward in time, tracking their metabolic health and their LDL cholesterol levels, to show that this population of patients undergoing a precision intervention do better than a control group of patients who are getting what is normally prescribed.” The research group hopes to proceed with a clinical trial.


The study was published in Med on May 11th, 2022.

Abstract. We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991). Microbiome composition was assessed in these cohorts using stool 16S rRNA amplicon and shotgun metagenomic sequencing, respectively. Microbiome associations with markers of statin on-target and adverse effects were tested via a covariate-adjusted interaction analysis framework, utilizing blood metabolomics, clinical laboratory tests, genomics, and demographics data. The hydrolyzed substrate for 3-hydroxy-3-methylglutarate-coenzyme-A (HMG-CoA) reductase, HMG, emerged as a promising marker for statin on-target effects in cross-sectional cohorts. Plasma HMG levels reflected both statin therapy intensity and known genetic markers for variable statin responses. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and adverse metabolic effects of statins, we find that heterogeneity in statin responses was consistently associated with variation in the gut microbiome across two independent cohorts. A Bacteroides-enriched and diversity-depleted gut microbiome was associated with more intense statin responses, both in terms of on-target and adverse effects. With further study and refinement, gut microbiome monitoring may help inform precision statin treatment.

Heterogeneity in statin responses explained by variation in the human gut microbiome. Tomasz Wilmanski, Sergey A. Kornilov, Christian Diener, Mathew Conomos, Jennifer C. Lovejoy, Paola Sebastiani, Eric S. Orwoll, Leroy Hood, Nathan D. Price, Noa Rappaport, Andrew T. Magis, Sean M. Gibbons. medRxiv; 2021.12.02.21267193; doi: https://doi.org/10.1101/2021.12.02.21267193

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