Overlooked Impact Of Cardiometabolic Drugs On The Gut Microbiome

January 5, 2022

By Deborah Borfitz

January 5, 2022 | A large-scale study involving more than 2,000 individuals across three countries could help disentangle associations between cardiometabolic disease, the gut microbiome, and metabolic markers in the blood—and, perhaps most importantly, the potential role played by the most prescribed drug treatments. These medications explain the interpersonal differences in the microbiome better than diet, disease, and smoking combined, according to Maria Zimmermann-Kogadeeva, one of the co-lead authors of the study, who now leads a group doing multiomics-based modeling of microbial ecosystems at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany).

Still, as has been previously reported, no more than 9% of the variation in microbial composition from person to person can be accounted for by factors (including age, sex, and body mass index) included in the statistical model, she says. Two individuals can share more than 99% of their genetic code but only 10% to 20% of the same bacterial genes, creating a mammoth-sized conundrum for scientists working in the microbiome field.

This large collaborative study, recently published in Nature (DOI: 10.1038/s41586-021-04177-9), also found that the negative effects of antibiotics on gut bacteria likely accumulate over time. The gut microbiome composition of patients taking multiple courses of antibiotics over five years became less diverse with a greater abundance of antimicrobial resistance genes.

Those taking higher dosages of specific drugs also experienced greater changes to their gut microbiome, and the associations can go two ways, says Zimmermann-Kogadeeva. It could be that the more drugs are given, the more changes occur to microbial abundance and metabolic markers associated with the severity of cardiometabolic disease. Conversely, the changing levels of those metabolic markers could be reflective of more severe disease, thus a higher drug dose must be given to these patients.

One of the big takeaways of the study is the importance of taking drug intake into account when looking for associations between the gut microbiome and disease states, says Sofia Forslund, the main co-lead author of the study, who now heads a group investigating host-microbiome factors in cardiovascular disease at Max Delbrück Center for Molecular Medicine in Berlin. The effects of medications used to treat disease—up to 13 drugs a day, among patients in the study cohort—are often overlooked when assessing the state of the microbiome and its associations with disease progression and severity.

This is pivotal, Forslund adds, because already 90% of the research in animal models is not translatable in humans. Signals “warped” by drugs not only mask the true interactions between disease and multiomics but can potentially put forward erroneous microbiome-based treatment candidates.

The new methodological framework accounts for the effects of multiple confounding factors so the effects of drugs and disease could be separated, she says. In doing so, the researchers have shown that medications can mask the signatures of disease and conceal potential biomarkers or therapeutic effects.

While this study looked specifically at cardiometabolic disease (with sub-groups for metabolic syndrome, severe and morbid obesity, type 2 diabetes, acute and chronic coronary artery disease, and heart failure), the statistical pipeline is publicly available to research groups elsewhere looking to better discriminate drug and host factors in other patient populations, says Forslund.

New Associations

Access to high-throughput sequencing approaches over the past two decades has enabled studies investigating the composition of the gut microbiota and its effects on different aspects of human health, as well as some experimental modulation of the microbiome, says Rima Chakaroun, a co-lead author of the study and clinician scientist at the Leipzig University Hospital in Germany. That certain microbes appear to play a role in cardiometabolic disease is nothing new.

What’s novel with this latest study is its scope, representing patients in the same disease sub-group (along with healthy controls) from three different clinical centers in France, Germany, and Denmark that were part of the MetaCardis consortium, Chakaroun says. Assembled in 2012, MetaCardis was a major EU-funded research project with 14 partners in six countries collectively investigating the role of gut microbes in cardiometabolic diseases.

Work in the early stages focused on standardizing patient treatment procedures and questionnaires and in more recent years shifted to metabolomic analysis of stool samples and blood and immune biomarkers, says Chakaroun. Although the MetaCardis project was only funded for five years, consortium members have continued working together and multiple other studies are expected to publish based on analysis of the enriched and informative data set, she adds. 

For the drug–microbiome associations study, a total of 28 drugs (taken by at least 10 patients in each of the disease sub-groups) were analyzed while considering potential confounding factors, such as the patient’s age, body mass index, diet, physical activity, and smoking status, says Zimmermann-Kogadeeva. The computational approach recaptured previously reported findings on the effect of antibiotics, proton pump inhibitors (PPIs), statins, beta-blockers, and metformin.

Importantly, it also identified new associations for these and other highly prevalent drugs—notably aspirin. The research team identified aspirin-associated changes in the abundances of microbial species and shifts in the serum lipidome and metabolome associated with improved cardiometabolic health. A recently identified proatherogenic intermediate of microbial metabolism (γ-butyrobetaine) was additionally lower in individuals taking aspirin.

The analysis also supported the hypothesis that PPIs cause oral bacteria to be transferred to the gut due to decreased stomach acidity.

Polypharmacy in cardiometabolic disease is common and these multi-medicated patients often have more pronounced disease or events commending the aggressive treatment, Chakaroun says. However, at a similar severity level, subjects with specific drug-combinations might have more pronounced improvement in disease markers compared to those receiving only one of the drugs.

Among patients with type 2 diabetes, loop diuretics appear to have marked synergistic effects on microbiome features when used in combination with aspirin, ACE inhibitors, and beta-blockers. Statins, on the other hand, seem most impactful on host features (e.g., lipoprotein levels and body fat mass) when combined with metformin or aspirin while also increasing microbiome richness and abundance, at least based on the observations in the study cohort, says Chakaroun.

Follow-Up Studies

The strong and severe effects on the gut microbiome of patients with recurrent infections taking antibiotics several times a year was a major and relatively novel finding but not terribly surprising since it is well known that antibiotics can disrupt the microbiota. One implication of the discovery is that patients with long-term exposure to antibiotics may need greater attention paid to restoring their microbiome to a more diverse and metabolically healthy state, Zimmermann-Kogadeeva says. Recommendations on how to do this might logically be tackled by follow-up studies.

The patient cohort was also large enough to quantify variation in microbiome composition that could be attributed to different host factors including medications taken as well as disease state, diet, whether they smoked, and how much they exercised. “A lot is going on with the microbiome and disease, and studies like ours help to disentangle those relationships and are also hypothesis-generating,” says Forslund.

Future studies can ascertain if specific drug-microbiome-host factor relationships can be used as clinical biomarkers or in the design of personalized treatments based on an individual’s microbiota composition or metabolic profile, she adds. Drug repurposing studies might also further explore drug combinations that appear to work synergistically to improve blood and microbiome markers.

The Forslund lab continues developing data-based models that show how the human host and microbiome develop together under different conditions toward health or disease. Longitudinal studies, such as the Berlin BeLOVE study in which her group is actively involved, should help shed light on the interplay of factors affecting cardiometabolic disease progression, she says.

Next steps for Zimmermann-Kogadeeva are more in the direction of microbes—specifically, the metabolic functions of microbes and how they relate to human health. Like growing numbers of researchers in the field, she is toggling from the top-down to the bottom-up approach to “mechanistically dissect some of the associations coming from these large-scale studies in laboratory conditions.”