Interaction between gut bacteria and drugs can influence cardiovascular disease

Not only can cardiovascular conditions affect life in the intestines, but the opposite is also true.

A new collaborative paper, including researchers from Imperial and published in Nature, reports how drug treatments can interfere with bacteria in the gut which can influence the course of cardiovascular disease, the opportunities and risks this presents as well as the need to better model the role played by drugs on gut bacteria.

Lead authors Dr. Sofia Forslund, Max Delbrück Center for Molecular Medicine, and Professor Peer Bork, European Molecular Biology Laboratory (EMBL), recently discovered that the diabetes drug metformin alters the gut microbiome, the ecosystem of bacteria in our intestinal tract. This frequently prescribed drug had a greater impact on gut flora than diabetes itself.

Building on the discovery, the MetaCardis consortium wanted to find out how cardiometabolic diseases and the gut microbiome influence each other, what role prescribed drugs and antibiotics play in this, and how the observed effects can be used in the future to refine and improve current treatment options. Cardiometabolic diseases include cardiovascular conditions like coronary heart disease and type 2 diabetes, both of which are widespread in Europe.

Working with the MetaCardis consortium, Imperial's metabolomics team led by Professor Marc-Emmanuel Dumas, used various established and novel statistical methods to analyze data from 2,173 European patients with cardiometabolic disease. The researchers could thus tease out the effects of drugs and disease separately.

It was known that the microbiome can reflect the status of a patient’s health and provide a range of biomarkers to assess the severity of diseases. However, what is often overlooked, is that the medication used to treat a disease also affects the state of the microbiome.

The data allowed the team to show that medication can mask the signature of disease and conceal potential biomarkers or therapeutic targets. One of the most important findings of the work is that drugs – both antibiotics and non-antibiotics – alter the molecular characteristics of the microbiome and the host to a similar extent as disease status and lifestyle factors, such as diet and smoking, combined. The extent of the observed changes was also dependent on the drug dosage level.

Speaking about the research, Professor Marc-Emmanuel Dumas from the Department of Metabolism, Digestion and Reproduction and the National Heart and Lung Institute, said: "This paper shows that when it comes to solving the complex interaction between drugs and the microbiome, metagenomics and metabolomics go hand in hand."

"The emerging field of pharmacomicrobiomics focuses on characterising the effect of the microbiome on drug absorption, distribution, metabolism and excretion, leading to toxicological responses or variation in the response to treatment. Pharmacomicrobiomics is becoming an integral part of our understanding of the response to treatment and ultimately, personalised medicine."

Speaking about the future of this research, Dr Forslund said: “It is now important to conduct follow-up studies to verify our findings on the impact of drugs on the microbiome. In order to identify truly causal relationships and not just coincidental correlations, studies in which individual groups of subjects are observed over a longer period of time would be helpful."

The research project MetaCardis (Metagenomics in Cardiometabolic Diseases), which began in 2012, involved clinical physicians, bioinformaticians, systems biologists and other specialists, and was funded by the European Union. 

Forslund, S.K., Chakaroun, R., Zimmermann-Kogadeeva, M. et al. Combinatorial, additive and dose-dependent drug–microbiome associations. Nature (2021). https://doi.org/10.1038/s41586-021-04177-9