Individual and synergistic effects of drugs on the gut microbiome

Disease and treatment 27. dec 2021 3 min Professor of Human Metabolism, Chief Research Physician, Specialist of Endocrinology Oluf Borbye Pedersen Written by Kristian Sjøgren

Many drugs influence the composition and function of bacteria in the gut, affecting the gut microbiome and thereby people’s health.

Many people who take a drug for diabetes, cardiovascular disease or infection may not consider that it not only affects them generally but also the many billions of bacteria in their gut. But perhaps they should.

Any drug that affects the composition and function of the gut microbiome likely affects human health.

A new study shows that some drugs and drug combinations improve or worsen the composition and function of the gut bacteria, contributing to either health or the risk of developing or aggravating various chronic diseases.

The discovery has been published in Nature.

“Many people are treated with several drugs targeting chronic disorders or risk states such as cardiovascular disease, diabetes, elevated cholesterol and others. Combining these drugs can affect their gut microbiome synergistically and can thereby also affect human health. We mapped how more than 20 types of drugs affect the gut microbiome and the potential health effects when the gut microbiome contains more or fewer of certain bacteria,” explains Oluf Pedersen, Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen and the leader of Denmark’s part of this major European research project.

Mathematical model disentangles microbiome signatures originating from either chronic disorders or drugs

The researchers used DNA technology and advanced bioinformatics analysis to map the distribution of the gut bacteria of 2,173 residents of Denmark, Germany and France and then linked the composition and function of the gut microbiome of each participant with their use of more than 20 drugs.

The participants were healthy or had various chronic diseases for which they received treatment, including diuretics, statins, antidiabetes drugs, blood pressure-lowering drugs, cholesterol-lowering drugs and proton pump inhibitors. Many were taking 5–10 drugs.

In such a complex experimental set-up, researchers have difficulty in identifying how much disease relates to the gut microbiome versus drugs or drug combinations.

The researchers therefore developed a mathematical model to disentangle the effects of drugs and disease on the host and microbiome.

According to Oluf Pedersen, the mathematical model is one of the reasons why Nature became so interested in the study.

“Differentiating data systematically as we did was not possible previously and enables us to identify how each drug or drug combination relates to the gut microbiome and thereby health,” says Oluf Pedersen.

Beneficial bacteria create a crown jewel of bacterial metabolites

The study shows that simultaneously taking loop-diuretics, blood pressure–lowering drugs (beta blockers) and statins improves microbiome-related health markers, including the abundance of the Roseburia bacterial genus in the gut.

This is good news for the people taking this drug combination, because Roseburia can convert plant fibre into butyric acid, which has many health benefits, including being anti-inflammatory and having positive regulatory effects on the epigenome.

Oluf Pedersen calls butyric acid a crown jewel among the bacterial metabolites.

“The association between this drug combination and the increased abundance of Roseburia is interesting because it indicates synergistic effects on health beyond the known effects on the heart and blood pressure. This synergy may suggest that the drugs have desirable effects individually but an even greater overall effect,” explains Oluf Pedersen.

Aspirin may have extra positive effects on cardiovascular health

Aspirin (acetylsalicylic acid) may have similar benefits for the gut microbiome and thus probably also health.

Taking aspirin is associated with reduced production of gamma-butyrobetaine by the gut microbiome.

Gut bacteria use meat to produce gamma-butyrobetaine, which is associated with an increased risk of atherosclerosis.

Aspirin is associated with a lower amount of gamma-butyrobetaine in the blood, which is therefore promising for health. Thus, aspirin might reduce the risk of atherosclerosis in addition to reducing the ability of platelets to clot.

“This observation deserves to be followed up in future clinical trials because it may be clinically relevant,” says Oluf Pedersen.

Some drugs harm the gut microbiome

Antibiotics clearly harm the gut microbiome and therefore health.

Unsurprisingly, the study confirms that people treated with antibiotics several times over the past 5–10 years have a smaller density and diversity of gut bacteria. This is unfavourable because a rich and diverse gut microbiome generally seem to be associated with health and less risk of developing many chronic diseases.

Proton pump inhibitors, taken by millions of people to lower the production of stomach acid and relieve heartburn or acid reflux, also harm the gut microbiome and health. The reduced stomach acid enables certain oral bacteria to remain alive through the stomach and colonise the gut.

These oral bacteria are healthy in the oral cavity, but research suggests that having these bacteria in the gut increases the risk of developing some types of colorectal cancer.

Oluf Pedersen is therefore also concerned that proton pump inhibitors are now sold over the counter in Denmark.

“Our findings call for investigating this association in more detail in a major registry study that compares the incidence of colorectal cancer among people treated and not treated with proton pump inhibitors. Using these drugs to treat heartburn and acid reflux should obviously be reconsidered if they increase the risk of colon cancer,” concludes Oluf Borbye Pedersen.

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