Medication caught meddling with the gut microbiome

One in four pharmaceuticals have been found to inhibit the growth of bacteria in the human gut, according to a large-scale international study.

It has been known for some time that the human gut contains a large number of species of bacteria, collectively referred to as the gut microbiome, whose composition has a noticeable effect on human health. It is also well known that antibiotics have a substantial impact on this microbiome, eg, causing gastrointestinal side effects.

However, recent studies have suggested that various non-antibiotic drugs — including antidiabetic, non-steroidal anti-inflammatory and atypical antipsychotic medications — can also change the composition of the gut microbiota, despite being designed to act on human cells rather than against bacteria. Until now, the full extent of this phenomenon has been unknown.

An international research team led by the European Molecular Biology Laboratory (EMBL) set out to systematically profile direct interactions between marketed drugs and individual gut bacteria. The team screened over 1100 drugs — including antibacterials, antivirals, drugs that act on human cells and veterinary drugs — against 40 representative bacteria from the human gut.

Published in the journal Nature, the study results found that 27% of the tested drugs and 24% of the drugs designed to act on human cells — including members from each therapeutic class — inhibited the growth of at least one species of gut bacterium. In addition, examination of previous cohort studies revealed that the human-targeted drugs have antibiotic-like side effects.

“The number of unrelated drugs that hit gut microbes as collateral damage was surprising,” said EMBL co-group leader Peer Bork. “Especially since we show that the actual number is likely to be even higher. This shift in the composition of our gut bacteria contributes to drug side effects, but might also be part of the drugs’ beneficial action.”

“This is just the beginning,” added co-group leader Kiran Patil. “We don’t know yet how most of these drugs target microbes, how these effects manifest in the human host, and what the clinical outcomes are. We need to carefully study these relationships, as this knowledge could dramatically improve our understanding and the efficacy of existing drugs.”

The study also highlights the previously unnoticed risk that consumption of non-antibiotic drugs may promote antibiotic resistance, as the general resistance mechanisms of microbes to human-targeted drugs and to antibiotics seem to largely overlap.

“This is scary, considering that we take many non-antibiotic drugs in our life, often for long periods,” said co-group leader Nassos Typas. “Still, not all drugs will impact gut bacteria and not all resistance will be common. In some cases, resistance to specific non-antibiotics will trigger sensitivity to specific antibiotics, opening paths for designing optimal drug combinations.”

The good news is that the findings may help refine medications and reduce side effects, alongside possibly leading to the repurposing of human-targeting drugs as new antibacterials or as microbiome modulators. And with each human harbouring a unique gut microbiome — including different bacterial species and strains — many drug-microbe interactions are likely to be individual, opening paths for personalised drug therapies aimed at the individual gut microbiome.

“We are excited to move on and explore drug-microbe interactions in complex gut microbial communities, as this will help us understand how individuals sometimes respond differently to the same medication,” said co-group leader Georg Zeller.

Commenting on the results of the study, Dr Hannah Wardill from the Adelaide Medical School was interested to learn that bacteria are not only sensitive to culture additives, but also to commonly prescribed drugs.

“It has always been known that antibiotics negatively affect the good bacteria that reside in our gut, but this study has shown that a number of non-antibiotic drugs also affect the viability of certain bacteria,” she said. “Although only shown in vitro, without the complexities of the human body, results showed that a number of antidiabetic, anti-inflammatory and antipsychotic medications affected bacterial viability.

“These results are critically important as it suggests that a wider group of medications may also be driving antibiotic resistance, a looming threat to the health of our current society.”

Ramiz Boulos, CEO of Boulos & Cooper Pharmaceuticals, has meanwhile provided his own interpretation of the results, saying the study’s actual findings were that “bacteria that were resistant to antibacterial drugs were more likely to be resistant to non-antibacterial drugs”.

“This correlation is not the same as saying the use of these non-antibacterial drugs leads to or causes antibiotic drug resistance, but highlights an area of interest that should be watched until more data becomes available,” Boulos said.

“Finally, it is important to stress that the studies were carried out in isolation in plates that contained at any one time no more than one bacterial species and one drug. Biological systems such as our guts are much more complicated, with tens of trillions of bacterial cells in competition and where there are complex relationships between bacteria, acid levels in the gut, biomolecules such as carbohydrates, enzymes, hormones and others.

“An important question that is yet to be answered is therefore whether these findings can be reproduced in holistic biological systems.”

Image credit: Iulia Cartasiova/EMBL.