Antibiotics are widely known to wreak havoc on the gut microbiome, causing uncomfortable symptoms such as bloating and diarrhea, and serious infections with Clostridioides difficile. These infections occur because antibiotics kill off other bacteria in the gut, allowing pathogens to proliferate. A new study from Lisa Maier’s lab at the University of Tübingen and University Hospital Tübingen now finds that non-antibiotic drugs can have similar effects.
This work has its roots in the 2010s when scientists began noticing that individual drugs such as proton pump inhibitors, metformin, and atypical antipsychotics could affect the composition of the microbiome. In 2018, Maier and colleagues from European Molecular Biology Laboratory published work that examined how 1,200 FDA-approved drugs affected 40 gut bacteria and found that over a quarter of the non-antibiotic drugs tested inhibited growth of at least one bacterial species.
“The gut microbiome provides colonization resistance,” said Jacobo de la Cuesta-Zuluaga, a bioinformatician in the University of Tübingen and University Hospital Tübingen, who was involved in the new study. “The question is, do non-antibiotic drugs affect or alter the ability of the microbiome to resist colonization by enteropathogens?”
To answer this question, de la Cuesta-Zuluaga and his colleagues created synthetic communities that mimicked the gut microbiome. He exposed these communities to the drugs and then introduced Salmonella to them. The team tested the effect of 53 drugs individually and found that untreated communities resisted pathogen growth while 15 drugs evaluated promoted Salmonella growth.
The team saw the same effect in mice with a native microbiota and in germ-free mice colonized with the synthetic community. These effects occurred either because the drug reduced the microbiome’s biomass, the drug altered the composition of the community to one that cannot resist Salmonella growth, or the drug affected the abundance of competitors that occupies the same ecological niche as Salmonella. “When that particular competitor is absent, then the pathogen can grow more easily,” said de la Cuesta-Zuluaga. “For the most part, non-antibiotic drugs tended to be either in the niche competitor group or the compositional alteration group.”
Elin Org, a microbiomics researcher at the University of Tartu who was not involved in this study, said that the study “elegantly showed in vitro models and validation in mice, which makes these conclusions really strong and relevant. It’s broadened our understanding of how drugs can have off-target effects on the microbiome that may then in turn influence infection risk.”
What does this mean for drug development?
Understanding how non-antibiotic drugs interact with the microbiome is an emerging field so de la Cuesta-Zuluaga said it’s important to see how well their studies translate to human data in the future.
Org agreed and said, “it’s very important to validate these findings in larger human cohorts.” Along these lines, Org, who studies microbiome-health interactions, has found that past use of medication, including the classes of non-antibiotics tested in de la Cuesta-Zuluaga’s study, alter the gut microbiome in humans even years later.
As for incorporating assays into drug development pipelines to test the impacts on the microbiome, de la Cuesta-Zuluaga doesn’t think it would be a large burden. He explained, “these assays can be done at a large scale. They can be done relatively quickly. It’s not a complex readout.”
