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A new study suggests the gut microbiome may retain long-term signatures of past medication use, with some drugs leaving detectable effects years after treatment ends.
Your gut may carry a record of medications you stopped taking years ago.
A large study from the University of Tartu Institute of Genomics suggests that prescription drugs can leave lasting marks on the gut microbiome, the vast community of bacteria and other microbes that helps shape digestion, immunity, metabolism, and overall health. The findings challenge a common assumption in microbiome research: that only the medications someone is taking right now need to be considered.
The researchers analyzed stool samples and prescription records from 2,509 participants in the Estonian Microbiome cohort, part of the Estonian Biobank. Because Estonia’s health records allowed the team to look back at years of medication use, they could compare a person’s current gut microbes with both recent and older drug exposure.
Long-Term Microbiome Signatures
Of the 186 drugs studied, 167 were associated with some type of microbiome difference. Even more surprising, 78 showed long-term effects, meaning their microbial signatures could still be detected well after treatment had ended. In some cases, these traces remained visible more than three years after the last recorded use.
Antibiotics were not the only drugs with lingering effects. The study found long-lasting microbiome changes linked to antidepressants, beta blockers, proton pump inhibitors, glucocorticoids, biguanides, and benzodiazepines, a class of medications often prescribed for anxiety or insomnia.
“Most microbiome studies only consider current medications, but our results show that past drug use can be just as important, as it is a surprisingly strong factor in explaining individual microbiome differences,” said lead author Dr. Oliver Aasmets.
Repeated Drug Use May Strengthen the Effect
The study also suggests that repeated drug use may have a cumulative effect. For some medications, the more prescriptions a person had filled in the previous five years, the stronger the microbiome signal appeared to be. This “additive” pattern had already been seen with antibiotics, but the new analysis found similar effects for some human-targeted drugs, including beta blockers, benzodiazepines, and glucocorticoids.
One of the most unexpected findings involved benzodiazepines. Their impact on the overall gut microbiome was comparable to that of broad-spectrum antibiotics, and their effects were still detectable years later. The researchers also found that drugs within the same class were not always equal. Alprazolam and diazepam, for example, are both benzodiazepines, but they appeared to affect gut microbes differently. Similar differences were seen among beta blockers and proton pump inhibitors.
Implications for Future Research
That detail could become important if future studies confirm that some medications are gentler on the microbiome than others while offering similar clinical benefits. However, for now, the results do not mean patients should stop or change prescribed medications.
The team also examined a smaller group of 328 participants who provided a second stool sample after a median follow-up of 4.4 years. These follow-up samples helped confirm that starting or stopping certain medications was followed by predictable changes in gut bacteria. Despite the smaller sample size, the researchers verified long-term effects for proton pump inhibitors, selective serotonin reuptake inhibitors, and antibiotics such as macrolides and combination penicillins.
“This is a comprehensive systematic evaluation of long-term medication effects on the microbiome using real-world medical health records,” said corresponding author Professor Elin Org. “We hope this encourages researchers and clinicians to factor in medication history when interpreting microbiome data.”
The authors note that the study has limits. It focused on prescription drugs, so over-the-counter medications were not included. The analysis also relied on purchased prescriptions as a proxy for actual drug use, which may not always reflect whether someone took the medication exactly as prescribed.
Reference: “A hidden confounder for microbiome studies: medications used years before sample collection” by Oliver Aasmets, Nele Taba, Kertu Liis Krigul, Reidar Andreson, Estonian Biobank Research Team and Elin Org, 5 September 2025, mSystems.
DOI: 10.1128/msystems.00541-25
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