Scientists from the University of Ottawa and Beijing Institute of Lifeomics found that SSRIs, SNRIs and Tricyclic Antidepressants, commonly prescribed anti-depressants that target the neurotransmitter serotonin, also alter the composition and functioning of the human gut microbiome.

The study was led by Professor Daniel Figeys, who is now Director of the Quadram Institute on the Norwich Research Park.

He commented “Our research shows that everyday drugs don’t just act on the body, they can also reshape the gut microbiome and this is dependent on the initial level of antibiotic-resistant proteins expressed for each gut microbiome. Drugs may push the microbiome into a new, less resilient state, reducing its ability to cope with challenges, especially when higher levels of antibiotic resistance are already present.”

“Encouragingly, we’ve also found that certain dietary compounds, such as prebiotics, can help restore this resilience and protect the microbiome from some of these drug effects.”

The human gut microbiome consists of trillions of microbes, including hundreds of different species of bacteria. They are complex communities, interacting in ways that support the whole ecosystem, and also our own health through the production of metabolites by microbiome enzymes and other proteins.

Therapeutic drugs are known to be able to change the composition of the microbiome, but the changes at the protein level, and how this affects functionality, haven’t been explored.

To fill in this knowledge gap, the team measured how over 300 commonly prescribed therapeutic drugs altered the proteomes of the gut microbiome from six different individuals using their previously developed microbiome assay called RapidAIM.   They measured how exposure to drugs altered each microbiome’s proteome, and how those changes in the proteins being produced affected the microbiome’s functionality.

As well as looking at the proteins, they also measured shifts in which species of microbes were present after drug treatments, as well as an assessment of the changes to the overall community, as a functional ecosystem.

Their findings, published in Nature Communications, showed that many drugs affect the gut microbiome and in particular a subset of neuropharmaceuticals produced remarkably high functional responses across different individual human gut microbiomes, despite each microbiome’s unique composition.

They also demonstrated that drugs substantially increased the level of antimicrobial-resistance proteins (ARPs) and decrease functional redundancy.  Functional redundancy is where a number of different species can contribute to the same function; if one species is lost there’s another ready to takes up its role in the productions of metabolites and proteins important to our health. This was particularly the case for individuals with high basal level of ARPs, meaning microbiomes with higher initial levels of ARP tend to have strong expression of ARP and lower redundancy following drug treatment.

These findings raise concerns about the effects of taking these drugs, especially over the long term as we learn more about the importance of links between the gut microbiome and health. Off-target effects detrimental to the microbiome could therefore negatively impact health by affecting the production of metabolites and proteins important to our health.

Could these microbiome changes be mitigated? Because the drugs effects were consistent across different microbiomes, targeting specific microbes might not be effective. Instead, the research team tested whether a common prebiotic could help. Prebiotics support a microbiome by providing an effective source of nutrition for heathy, probiotic, bacteria. They used fructooligosaccharides (FOS), a type of fibre that can be derived from plants, which isn’t digested in the upper digestive tract but instead passes through to the large intestine, where the microbiome resides.

FOS can increase the overall function redundancy of the microbiome by supporting a wide range of beneficial bacteria, making it more resilient. When FOS was added to the microbiomes in this experimental set up, this seemed to be the case as the drug that previously had had the profoundest negative effects didn’t lead anymore to changes in functional redundancy and increase expression of ARP.

This suggests that FOS could help mitigate the detrimental effects of neuropharmaceuticals  like SSRIs, SNRIs, and TCA have on the microbiome.

Prof. Figeys commented “These findings reinforce the urgent need to understand how drugs and other xenobiotics affect the gut microbiome. They also highlight the importance of studying antibiotic resistance within the commensal microbiome and its link to drug effects. Finally, they offer a note of hope, as prebiotics may help counteract some of the negative impacts of drugs on the microbiome when given together.”

Reference: Systematic Metaproteomics Mapping Reveals Functional and Ecological Landscapes of Ex Vivo Human Gut Microbiota Responses to Therapeutic Drugs, Nature Communications 16, 9383 (2025). DOI: 10.1038/s41467-025-64433-8