When oral medications reach the intestines, they’re met with a myriad of microbes. Here, microbes can alter a drug’s efficacy by sequestering or modifying it. At the same time, the drugs themselves can influence the composition of the gut microbiome, even if they’re not intended to kill bacteria.

Many studies examining these effects use single species in isolation. However, microbes don’t exist as isolated species in nature. “This was the motivation, basically, to understand how much can you rely on the analysis in monocultures versus in communities,” said Sarela Garcia-Santamarina, a microbiologist at NOVA University Lisbon, who led a study while she was a postdoctoral researcher at the European Molecular Biology Laboratory to understand how drugs affect microbial communities in the gut (1).

In this work, the team created a synthetic microbial community containing 32 gut microbiome species. The researchers tested the effects of 30 drugs at three different concentrations on the microbes in community and in isolation. These drugs include 21 drugs that target human processes and nine antibiotics. Using 16S rRNA sequencing, they determined the relative abundance of each species after drug exposure.

They looked for three possible outcomes: no difference in the species’ growth between the community and a monoculture, reduced abundance of the species in the community compared to a monoculture (cross-sensitization), or increased abundance of the species in the community compared to a monoculture (cross-protection).

Over a quarter of the bacteria-drug combinations that the researchers tested resulted in communal behaviors among the microbial species. “The behavior that we found the most is that bacteria cross-protect each other, so they really act as a community,” said Garcia-Santamarina. “When the stress is a bit high, they start to be a little more, let’s say, selfish,” she added.

Garcia-Santamarina and her colleagues then began looking for explanations behind these communal behaviors. One possibility could be that some bacteria modify or accumulate drugs to protect otherwise sensitive bacteria. To test this hypothesis, the scientists used liquid chromatography-mass spectrometry to measure the drug concentrations in the entire synthetic microbiome or in the supernatant only. If bacteria modified the drug, the researchers would detect less of it in the entire community. But if bacteria accumulated the drug inside themselves, there would be less of it in the supernatant. Overall, they found that bacteria tended to protect others when they transformed the drug rather than when they accumulated it. However, there were also unknown mechanisms at play. For instance, none of the microbes accumulated or transformed the nonsteroidal estrogen, dienestrol, but half of the species susceptible to dienestrol in monoculture grew in the community.

It's important to realize that for drug development, ignoring the microbiome is no longer an option. 
- Sarela Garcia-Santamarina, NOVA University Lisbon

Caetano Antunes, a microbiologist at the University of Kansas who was not involved in this study, noted the importance of studying how non-antibiotic drugs affect the microbiome. “We take a whole bunch of other drugs that, as far as we know, don't have antimicrobial activity,” he said. “But they still could probably have a significant impact on the microbiome, and some of them might actually have antimicrobial activity even though they're not used as antimicrobials.”

Antunes added, “The fact that certain components of the microbiome can protect others or sensitize others to drugs [is] definitely the main contribution from this paper.”

Garcia-Santamarina is now following up on the metabolic drugs used in the study to understand their mechanisms behind cross-protection and cross-sensitization. She hopes to take this work further by seeing how these communal behaviors can affect drug efficacy in animal models.

But there’s a long way to go to completely understand the roles of these communal behaviors in the human gut. “It's complicated to extrapolate this into clinical settings,” said Garcia-Santamarina.

But, she added, “It's important to realize that for drug development, ignoring the microbiome is no longer an option.” 

Reference

1. Garcia-Santamarina, S. et al. Emergence of community behaviors in the gut microbiota upon drug treatment. Cell   187, 6346–6357 (2024).