Many common medications designed for human ailments can directly disrupt the growth and function of the bacteria that reside in our gut, collectively known as the gut microbiome. However, researchers at EMBL Heidelberg have discovered that when bacteria form communities, this effect is significantly reduced.

In a groundbreaking study, the teams of Typas, Bork, Zimmermann, and Savitski at EMBL Heidelberg, alongside many collaborators, including Kiran Patil from the MRC Toxicology Unit in Cambridge, UK, and other alumni, explored drug-microbiome interactions. The study, recently published in Cell, compared how various medications affect bacteria grown alone versus those in a microbial community.

The researchers analyzed the effects of 30 drugs on 32 bacterial species representing the human gut microbiome, drawing from data collected across five continents. Their findings were eye-opening: drug-resistant bacteria, when part of a community, displayed behaviors that protected drug-sensitive bacteria. This phenomenon, known as ‘cross-protection,’ allowed sensitive bacteria to thrive even when exposed to drugs that would normally kill them if they were isolated.

“We didn’t expect such resilience,” remarked Sarela Garcia-Santamarina, a co-first author and former postdoc in the Typas group, now leading a team at the Instituto de Tecnologia Química e Biológica (ITQB) in Portugal. “It was surprising to find that up to half of the cases where a bacterial species was affected by a drug when grown alone showed no such effect when in a community.”

Digging deeper, the team investigated the molecular mechanisms behind this cross-protection. “Bacteria support each other by either absorbing or breaking down the drugs,” explained Michael Kuhn, co-first author and Research Staff Scientist in the Bork Group. These mechanisms, known as bioaccumulation and biotransformation, help shield the community from the drugs’ effects.

“This study highlights that gut bacteria have a greater ability to transform and accumulate medicinal drugs than we previously understood,” added Michael Zimmermann, a Group Leader at EMBL Heidelberg.

But there’s a limit to the community’s strength. At higher drug concentrations, the protective behaviors break down, leading to what the researchers call ‘cross-sensitization.’ In this scenario, bacteria that are typically resistant to certain drugs become vulnerable when part of a community—essentially the opposite of what happens at lower drug concentrations.

“At low drug concentrations, the community stays resilient as members protect sensitive species,” said Nassos Typas, EMBL group leader and senior author of the study. “But as the drug concentration increases, protection decreases, and more species become sensitive, triggering harmful interactions that sensitize additional members of the community. We aim to explore the mechanisms behind this cross-sensitization in future research.”

The success of this study was built on a collaborative approach. Each group brought unique expertise to the project: Typas’s team led experimental microbiology efforts, Bork’s group handled bioinformatics, Zimmermann’s group focused on metabolomics, and Savitski’s team conducted proteomics research. External collaborators, like Kiran Patil’s group, contributed insights into gut bacterial interactions and microbial ecology.

Looking ahead, the researchers hope to apply their findings to develop synthetic microbial communities that maintain their composition during drug treatment.

“This study is a key step towards understanding how medications influence our gut microbiome,” said Peer Bork, Group Leader and Director at EMBL Heidelberg. “In the future, we may be able to use this knowledge to reduce drug side effects through tailored prescriptions.” Kiran Patil added, “We are also investigating how interactions between species are shaped by nutrients to create more accurate models for understanding the interplay between bacteria, drugs, and the human host.”