Cross-protection promotes drug resistance in the gut microbiome

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Many drugs can directly inhibit the growth of the bacteria that make up our gut microbiome and alter their function. Researchers at EMBL Heidelberg have now discovered that this effect decreases when bacteria form communities.

In a unique study, researchers from the Typas, Bork, Zimermann and Savitski groups at EMBL Heidelberg and numerous EMBL graduate students, including Kiran Patil (MRC Toxicology Unit Cambridge, UK), Sarela Garcia-Santamarina (ITQB, Portugal), André Mateus (Umeå University, Sweden) and Lisa Maier and Ana Rita Brochado (University of Tübingen, Germany) compared a large number of drug-microbiome interactions between bacteria grown in isolation and those that are part of a complex microbial community. Their results were recently published in the journal cell.

For their study, the team examined how 30 different drugs (including those for infectious and non-infectious diseases) affect 32 different species of bacteria. These 32 species were selected as representative of the human gut microbiome based on data from five continents.

They found that certain drug-resistant bacteria in communities exhibit a shared behavior that protects other bacteria that are sensitive to drugs. This “cross-protection” behavior allows these sensitive bacteria to grow normally in a community in the presence of drugs that would have killed them in isolation.

“We did not expect such great resilience,” said Sarela Garcia-Santamarina, a former postdoctoral fellow in the Typas group and co-first author of the study, currently a group leader at the Instituto de Tecnologia Química e Biológica (ITQB) at the Universidade Nova de Lisboa in Portugal. “It was very surprising to see that in up to half of the cases where a bacterial species was affected by the drug when grown alone, it remained unaffected in the community.”

The researchers then investigated the molecular mechanisms underlying this cross-protection. “The bacteria help each other by absorbing or breaking down the drugs,” explains Michael Kuhn, a research associate in the Bork group and co-first author of the study. “These strategies are called bioaccumulation and biotransformation, respectively.”

“These results show that intestinal bacteria have greater potential for converting and accumulating drugs than previously thought,” said Michael Zimmermann, group leader at EMBL Heidelberg and one of the study collaborators.

However, the strength of this community is also limited. The researchers found that high drug concentrations lead to the collapse of microbiome communities and the cross-protection strategies are replaced by “cross-sensitization.” In cross-sensitization, bacteria that are normally resistant to certain drugs become sensitive to them in a community – the opposite of what the authors observed at lower drug concentrations.

“This means that at low drug concentrations, the community composition remains stable because individual members of the community can protect sensitive species. However, as the drug concentration increases, the situation is reversed. Not only do more species become sensitive to the drug and the ability to protect each other decreases, but negative interactions also arise that sensitize more members of the community. We are interested in understanding the nature of these mechanisms of mutual sensitization in the future,” said Nassos Typas, EMBL group leader and lead author of the study.

As with the bacteria they studied, the researchers followed a collaborative strategy for this study, combining their scientific strengths. The Typas group is an expert in high-throughput experimental microbiome and microbiology approaches, while the Bork group contributed its expertise in bioinformatics, the Zimmermann group conducted metabolomics studies, and the Savitski group carried out the proteomics experiments. External collaborators included the group of EMBL alumnus Kiran Patil at the Medical Research Council Toxicology Unit at the University of Cambridge (UK), which contributed its expertise in gut bacterial interactions and microbial ecology.

In a groundbreaking experiment, the authors also used this new knowledge of mutual protective effects to assemble synthetic communities whose composition could remain intact during drug treatment.

“This study is a milestone on the way to understanding the effects of drugs on our gut microbiome. In the future, we could use this knowledge to adapt prescriptions to reduce the side effects of drugs,” said Peer Bork, group leader and director at EMBL Heidelberg. “To achieve this goal, we are also studying how nutrients affect interactions between species so that we can create even better models to understand the interactions between bacteria, drugs and the human host,” Patil added.

Reference: Garcia-Santamarina S, Kuhn M, Devendran S, et al. Emergence of community behavior in the gut microbiota after drug treatment. cell. 2024. doi: 10.1016/j.cell.2024.08.037

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