Many widely-used medications can alter the makeup of communities in our gut microbiome. For the first time, scientists have directly compared how 30 different drug treatments affect bacteria when isolated versus within a complex community. They discovered that drugs often have a milder effect on bacteria when these bacteria are part of a community, thanks to protective strategies they use together. Understanding how drugs interact with the microbiome in a community context could lead to enhanced therapies that minimize side effects and enhance drug effectiveness in the future.
Numerous medications can inhibit the growth and change the functionality of the bacteria that make up our gut microbiome. Researchers at EMBL Heidelberg have found that the effects of these drugs are less significant when bacteria are in community settings.
In a groundbreaking study, scientists from multiple EMBL Heidelberg groups—including Typas, Bork, Zimmermann, and Savitski—and several EMBL alumni such as Kiran Patil (MRC Toxicology Unit, UK), Sarela Garcia-Santamarina (ITQB, Portugal), André Mateus (Umeå University, Sweden), along with Lisa Maier and Ana Rita Brochado (University Tübingen, Germany), analyzed numerous drug-microbiome interactions. Their findings were published in the journal Cell.
The research focused on how 30 different medications, aimed at treating both infectious and noninfectious conditions, influenced 32 distinct bacterial species that represent the human gut microbiome, based on global data from five continents.
They observed that when bacteria grew in clusters, certain drug-resistant strains interacted in ways that shielded more vulnerable bacteria from the harsh effects of drugs. This behavior, known as ‘cross-protection’, enabled these sensitive bacteria to thrive even when exposed to drugs that would have otherwise been lethal in isolation.
“We were surprised by the level of resilience we observed,” noted Sarela Garcia-Santamarina, a former postdoc in the Typas group and co-first author of the study, now a group leader at the Instituto de Tecnologia QuÃmica e Biológica (ITQB) at Universidade Nova de Lisboa, Portugal. “It was astonishing to find that in nearly half of the instances where a bacterial species was impacted by the drug when grown alone, it remained unaffected within the community.”
To further explore this protective phenomenon, researchers investigated the underlying molecular mechanisms. “Bacteria support each other by either absorbing or breaking down the drugs,” explained Michael Kuhn, Research Staff Scientist in the Bork Group and co-first author of the study. “These processes are termed bioaccumulation and biotransformation.”
“Our results indicate that gut bacteria possess a greater capacity to modify and accumulate medicinal drugs than we had previously assumed,” stated Michael Zimmermann, Group Leader at EMBL Heidelberg and study collaborator.
However, there are limits to this communal support. The team found that when drug concentrations were high, the microbiome communities could deteriorate, resulting in a shift from ‘cross-protection’ to ‘cross-sensitisation’. In cross-sensitisation, bacteria that are usually drug-resistant become vulnerable when in a community, which is contrary to what they observed at lower drug levels.
“This suggests that at low drug concentrations, the community structure remains stable, as its members can protect the sensitive species,” explained Nassos Typas, an EMBL group leader and senior author of the study. “But with increased drug concentration, more species lose their resistance, and not only does cross-protection decline, but detrimental interactions arise that further sensitise other community members. We aim to investigate these cross-sensitisation mechanisms in future research.”
The researchers also employed a collaborative approach, pooling their expertise for this study. The Typas Group excelled in high-throughput microbiome and microbiology techniques, while the Bork Group provided bioinformatics knowledge. The Zimmermann Group focused on metabolomics, and the Savitski Group conducted proteomics studies. External collaborator Kiran Patil’s group at the Medical Research Council Toxicology Unit, University of Cambridge, UK, brought valuable insights into gut bacterial interactions and ecology.
Looking ahead, the researchers leveraged their newfound understanding of cross-protection to create synthetic communities that could maintain their makeup even when treated with drugs.
“This research serves as a foundational step toward comprehending how medications interact with our gut microbiome. In the future, we may be able to customize prescriptions to lessen drug side effects,” mentioned Peer Bork, Group Leader and Director at EMBL Heidelberg. “We are also exploring how the interactions between different species are influenced by nutrients to develop even more accurate models for studying the relationships between bacteria, medications, and the human host,” added Patil.
