Many human drugs can directly inhibit the growth and disrupt the function of the bacteria that make up our gut microbiome. EMBL Heidelberg researchers have found that this effect is reduced when bacteria form communities.
In a first-of-its-kind study, researchers from the Typas, Bork, Zimmermann and Savitski groups at EMBL Heidelberg and many EMBL alumni including Kiran Patil (MRC Toxicology Unit Cambridge, UK), Sarela García-Santamarina (ITQB, Portugal), André Mateus (Umeå University, Sweden) as well as 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 findings were recently published in the journal Cell.
For their study, the team investigated how 30 different drugs (including those targeting infectious and non-infectious diseases) affect 32 different bacterial species. These 32 species were chosen as representative of the human gut microbiome based on available data from five continents.
They found that when found together, certain drug-resistant bacteria display community behaviors that protect other drug-sensitive bacteria. This “cross-protective” behavior allows these sensitive bacteria to grow normally when in a community in the presence of drugs that would have killed them if they were isolated.
“We were not expecting such resilience,” said Sarela Garcia-Santamarina, a former postdoctoral researcher in the Typas group and co-lead author of the study, currently a group leader at the Institute of Chemical and Biological Technology (ITQB), Universidade Nova de Lisboa, 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 was not affected in the community.”
The researchers delved deeper into the molecular mechanisms underlying this cross-protection. “Bacteria help each other by absorbing or breaking down drugs,” explained Michael Kuhn, a research scientist in the Bork group and one of the first authors of the study. “These strategies are called bioaccumulation and biotransformation, respectively.”
“These findings show that gut bacteria have a greater potential to transform and accumulate drugs than previously thought,” said Michael Zimmermann, group leader at EMBL Heidelberg and one of the study’s collaborators.
However, this community strength also has a limit. The researchers observed that high drug concentrations cause microbiome communities to collapse and cross-protective strategies to be replaced by “cross-sensitization.” In cross-sensitization, bacteria that would normally be resistant to certain drugs become sensitive to them when they are in a community — the opposite of what the authors observed to happen at lower concentrations of the drug.
“This means that the community composition remains robust at low drug concentrations, as individual community members can protect sensitive species,” said Nassos Typas, EMBL group leader and senior author of the study. “But, when the drug concentration increases, the situation is reversed. Not only do more species become sensitive to the drug and the cross-protection capacity decreases, but negative interactions also arise, sensitizing more community members. We are interested in understanding the nature of these cross-sensitization mechanisms in the future.”
Like the bacteria they studied, the researchers also adopted a community-based approach to this study, combining their scientific strengths. The Typas Group is an expert in high-throughput experimental approaches to microbiome and microbiology, while the Bork Group contributed its expertise in bioinformatics, the Zimmermann Group performed metabolomics studies, and the Savitski Group performed the proteomics experiments. Among the external collaborators, the group of EMBL alumnus Kiran Patil at the Medical Research Council Toxicology Unit at the University of Cambridge, UK, contributed its expertise in gut bacterial interactions and microbial ecology.
As a forward-looking experiment, the authors also used this new knowledge of cross-protective interactions to assemble synthetic communities that could maintain their composition intact during drug treatment.
“This study is a step towards understanding how drugs affect our gut microbiome. In the future, we could use this knowledge to tailor prescriptions and reduce the side effects of drugs,” said Peer Bork, group leader and director of EMBL Heidelberg. “To achieve this goal, we are also studying how species interactions are influenced by nutrients, so that we can create even better models to understand the interactions between bacteria, drugs and the human host,” added Patil.