Evaluating the impact of pharmaceuticals on the human gut microbiome Raw sequence reads

Drugs initially designed to specifically target human cells often can affect microbes as well. As a result of poor gastrointestinal absorption and/or biliary secretion, many of these drugs reach the large intestine where they encounter - and potentially interact with - hundreds to thousands of different microbial species that play important roles in various aspects of human physiology. Indeed, several cohort studies have reported significant associations between the use of medication and shifts in gut microbial composition and function. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. In this study we combined quantitative microbiome profiling and long-read metagenomics, stable isotope probing and single-cell chemical imaging to investigate the impact of two nervous system-targeted drugs on the gut microbiome.Ex vivosupplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and further identifies metal sequestration as a mechanism of drug-induced microbiome disturbance. Sequencing was performed at the Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna under the project IDs JMF-2103-29 and JMF-2208-05.