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In the last decade, disease-association studies have dominated gut microbiome research. In many cases, the set-up of these studies has been explorative, screening faecal microbiomes for diagnostic signals with potential predictive or therapeutic perspectives. While such data-driven approaches contributed substantially to tool development and the establishment of metagenome research as a stand-alone field within microbial sciences, they also demonstrated that the untargeted characterisation of microbiome variation in the function of disease pathology is far from trivial. 1 Researchers able to successfully establish microbiota–disease associations beyond microbiome background variation awaited the long and painful task to discriminate between causes and consequences, taking into account the continuously expanding list of microbiome covariates. Top-ranked among those covariates is the use of medication …