Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes

The gut microbiota is the most predominant and most diverse microbial community residing in the human body [1]. It comprises hundreds of microbial species, together constituting about 10 times the number of body cells [2,3], and contributes substantially to human metabolic processes to the extent that up to 36 % of small molecules in human blood are contributed by the gut microbiome [4]. The gut microbiota’s impact on drug response and metabolism has been explored since the mid 20th century (reviewed in [5]); however, past studies have mostly focused on assessing the metabolic activity of gut microbial communities on antibiotics and botanicals [6-9]. Meanwhile, the influence of the host genetic makeup on drug response occupied the center stage of personalized medicine research, specifically in the clinical domain, leading to the rise of pharmacogenomic approaches to personalized therapy, while a pivotal player in xenobiotic metabolism, the microbiota, was mostly being overlooked [10,11].The various metabolic capabilities of the gut microbiota fueled the study of its effects on drug metabolism [11,12]. Several approaches were adopted, including comparisons between metabolic patterns of conventional and germfree mice, biochemical assays of microbial metabolic activities in cultures, and mutagenicity tests [5,6,13]. Population-based approaches, such as investigating the correlation between compositional variations in gut microbiota and response to a particular drug, e.g., digoxin, were followed as well [9].The evolution of microbial genomics from culture-based (i.e., sequencing genomes of bacterial species after isolating their colonies) to culture-independent strategies (metagenomics—or shotgun sequencing of microbial and viral communities [14,15]) has allowed the identification of the molecular signature of the gut microbiome associated with a certain disease or with altered drug response [16]. To describe this new expansion of pharmacogenomics, we suggested the term