Trillions of diverse microbes reside in the gut and are deeply interwoven with the human physiological process, from food digestion, immune system maturation, and fighting invading pathogens, to drug metabolism. Microbial drug metabolism has a profound impact on drug absorption, bioavailability, stability, efficacy, and toxicity. However, our knowledge of specific gut microbial strains, and their genes that encode enzymes involved in the metabolism, is limited. The microbiome encodes over 3 million unique genes contributing to a huge enzymatic capacity, vastly expanding the traditional drug metabolic reactions that occur in the liver, manipulating their pharmacological effect, and, ultimately, leading to variation in drug response. For example, the microbial deactivation of anticancer drugs such as gemcitabine can lead to resistance to chemotherapeutics or the crucial role of microbes in modulating the efficacy of the anticancer drug, cyclophosphamide. On the other hand, recent findings show that many drugs can shape the composition, function, and gene expression of the gut microbial community, making it harder to predict the outcome of drug-microbiota interactions. In this review, we discuss the recent understanding of the multidirectional interaction between the host, oral medications, and gut microbiota, using traditional and machine-learning approaches. We analyze gaps, challenges, and future promises of personalized medicine that consider gut microbes as a crucial player in drug metabolism. This consideration will enable the development of personalized therapeutic regimes with an improved outcome, ultimately leading to precision medicine.

The consortium of microbes inhabiting the human body, together with their encoded genes and secreted metabolites, is referred to as the “human microbiome.” Several studies have established a link between the composition of the microbiome and its impact on human health. This impact spans local gastrointestinal inflammation to systemic autoimmune disorders and neurodegenerative diseases such as Alzheimer’s and Autism. Some of these links have been validated by rigorous experiments that identify specific strains as mediators or drivers of a particular condition. Consequently, the development of probiotics to compensate for a missing beneficial microbe(s) has advanced and become popular, especially in the treatment of irritable bowel diseases and to restore disrupted gut flora after antibiotic administration. The widespread use of probiotics is often advocated as a natural ecological therapy. However, this perception is not always accurate, as there is a potential for unexpected interactions when administering live microbial cultures. Here, we designed this research to explore the intricate interactions among probiotics, the host, and microbes through a series of experiments. Our objectives included assessing their immunomodulatory effects, response to oral medications, impact on microbial population dynamics, and mediation of antibiotic resistance. To achieve these goals, we employed diverse experimental protocols, including cell-based enzyme -linked immunosorbent assay (ELISA), antibiotic susceptibility testing, antimicrobial activity assays, computational prediction of probiotic genes responsible for antibiotic resistance, polymerase chain reaction (PCR)-based validation of predicted genes, and survival assays of probiotics in the presence of selected oral medications. Our findings highlight that more than half of the tested probiotics trigger an inflammatory response in the Caco-2 cell line, are influenced by oral medications, exhibit antibacterial activity, and possess genes encoding antimicrobial resistance. These results underscore the necessity for a reevaluation of probiotic usage and emphasize the importance of establishing regulations to govern probiotic testing, approval, and administration.