Dissecting the human gut microbiome to better decipher drug liability: A once-forgotten organ takes center stage

BACKGROUND: The gut microbiome is a diverse system within the gastrointestinal tract composed of trillions of microorganisms (gut microbiota), along with their genomes. Accumulated evidence has revealed the significance of the gut microbiome in human health and disease. Due to its ability to alter drug/xenobiotic pharmacokinetics and therapeutic outcomes, this once-forgotten “metabolic organ” is receiving increasing attention. In parallel with the growing microbiome-driven studies, traditional analytical techniques and technologies have also evolved, allowing researchers to gain a deeper understanding of the functional and mechanistic effects of gut microbiome. AIM OF REVIEW: From a drug development perspective, microbial drug metabolism is becoming increasingly critical as new modalities (e.g., degradation peptides) with potential microbial metabolism implications emerge. The pharmaceutical industry thus has a pressing need to stay up-to-date with, and continue pursuing, research efforts investigating clinical impact of the gut microbiome on drug actions whilst integrating advances in analytical technology and gut microbiome models. Our review aims to practically address this need by comprehensively introducing the latest innovations in microbial drug metabolism research— including strengths and limitations, to aid in mechanistically dissecting the impact of the gut microbiome on drug metabolism and therapeutic impact, and to develop informed strategies to address microbiome-related drug liability and minimize clinical risk. KEY SCIENTIFIC CONCEPTS OF REVIEW: We present comprehensive mechanisms and co-contributing factors by which the gut microbiome influences drug therapeutic outcomes. We highlight in vitro, in vivo, and in silico models for elucidating the mechanistic role and clinical impact of the gut microbiome on drugs in combination with high-throughput, functionally oriented, and physiologically relevant techniques. Integrating pharmaceutical knowledge and insight, we provide practical suggestions to pharmaceutical scientists for when, why, how, and what is next in microbial studies for improved drug efficacy and safety, and ultimately, support precision medicine formulation for personalized and efficacious therapies.