The complexity of integrating microbiota into clinical pharmacology, environmental toxicology, and opioid studies arises from bidirectional and multiscale interactions between humans and their many microbiota, notably those of the gut. Hosts and each microbiota are governed by distinct central dogmas, with genetics influencing transcriptomics, proteomics, and metabolomics. Each microbiota's metabolome differentially modulates its own and the host's multi‐omics. Exogenous compounds (e.g., drugs and toxins), often affect host multi‐omics differently than microbiota multi‐omics, shifting the balance between drug efficacy and toxicity. The complexity of the host‐microbiota connection has been informed by current methods of in vitro bacterial cultures and in vivo mouse models, but they fail to elucidate mechanistic details. Together, in vitro organ‐on‐chip microphysiological models, multi‐omics, and in silico computational models have the potential to supplement the established methods to help clinical pharmacologists and environmental toxicologists unravel the myriad of connections between the gut microbiota and host health and disease.