Pharmacomicrobiomics in Space: Understanding the interplay between microgravity, drug processing, and the gut microbiome for sustainable space exploration

Spaceflight presents a major challenge for safe and effective pharmacotherapy as missions extend to the Moon and Mars. Physiological changes including fluid redistribution, altered gastrointestinal transit, modified hepatic metabolism, and immune dysregulation directly affect drug absorption, distribution, and clearance. In parallel, the gut microbiome is reshaped by microgravity, radiation, controlled diet, confinement, and stress. These processes are usually considered independently. However, pharmacomicrobiomics, the study of bidirectional interactions between drugs and the gut microbiome, highlights their interdependence: gut microbes activate prodrugs, regenerate conjugated metabolites, influence hepatic biotransformation, and are themselves perturbed by many medications, including non-antibiotics. This review examines the drug–microbiome–host triad under spaceflight conditions. It outlines the roles of the gut microbiome in terrestrial pharmacology and synthesizes evidence for spaceflight-induced changes in drug disposition and microbial composition and function. It evaluates microbiome interactions with medications currently used on the International Space Station and those likely to be included in exploration-class formularies. Potential countermeasures such as prebiotics, postbiotics, and stability-adapted probiotics are discussed in the context of operational constraints for long-duration missions. A central limitation emerges: no study has yet measured drug exposure and gut microbiome composition concurrently in the same crewmembers under a protocol designed to link them. Although in-flight pharmacokinetic sampling and microbiome profiling have each been demonstrated, they have never been integrated. Addressing this gap requires longitudinal in-flight and analogue studies combining pharmacokinetics, metagenomics, systematic medication tracking, and dedicated pharmacovigilance frameworks. Such approaches may also translate to vulnerable terrestrial populations, including hospitalized, immunocompromised, and frail patients.