"In spaceflight biology and aerospace medicine, understanding microbial responses to spaceflight is essential for supporting astronaut health and enabling sustainable life beyond Earth. The rodent habitat on the International Space Station has provided crucial insights into how spaceflight affects mammals, including symptoms characteristic of liver disease, insulin resistance, osteopenia and myopathy. While these responses involve the microbiome on Earth, the specific effects of spaceflight on host-gut microbiome interactions remain unclear. Here, NASA GeneLab multiomic data from the Rodent Research-6 mission were used to determine changes in gut microbiota and host colon and liver gene expression after 29 and 56 days of spaceflight. Using amplicon and whole metagenome sequencing analysis, significant spaceflight-associated alterations in 44 microbiome species were identified. These included relative reductions of bacteria associated with bile acid and butyrate metabolism, such as Extibacter muris and Dysosmobacter welbionis. Functional prediction suggested over-representation of fatty acid and bile acid metabolism, extracellular matrix interactions, and antibiotic resistance genes within the gut microbiome, while host intestinal and hepatic gene expression reflected corresponding changes in bile acid and energy metabolism, and immune suppression from spaceflight. Taken together, these changes imply that interactions at the host-gut microbiome interface contribute to spaceflight pathology and highlight how these interactions might critically influence human health and the feasibility of long-duration spaceflight. Ireland’s expertise in microbiome science, multiomics and translational research offers a valuable contribution to this growing field. Spaceflight microbiology provides a platform to apply and extend these capabilities, with benefits for both exploration and life on Earth."