Laboratory mice housed under specific pathogen-free conditions are the standard model in biomedical research. However, frequent germ-free rederivation and barrier housing restrict microbial exposure and interactions with commensal and pathogenic microorganisms. In contrast, wild mice encounter diverse microbial environments, undergo natural selection, and rely on robust immune responses for survival. Consequently, lifelong microbial exposure is a key driver in shaping mammalian physiology, establishing the need for naturalizing rodent models in biomedical research. By defining the concepts of ‘microbial self’ and ‘microbial nonself’, we propose a four-step guide for establishing a multigenerational wildling colony that accounts for both microbial self and microbial nonself. This reestablishes the common biological link shared by all free-living mammals, thereby improving the comparability between murine and human studies.
