Laboratory mice engrafted with natural gut microbiota possess a wildling-like phenotype

Conventional laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, in the past years, many published results involving rodents have been considered irreproducible, raising concerns about the suitability of mice as model organisms. Emerging evidence indicates that variations in SPF microbiota contribute significantly to data variability across different laboratories. Despite efforts to standardize the microbiota, current microbial consortia lack the complexity and resilience needed to replicate interactions in free-living mammals. We present a standardizable and feasible approach for transplanting natural gut microbiota from wildlings into conventional laboratory mice. After engraftment, these TXwildlings adopt a structural and functional wildling-like microbiota and host physiology toward a more mature immune system, with characteristics similar to those of adult humans. We anticipate that using wild mouse-derived microbiota as standard for laboratory mouse models will improve the reproducibility and generalizability of basic and preclinical biomedical research.