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.

Botnar Institute of Immune Engineering - BIIE has a job opening for Doctoral studentships, Molecular Mucosal Immunology Group in Zürich (published: 29.10.2025). Apply now or check the other available...

Botnar Institute of Immune Engineering - BIIE has a job opening for Postdoctoral Researcher (100%): Mechanisms of action of mucosal adjuvants in Zürich (published: 30.10.2025). Apply now or check the ...

Here, the authors apply a standardized system, called TXsystem, to transplant wild mouse gut microbiota into SPF mice, developing “TXwildlings” mice that stably retain natural microbiota and human-lik...

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal ant...

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Laboratory mice housed under specific pathogen–free (SPF) conditions are the standard model in biomedical research. However, experiments with a particular inbred mouse strain performed in different laboratories often yield inconsistent or conflicting data due to housing-specific variations in the composition and diversity of SPF microbiota. These variations affect immune and nonimmune cell functions, leading to systemic physiological changes. Consequently, microbiota-dependent inconsistencies have raised general doubts regarding the suitability of mice as model organisms. Since stability positively correlates with biological diversity, we postulate that increasing species diversity can improve microbiota stability and mouse physiology, enhancing robustness, reproducibility, and experimental validity. Similar to the generation of inbred mouse strains in the last century, we suggest a worldwide initiative to define a transplantable ‘wild’ microbiota that stably colonizes mice irrespective of housing conditions.