Integrating natural commensals and pathogens into preclinical mouse models

Abstract

Fundamental discoveries in many aspects of mammalian physiology have been made using laboratory mice as research models. These studies have been facilitated by the genetic tractability and inbreeding of such mice, the large set of immunological reagents that are available, and the establishment of environmentally controlled, high-throughput facilities. Such facilities typically include barriers to keep the mouse colonies free of pathogens and the frequent re-derivation of the mice severely limits their commensal flora. Because humans have co-evolved with microorganisms and are exposed to a variety of pathogens, a growing community of researchers posits that preclinical disease research can be improved by studying mice in the context of the microbiota and pathogens that they would encounter in the natural world. Here, we provide a perspective of how these different approaches can be combined and integrated to improve existing mouse models to enhance our understanding of disease mechanisms and develop new therapies for humans. We also propose that the term 'mice with natural microbiota' is more appropriate for describing these models than existing terms such as 'dirty mice'.

Fig. 1 |. Use of mouse models with natural microbiota in translational research.

Questions and hypotheses derived from observations of humans, mice and other mammals in the complex natural environment are translated into clinical research studies and/or into laboratory studies in research facilities. Mouse models that include microorganisms and pathogens from the natural world are used both for basic research and for translational research on specific diseases. These studies benefit from the full range of classic research tools and the established reductionist models, including standard specific-pathogen-free laboratory mice. Such approaches may facilitate studies on disease pathogenesis and help to identify new targets for intervention. Finally, mouse models with complex, natural microbiota can be used for preclinical drug testing as such mice have an increased ability to model human responses.