Of men in mice: the development and application of a humanized gnotobiotic mouse model for microbiome therapeutics

Considerable evidence points to the critical role of the gut microbiota in physiology and disease. The administration of live microbes as a therapeutic modality is increasingly being considered. However, key questions such as how to identify candidate microorganisms and which preclinical models are relevant to recapitulate human microbiota remain largely unanswered. The establishment of a humanized gnotobiotic mouse model through the fecal microbiota transplantation of human feces into germ-free mice provides an innovative and powerful tool to mimic the human microbial system. However, numerous considerations are required in designing such a model, as various elements, ranging from the factors pertaining to human donors to the mouse genetic background, affect how microbes colonize the gut. Thus, it is critical to match the murine context to that of human donors to provide a continuous and faithful progression of human flora in mice. This is of even greater importance when the need for accuracy and reproducibility across global research groups are taken into account. Here, we review the key factors that affect the formulation of a humanized mouse model representative of the human gut flora and propose several approaches as to how researchers can effectively design such models for clinical relevance. Gut microbiome: making a human model in mice Gut microbiota play important roles in health and disease, and now the effects of specific microbes sourced from humans can be tested in germ-free mice, which have no microbiome of their own. Many factors can affect how well the transplanted microbiome will reflect the human microbiome it is meant to mimic. Sin-Hyeog Im and John Chulhoon Park of POSTECH in South Korea have reviewed key factors that affect donor microbiomes and how well they transplant to mouse models. Diet, socioeconomic background, ethnicity, and exercise regime affect the human source microbiome. Differences in mouse and human anatomies, murine genetic and immunological backgrounds, and the conditions under which the mice are reared can affect how faithfully the transplanted microbiome reflects its human source. This review will help in designing more translatable animal models to test microbial-based therapies.