Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, here we report the development of a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and the derivation of a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. In this work, we show that the GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers opportunities for research focused on how the microbiota shapes host physiology in health and disease.

25 26 Mus musculus is the classic mammalian model for biomedical research. Despite global efforts 27 in standardizing breeding and experimental procedures, the undefined nature and inter-28 individual diversity of laboratory mouse microbiota remains a limitation. In an attempt to 29 standardize preclinical studies, we have developed a simplified mouse microbiota composed 30 of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal 31 microbiota found in specific opportunistic-and pathogen-free (SOPF) C57BL/6J animals and 32 derived a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively 33 the functionalities found in C57BL/6J SOPF microbiota metagenome and GM15 animals are 34 phenotypically similar to SOPF. They even perform better in a model of post-weaning 35 malnutrition. The GM15 model ensures an increased reproducibility and robustness of 36 preclinical studies by limiting the confounding effect of microbiota composition fluctuation and 37 offers new possibilities for research focusing on how the microbiota shapes host physiology in 38 health and diseases. 39 40