Case Study

GM15

A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF/SPF phenotypes.

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Background

The gut microbiome plays a major role in animal and human health, and may influence the development of diseases, as well as the host response to drugs. Thus, there is a need for reproducible animal models with standardized gut microbiota for the study of drug-host-microbiota interactions.

Challenges

Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice result in several limitations:

  1. Reproducibility and robustness of preclinical studies are affected by the confounding effect of fluctuation in microbiota composition
  2. Understanding mechanisms through which gut microbiota takes part in health, and through which dysbiosis contributes to disease is limited
  3. Moving from correlation to causal links in the host–microbiome field remains a challenge

In this context, BIOASTER undertook the ambitious project to generate a standardized gnotobiotic mouse model with a representative mouse gut microbial consortium.

Solution

BIOASTER developed and validated in collaboration with academic partners a simplified mouse gut microbiota and its related gnotobiotic mouse model.

In this project, we implemented and combined several technologies in order to:

  1. Identify a representative and simplified microbial consortium by in silico design
  2. Isolate defined bacterial strains from the feces or the caecum of C57BL/6J specific and opportunistic pathogen-free mice
  3. Colonize germ-free mice with the GM15 consortium on a stable and long-term basis, and in two different animal facilities
  4. Monitor with a rapid and sensitive assay the microbiota composition
  5. Characterize the macroscopic, immune, endocrine and metabolic phenotypic profile of the GM15 mouse model and compare it to the
    SOPF standard
  6. Assess the impact of post-weaning malnutrition on host physiological response

Results

Taken together, our results establish that the GM15 mouse model offers the potential to ensure an increased reproducibility and robustness of preclinical studies in the host- microbiome field.

  1. The GM15 consortium recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome
  2. The GM15 bacterial strains colonize C57BL/6J germ-free mice with long-term stability over generations on open source diets and reproducibility across facilities
  3. The GM15 mouse model with its simplified mouse gut microbiota proved to be able to restore many phenotypical traits of SOPF or SPF mice in two different animal facilities
  4. GM15 mice are also less sensitive to the deleterious effects of post-weaning malnutrition than SOPF or SPF mice

Outlook

The GM15 mouse model will benefit the scientific and industrial community by providing in vivo experimental evidence sustaining the causal link between a given microbiota and health or disease.
In addition, the GM15 model offers exciting perspectives for preclinical research focusing on drug-host-microbes interactions to evaluate antimicrobial resistance and the impact of drugs on commensals and on the intestinal barrier function. Finally, the GM15 model with its simplified gut microbiota also offers the possibility to use it as a template for establishing customized and further complex consortia to investigate specific biological questions.

Additional information

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