Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility

Becca V Baby,Morgan L Waide,Joshua E Denny,Nejat K Egilmez,Rabindra K Mandal,Charles D Anderson,Neal Bhutiani,Nathan W Schmidt,Qingsheng Li,Venkatakrishna R Jala

doi:10.1186/s12915-020-00810-7

Abstract

BackgroundExperimental reproducibility in mouse models is impacted by both genetics and environment. The generation of reproducible data is critical for the biomedical enterprise and has become a major concern for the scientific community and funding agencies alike. Among the factors that impact reproducibility in experimental mouse models is the variable composition of the microbiota in mice supplied by different commercial vendors. Less attention has been paid to how the microbiota of mice supplied by a particular vendor might change over time.ResultsIn the course of conducting a series of experiments in a mouse model of malaria, we observed a profound and lasting change in the severity of malaria in mice infected with Plasmodium yoelii; while for several years mice obtained from a specific production suite of a specific commercial vendor were able to clear the parasites effectively in a relatively short time, mice subsequently shipped from the same unit suffered much more severe disease. Gut microbiota analysis of frozen cecal samples identified a distinct and lasting shift in bacteria populations that coincided with the altered response of the later shipments of mice to infection with malaria parasites. Germ-free mice colonized with cecal microbiota from mice within the same production suite before and after this change followed by Plasmodium infection provided a direct demonstration that the change in gut microbiota profoundly impacted the severity of malaria. Moreover, spatial changes in gut microbiota composition were also shown to alter the acute bacterial burden following Salmonella infection, and tumor burden in a lung tumorigenesis model.ConclusionThese changes in gut bacteria may have impacted the experimental reproducibility of diverse research groups and highlight the need for both laboratory animal providers and researchers to collaborate in determining the methods and criteria needed to stabilize the gut microbiota of animal breeding colonies and research cohorts, and to develop a microbiota solution to increase experimental rigor and reproducibility.

Highlights

Experimental reproducibility in mouse models is impacted by both genetics and environment
We demonstrate that a marked change in gut bacteria occurred within a defined vendor production suite that impacted experimental reproducibility in two infectious disease models and a murine tumorigenesis model
Change in the severity of malaria within Taconic mice correlates with shift in gut bacteria populations In an effort to avoid variation in gut microbiota, our laboratory has ordered C57BL/6NTac mice from Taconic Biosciences from the production room Isolated Barrier UnitTM (IBU)15 located at the Germantown, New York facility

Summary

Introduction

Experimental reproducibility in mouse models is impacted by both genetics and environment. Among the factors that impact reproducibility in experimental mouse models is the variable composition of the microbiota in mice supplied by different commercial vendors. The self-correcting nature of science is a virtue, recent years have experienced a growing awareness and concern across diverse scientific disciplines that published studies are not always reproducible [1, 2]. A Nature survey of 1576 scientists identified that 70% of researchers have failed to reproduce a published result [2]. There is a growing recognition that mouse studies that fail to control for differences in murine gut microbiota are factors that impact reproducibility of mouse studies [7,8,9]

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