Mouse models for human intestinal microbiota research: a critical evaluation

Abstract

Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between intestinal microbiota in mice and humans need to be considered. This is done here with specific attention for the comparative physiology of the intestinal tract, the effect of dietary patterns and differences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the human and murine intestine, these differ strongly in abundance and in total only 4% of the bacterial genes are found to share considerable identity. Moreover, a large variety of murine strains is available yet most of the microbiota research is performed in wild-type, inbred strains and their transgenic derivatives. It has become increasingly clear that the providers, rearing facilities and the genetic background of these mice have a significant impact on the microbial composition and this is illustrated with recent experimental data. This may affect the reproducibility of mouse microbiota studies and their conclusions. Hence, future studies should take these into account to truly show the effect of diet, genotype or environmental factors on the microbial composition.

Keywords: Diet; Metagenome; Microbiome; Murine models; Phylogeny; Reproducibility.

Fig. 1

A simplified family tree of the main mouse strains used in intestinal microbiota research. Solid lines indicate inbreeding and dotted lines indicated outbreeding of a mouse line. When lines are connected a cross or a new line was created by selection. Data adapted from [20, 21]

Fig. 2

Comparison of the intestinal tract features of human and mouse. The main similarities and differences are listed in a Venn diagram [–39]

Fig. 3

Major different human and murine intestinal genera. Only genera are shown that showed consistent differences in relative abundance between humans and mice [73, 74, 76]

Fig. 4

Redundancy analysis of the large intestine samples of seven studies, containing a total of 244 samples [, –100]. Genotype, facility and provider are taken along as variables for the analysis and explain 43.5% of the data. Colors 1–7 are per cohort, black triangles indicate the centers of the different mouse genotype variables and pink triangles indicate the centers of providers and facilities variables. Here the level of clustering per cohort is less than on probe level (Supplementary Fig. S1) and the facility Wageningen University and different providers (Supplementary Fig. S2A) explain a significant proportion of the data over the effect of the strain C57BL/6J (Supplementary Fig. S2B), which comes fourth in percentage that it can explain as a variable in the data. In Table 1 are the significant variables shown