Rewilding Nod2 and Atg16l1 Mutant Mice Uncovers Genetic and Environmental Contributions to Microbial Responses and Immune Cell Composition

Lin, Jian; Devlin, Joseph C.; Yeung, Frank; McCauley, Caroline; Leung, Jacqueline M.; Chen, Ying Han; Cronkite, Alex; Hansen, Christina; Drake-Dunn, Charlotte; Ruggles, Kelly V.; Cadwell, Ken; Graham, Andrea L.; Loke, P’ng

doi:10.1016/j.chom.2020.03.001

Cited by 70 publications

(80 citation statements)

References 39 publications

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“…Similar upregulation of memory T cells has been reported in feral and pet-store mice, in lab mice co-housed with pet-store mice and in rewilded mice (Beura et al, 2016;Abolins et al, 2017;Lin et al, 2020). Following ex vivo stimulation, we found that T-cells in feralized and feral mice responded more potently with IFN-gamma production compared to lab mice, similar to previous reports in feral and rewilded mice (Abolins et al, 2017;Lin et al, 2020).…”

Section: Discussionsupporting

confidence: 90%

“…However, in all the studies mentioned above, lab mice remained in conventional cages, with limitations of space and behavioral opportunities relative to a wild house mouse lifestyle. A recently described model where mice were kept in large outdoor enclosures, showed altered microbiota, a shift toward Th1-type immunity and an increased susceptibility to helminth infection ( Leung et al, 2018 ; Lin et al, 2020 ; Yeung et al, 2020 ). While offering a habitat clearly representing wild conditions, this setup allows limited surveillance of the animals and may prove inaccessible for most researchers.…”

Section: Introductionmentioning

confidence: 99%

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A Model System for Feralizing Laboratory Mice in Large Farmyard-Like Pens

et al. 2021

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Laboratory mice are typically housed under extremely clean laboratory conditions, far removed from the natural lifestyle of a free-living mouse. There is a risk that this isolation from real-life conditions may lead to poor translatability and misinterpretation of results. We and others have shown that feral mice as well as laboratory mice exposed to naturalistic environments harbor a more diverse gut microbiota and display an activated immunological phenotype compared to hygienic laboratory mice. We here describe a naturalistic indoors housing system for mice, representing a farmyard-type habitat typical for house mice. Large open pens were installed with soil and domestic animal feces, creating a highly diverse microbial environment and providing space and complexity allowing for natural behavior. Laboratory C57BL/6 mice were co-housed in this system together with wild-caught feral mice, included as a source of murine microbionts. We found that mice feralized in this manner displayed a gut microbiota structure similar to their feral cohabitants, such as higher relative content of Firmicutes and enrichment of Proteobacteria. Furthermore, the immunophenotype of feralized mice approached that of feral mice, with elevated levels of memory T-cells and late-stage NK cells compared to laboratory-housed control mice, indicating antigenic experience and immune training. The dietary elements presented in the mouse pens could only moderately explain changes in microbial colonization, and none of the immunological changes. In conclusion, this system enables various types of studies using genetically controlled mice on the background of adaptation to a high diversity microbial environment and a lifestyle natural for the species.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

A Model System for Feralizing Laboratory Mice in Large Farmyard-Like Pens

et al. 2021

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“…The need for capturing wild mice and performing embryo transfers into pseudopregnant females can make this model somewhat more complex than others, but the fact that the natural microbiota are stable over numerous generations suggests commensal transfer from wild mother to wildling offspring is sufficient to obtain a phenotypically and functionally more mature immune system. In a related model, Graham and colleagues ( 24) simply transferred laboratory mice to an outdoor enclosure that exposed the mice to soil, vegetation, and weather in a more natural habitat (25,26). These "rewilded" mice showed maturation/differentiation of the T cell compartment, increases in circulating granulocytes, and alterations in gut microbiota similar to what has been observed in other dirty mouse models.…”

Section: Models Of Microbially Experienced Dirty Micementioning

confidence: 95%

New Insights into the Immune System Using Dirty Mice

Hamilton

Badovinac

Beura

et al. 2020

The Journal of Immunology

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The mouse (Mus musculus) is the dominant organism used to investigate the mechanisms behind complex immunological responses because of their genetic similarity to humans and our ability to manipulate those genetics to understand downstream function. Indeed, our knowledge of immune system development, response to infection, and ways to therapeutically manipulate the immune response to combat disease were, in large part, delineated in the mouse. Despite the power of mouse-based immunology research, the translational efficacy of many new therapies from mouse to human is far from ideal. Recent data have highlighted how the naive, neonate-like immune system of specific pathogen–free mice differs dramatically in composition and function to mice living under barrier-free conditions (i.e., “dirty” mice). In this review, we discuss major findings to date and challenges faced when using dirty mice and specific areas of immunology research that may benefit from using animals with robust and varied microbial exposure.

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“…The fact that approximately 35% of genes in E. coli , perhaps the best studied organism in the lab, have no known function ( Ghatak et al, 2019 ) is certainly not due to lack of effort, but speaks to the difficulty of understanding organisms in isolation. The function of genes that are recalcitrant to mutational knockout analysis in the laboratory can be revealed under their natural biotic conditions ( Barbaric et al, 2007 ; Chanin et al, 2019 ; Cruz et al, 2016 ; Hutchison et al, 2016 ; Lin et al, 2020 ; Richter et al, 2009 ; Ruff et al, 2015 ). It stands to reason that the full elucidation of gene function, regulatory architecture and developmental robustness will require investigation in an organism’s natural environment.…”

Section: Does It Matter?mentioning

confidence: 99%