Laboratory mice born to wild mice have natural microbiota and model human immune responses

Abstract

Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating “wildlings.” These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.

Pneumonia recovery reprograms the alveolar macrophage pool

“…Lung protection depends on an immunological tone that microbial exposures establish (3). This dictates outcomes for subsequent infections and is as important as or more important than species or genome when using animal models to study human health and disease (7)(8)(9). Lymphocytes become long-term residents in the lung after resolution of respiratory infection, including resident memory T (Trm) cells, Brm cells, and others, helping improve pulmonary defense (3,(10)(11)(12).…”

Housing laboratory mice deficient for Nod2 and Atg16l1 in a natural environment uncovers genetic and environmental contributions to immune variation

“…This unsupervised visualization strategy was useful for identifying unexpected differences (e.g. in the CD19+ compartment and other populations not investigated by (Beura et al, 2016; Rosshart et al, 2019; Rosshart et al, 2017)) in cell clusters of the peripheral blood at a single cell level, which might have been overlooked by traditional flow cytometry gating.…”

“…Recently, there has been a growing effort to characterize wild mice and pet shop mice, which appear to share greater similarity to the immunological state of humans than laboratory mice (Abolins et al, 2017; Beura et al, 2016; Rosshart et al, 2019; Rosshart et al, 2017). We have developed an outdoor enclosure facility that enables us to reintroduce laboratory mice into a more natural environment, a process termed “rewilding” (Leung et al, 2018).…”

Herpes Simplex Virus Infection, Acyclovir and IVIG Treatment All Independently Cause Gut Dysbiosis

“…These tantalizing results warrant independent validation and further detailed studies using a murine autologous BMT model to more rigorously evaluate the impact of long-term ACV prophylaxis on GVHD and engraftment, because results from such studies might eventually lead to improved outcomes for HSCT patients. Ideally, such future studies should be performed with mice harboring wild microbiota, because several recent reports show that immune responses in mice with wild microbiomes model human immune responses more closely than conventional mice with SPF microbiota [74-76].…”