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Research Models
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Kourtney Nickerson, PhD

Wildling Mice: The Answer to the Translatability Problem?

What happens when we colonize laboratory mice with microbiomes from wild mice?

Just a few years ago our team received a curious email [1]. “Your lab can do unconventional things, right?” the writer inquired. “ We want to work with animals, but our facility won’t allow them here. They’re too dirty.” We were hooked.

Our team was accustomed to keeping research animals clean, so the concept of a ‘dirty’ mouse suiting a research project was intriguing. A few months earlier, a major journal published a tantalizing headline – “Laboratory mice born to wild mice have natural microbiota and model human immune responses [2] ”. Had researchers done it? Had they found the holy grail of animal models: a model that truly recapitulates the complexities of the human immune system?

The Relationship between the Microbiome and Immune System

For over a decade, the gastrointestinal microbiome, or the commensal microorganisms that reside in the gut, have been a critical focus of research. These microbes contribute to digestion, development of the immune system and protection from pathogenic microbes. Likewise, the microbiome composition is dynamic and affected by diet, stress, sleep, infection and more [3]. Despite an appreciation for the various roles these microbes hold, there is a distinct lack of knowledge regarding the precise functional role an individual microbe or microbial community plays in a model’s phenotype.

What we do know is that the commensal microbiome is essential for development of the immune system; characterization of germ-free mice reveals the presence of a significantly “weakened or underdeveloped immune system”  [4] as evidenced by the small size of the mesenteric lymph nodes and gut epithelial-associated Peyer’s patches. Further, specialized immune cells (Th17 cells) are reduced in number and others are defective in function (regulatory T cells).

If germ-free mice have a disrupted immune system, what does that mean for laboratory mice that haven’t had their immune system challenged by pathogens? For that matter, what does that mean for mice that we’ve specifically tried to keep clean from all of those pathogens over the years?

Challenges of Conventional Laboratory Mice

Clean mice share a common baseline with an untested immune system. By sharing a common environment including housing, food, light/dark cycles, and investigator interaction, they retain a relatively stable microbiome. However, composition from one facility’s room to another, or one institution to another, lends itself to variation in the community composition of these microbes, which is largely hypothesized to underscore variation and lack of study reproducibility. When the ability to reproduce experiments is lost, the value of the study is questioned.

Enter Wildling Mice

Two studies over the past few years have demonstrated the value of studying wild mice to understand the interplay between wild mice species and immune physiology relative to its laboratory counterpart. In the initial study by Rosshart et al [5] comparison of microbiomes between trapped wild mice and laboratory mice demonstrated remarkable consistency in wild microbiomes at the phylum level, with significant differences among the three major commercial laboratory animal vendors. This translates to a functional benefit when challenged with lethal pathogen infection where commercial laboratory mice succumbed, and wild mice survived.

When the microbiome from a wild mouse was transferred into a conventional mouse, immune system maturation and localization to different organs were significantly different, particularly in the spleen which is a central lymphoid organ [2]. It was important to note that not all organs had differing immune phenotypes, demonstrating that both mouse genetics and commensal microbiome contribute to the development of the total immune profile. Further, the composition of the microbiome includes viruses, fungi, and protozoa, including Helicobacter species which are frequently excluded from research animal vivaria. A third point for consideration is that no studies have been published that reproduce these findings; given commercial availability of these mice, it is curious that we have not seen practical application published elsewhere.

Advantageous to both worlds? Humanized mice or laboratory mice colonized with wild microbiome

In the fast pace world of pharmaceutical research, the path from drug discovery to functional therapeutic favors models that recapitulate the human immune response. The wilding mouse affords an opportunity to model immune system responses that may be closer to human, but with the unknown of how the microbiome contributes to shaping that immune response. This unknown lends itself to the same unpredictability for how treatments may fair in clinical trials. Other options, such as humanized mice, may provide similar benefits in closing the gap between mouse and human immune system models as the immune systems in these animals are well-characterized and targeted to human immune cells. Other strategies where a controlled microbiome might be needed could include use of germ-free mice.

Critical Lessons Learned

The microbiome continues to play a fundamental, but poorly understood, role in model homeostasis. Should an investigator anticipate the microbiome to contribute to their observations, steps to homogenize the microbiome across study animals at the beginning of the study are paramount [6] . It also doesn’t hurt to collect a few extra samples for microbiome monitoring throughout a study!

References:

1. Loosely paraphrased to protect the curious and entertain the audience

2. Rosshart et al. “Laboratory mice born to wild mice have natural microbiota and model human immune responses”. 2 Aug 2019, Vol 365 Issue 6452. DOI: 10.1126/science.aaw4361. Accessed: 22OCT2021.

3. Gonzalez R and Elena S. “The Interplay between the Host Microbiome and Pathogenic Viral Infections.” mBio 02 Nov 2021. Doi.org/10.1128/mBio.02496-21

4. Round JL and Mazmanian SK. “The gut microbiota shapes intestinal immune responses during health and disease” Nature Reviews Immunology volume 9, pages 313–323 (2009)

5. Rosshart et al. “Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance” Cell: 16 Nov 2017, 171, 1015-1028. Doi.org/10.1016/j.cell.2017.09.016

6. Ericsson AC and Franklin CL. “The gut microbiome of laboratory mice: considerations and best practices for translational research”. Mammalian Genome 32, 239-250 (2021).

Kourtney Nickerson, PhD, is a Scientist II, researching infectious agents in laboratory animals and providing scientific support for the laboratories in the Research Animal Diagnostics group. Before joining the CRL team, Dr. Nickerson researched the role of intestinal microbiota in human disease.