In the confines of the animal room, lab mice reared for research encounter few microbes. While this safeguards against random infections and improves experimental reproducibility, the artificially sterile environment on its own may have effects on the mice. Now, scientists led by Barbara Rehermann of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, report in the October 19 Cell online that transplanting intestinal flora from wild mice into the guts of their lab cousins bolsters the latter’s response to viral infection and cancer. The results suggest that rounding out the microbiomes of lab mice could make them more resilient. It could also make disease models scientists use to study neurodegenerative diseases more representative of real-world conditions.
“Recent years have seen the increasing realization that gut microbiota can influence a wide range of host immune and homeostatic processes,” wrote Malu Tansey, Madelyn Houser, and Andrew Neish at Emory University in Atlanta (see full comment below). Laboratory mice are kept in sterile environments, and mice with minimal gut microbiota, or even germ-free mice, increasingly have been touted as necessary controls, they noted. “However, this work by [first author Stephan] Rosshart and colleagues vividly illustrates a limitation of this trend,” they added.
Robert Friedland, University of Louisville School of Medicine in Kentucky, said the present study could have implications for neurodegenerative disease. “Researchers of Alzheimer’s and related disorders who use animal models should consider the possible role gut bacteria play in their animal systems,” he told Alzforum. “The nature of these bacteria is critical for the development, maturation, and education of the immune system, which is involved in diseases such as cancer, Alzheimer’s, Parkinson’s, and ALS.”
Rehermann, along with Rosshart and colleagues, suspected that since lab mice lack a complete set of symbiotic microbes, they miss out on the immune-boosting and inflammation-reducing capabilities of mice in the wild (Feng and Elson, 2011). To explore this hypothesis, Rosshart and colleagues transplanted the gut microbiota of wild mice into lab-dwelling cousins and observed the response to infection and cancer.
The scientists went into horse barns in Maryland, trapped 100 house mice, and determined that they were close genetic relatives of the inbred C57BL/6 lab strain. They analyzed the wild mouse gut microbiomes, which, while similar among the wild mice, were more diverse than the microbiome of C57BL/6. Next, the scientists engrafted bacteria from three of these wild mice into C57BL/6 mice specifically raised to be germ-free; these mice have no microbiome. The researchers examined how the wild microbiome recipients (WildR) responded to intranasal infection with the influenza virus, and compared them to germ-free C57BL/6 controls that received the microbiome of a lab littermate (LabR).
Seventeen percent of LabR mice survived 11 days after viral infection, whereas 92 percent of the WildR mice did. The latter had 10-fold fewer viruses in their lungs, as well as less bronchitis and cell death. Their lungs harbored fewer inflammatory cells and pro-inflammatory cytokines, but their anti-inflammatory cytokines were elevated compared to LabR mice. Likewise, if the researchers induced colorectal cancer by injecting a mutagen and encouraging an inflammatory response, the wild microbiome led to fewer tumors, which spread more slowly than in mice that received the lab animal microbiome.
Together, the results suggest wild gut microbiota protects lab mice against flu, cancer, and inflammation. Previous studies suggested that intestinal flora was important in these responses, because depleting the already limited microbiome of lab animals makes them more susceptible to infections and cancer (Abt et al., 2012; Zackular et al., 2016).
The authors hypothesize that microbes, which co-evolved with their hosts, help fight against pathogens and mutagens in the environment. Perhaps introducing a complete microbiome in the gastrointestinal tract, lung, skin, and vagina could improve responses and make more representative disease models, they suggested.
Other research suggests that microglia need a healthy microbiome to function optimally in the brain, that the microbiome changes with ongoing neurodegenerative disease, and that it may exacerbate pathology in animal models (see June 2015 news; December 2016 news; April 2017 news). Given our growing appreciation for the role of neuroinflammation in different neurodegenerative diseases, it will be essential to understand both the mechanisms that are common and those that are specific to each, noted Mike Sasner, The Jackson Laboratory, Bar Harbor, Maine.
Sasner cautioned that improved fitness due to a more natural microbiota could be beneficial or detrimental. “The typical lab mouse model of colitis-induced tumorigenesis may be more useful for some experimental applications than the wild-mouse microbiome-reconstituted model that gets far fewer tumors,” he wrote (see full comment below). Nonetheless, Sasner thinks more attention should be paid to the choice and health status of experimental models. “We need to work toward using multiple complementary model systems that take into account not only disease-related genetic variants but also genetic and epigenetic context and environmental and health/microbiome status.”
Rosshart SP, Vassallo BG, Angeletti D, de Villen FP, Yewdell JW, Rehermann B. Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171, 1–13, November 16, 2017
Feng T, Elson CO. Adaptive immunity in the host-microbiota dialog. Mucosal Immunol. 2011 Jan;4(1):15-21. Epub 2010 Oct 13 PubMed.
Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, Wherry EJ, Artis D. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012 Jul 27;37(1):158-70. Epub 2012 Jun 14 PubMed.
Zackular JP, Baxter NT, Chen GY, Schloss PD. Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis. mSphere. 2016 Jan-Feb;1(1) Epub 2015 Nov 4 PubMed.
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