One of the main challenges of microbiome work, is difficulty when comparing experimental results due to "batch effects" or "legacy effects." This challenge is seen by researchers in different labs, who despite using same exact breed of mice with the same genetic background still observe significant differences in the microbiome. Moreover, the microbiome varies greatly from individual to individual and is largely determined by the microbiome of the source animal, diet, and environment. Previous research suggests that the source animal's genetics has some impact on the microbial composition of recipients. Therefore, researchers set out to use germ-free mice to learn how polymorphic host genes shape the intestinal microbial communities of recipients.
The research team used germ-free mice from UChicago's gnotobiotic (germ-free) mouse facility. They transferred microbes from one conventionally raised mouse to many genetically identical mice. These mice were bred they don't have any bacteria in their bodies or digestive tracts from birth to provide a blank slate to see what happens when they're colonized with bacteria. Researchers repeated these steps many times in mice with similar backgrounds ad others with slight differences in their immune system.
The differences occurred in the histocompatibility locus (MHC), which determines adaptive immunity. The adaptive immune system "learns" as it encounters different pathogens and uses T cells and B cells to target pathogenic antigens. The MHC binds antigens so T cells can recognize them as "self" or "non-self."
The results from sequencing the genome of the microbiome from recipient mice revealed that adaptive immunity had some effect on certain strains of bacteria, but overall the effects were not dramatic. In some cases, bacteria even took advantage of the adaptive immune response to thrive. Instead, the majority of the differences they saw could be attributed to innate polymorphic genes, or different variations of genes in the MHC.
"Manipulation of the adaptive system leads to some changes, but to our surprise, they were not dramatic," said Alexander Chervonsky, MD, PhD, a senior author of the study. "The vast majority of the mechanisms that determine differences in the outcome are those which are polymorphic but not part of the adaptive immune response."
The researchers hope that this work will help standardize microbiome studies. By using standard tools like germ-free mice to control experiments, researchers can build upon previous work instead of conducting one-off, standalone experiments.
"There are standards in many different types of research, but they're almost non-existent in microbiome research," said Tatyana Golovkina, PhD, co-senior author of the study. "We're trying to set up a standard of analysis for these questions about how to compare differences in microbial composition."
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