The new data, published in Cell Reports, shows that the genetics that lay the foundation for our immune system may have an important impact on the way bacteria colonise gut ecosystems.
In carefully controlled experiments the team used germ-free mice (mice born with no microbiome) populated with microbes from conventionally raised mice to reveal that while the makeup of the microbial input ‘largely determined’ the resulting microbiome of the recipients, genetic differences between strains of mice played a role as well.
Led by Alexander Chervonsky and Tatyana Golovkina from the University of Chicago, the team said the findings of the study underscore the importance of using genetically identical germ-free mic, and have implications for researchers focusing on the microbiome – with Golovkina noting that she hopes the work will set an example for how to standardise microbiome studies.
"There are standards in many different types of research, but they're almost non-existent in microbiome research," she said. "We're trying to set up a standard of analysis for these questions about how to compare differences in microbial composition."
The microbiome conundrum
The team noted that one of the challenges facing microbiome researchers is that it can be difficult to compare the results of experiments due to ‘batch effects’ or ‘legacy effects.’
This is because when scientists transfer microbes from one mouse to another, the result is largely determined by the microbiome of the source animal, including what kind of food they eat, where they live, and such, they noted – adding that even if researchers in two different labs use the exact same breed of mice with the same genetic backgrounds, they will see two different pictures when they analyse the microbiome of the recipients.
"Input defines the output," Chervonsky commented.
"When the input is standardised, you can compare mice of different genetic strains and see what these genetics do to the microbiome in recipient mice," he explained. "This approach allowed us to tell whether there was a genetic influence, and indeed there is.”
“So, the next question was what mechanisms are involved?"
Genetic variation
Chervonsky and Golovkina transferred microbes from one conventionally raised mouse to many genetically identical mice from UChicago's gnotobiotic (germ-free) mouse facility. These mice are specially bred so 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 colonised with bacteria.
The team repeated these steps many times, transferring microbes from one source mouse to many recipients – some with similar genetic backgrounds and some with slight differences in their immune systems.
Some of the mice used in the experiments were congenic, or genetically identical except for differences in part of the genome called the major histocompatibility locus (MHC), which determines adaptive immunity.
The Chicago-based team analysed the microbiomes of recipient mice and their offspring to compare the effects of these different immune system genes, finding that that while adaptive immunity had some effect on certain strains of bacteria, overall the effects were not dramatic.
In some cases, bacteria even took advantage of the adaptive immune response to thrive, they said.
The majority of differences were found to be linked to different forms of genes relating to the innate immune system 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," Chervonsky said.
"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."
Both innate (anti-microbial peptides, complement, pentraxins, and enzymes affecting microbial survival) and adaptive (MHC-dependent and MHC-independent) pathways were found to influence the microbiota, the team added – noting that each genetic difference was related to benefits for distinct strains of bacteria.
“Overall, it can be concluded that genetic backgrounds shape input microbial repertoires in their own idiosyncratic fashion,” concluded the team. “However, we find it remarkable that the host-determined polymorphic influences on microbial composition are limited in scope and target only select microbial lineages.”
“That implies that total control over the enormous body of microorganisms by the host immunity is unlikely (probably due to its extremely high cost) and that both non-polymorphic control mechanisms and other natural forces could be involved,” they said.
Source: Cell Reports
Volume 29, Issue 3, Pages 541-550, doi: 10.1016/j.celrep.2019.09.010
“Polymorphic Immune Mechanisms Regulate Commensal Repertoire”
Authors: Aly A. Khan, et al