Body surfaces and the lower intestine of mammals are colonized by vast numbers of micro-organisms. These are generally not harmful to their animal or human host as they provide the host with micronutrients, harvest energy from otherwise indigestible food, and compete with harmful (pathogenic) microbes to prevent infections. We have approximately as many microbes in our intestines as cells in our body, and cumulatively the microbes have about 100 times as many genes as we have in our own genome. The microbiota can synthesize and breakdown many more biochemicals than our own cells and many of these penetrate the body and reach different tissues via the blood. Comparisons of germ-free mice (whose intestines and body surfaces are free of live microbes) with mice that are colonized show that the microbiota directly or indirectly shape every host organ system.
Specific approach and objectives of the project
All babies start to be colonized with their microbiota very soon after birth from microbes present in their mother’s birth canal. To assess the effects of the microbiota, we have used healthy germ-free mice that are kept in special incubators free of microbial contamination. Our particular approach has been to colonise germ-free mice with specially engineered live microbes that cannot continue to live in the intestine, so after transitory colonization the animals become germ-free again. This has allowed us to determine the effects of microbiota exposure at different times during development without permanent colonization, to understand the timing of responses of the early-life animals and the cellular and molecular mechanisms involved.
Scientific outcomes
Since biochemicals from the microbiota enter a mother’s body and cross her placenta, we studied transient colonization systems during pregnancy and in pups at different times after birth. We found that maternal colonization during pregnancy affects the cellular composition and gene expression in the offspring, but microbiota exposure after birth affects which microbial molecules are targeted by antibodies and white cells (T cells). Maternal colonization during pregnancy can also shape the DNA structures (epigenetics), especially the offspring’s surface intestinal epithelial and placental cells. The sequence of colonization after birth depends more on which microbes are present and inoculate the offspring more than the effects of exposure in utero to molecules from the maternal microbiota.
Societal importance
We have studied a period in early life when cellular decisions are being made that have life-long effect on the mammal. Pregnant women need information to ensure that their baby in utero and after birth grows and develops normally, and the outcomes of this project show important biological mechanisms that shape this process.
