Impact of the maternal microbiota on the prenatal development of the immune system

The immune system is primed by the maternal microbiota early in life, beginning already before birth.

Interactions with a diverse microbiota program the developing immune system to tolerate commensal microbes and to repel pathogens. Insufficient microbial exposure predisposes the offspring to immunopathologies like allergy, asthma and inflammatory bowel disease. Concurrently, the newborn is vulnerable to pathogen infections.

We aim to identify mediators and mechanisms delivering safe microbial exposure to the developing immune system. Recent research by our laboratory and others indicate that the priming can be mediated by microbial metabolites and macromolecules, but the exact compounds and physiological mechanisms involved are mostly unknown.

To discover novel immunomodulatory microbial metabolites, we will utilize our recent metabolomics and transcriptomics data comparing fetal tissues from germ-free and normal mice. We will identify biologically active compounds which are shared across mammalian species and dissect their physiological roles using a mouse model and efficient in vitro reporter systems for immunological activation. We collaborate with metabolomics experts in the University of Eastern Finland and the University of Turku.

Extracellular vesicles (EVs) generated by the maternal microbiota may deliver microbial macromolecules to the fetus without risk of infection by intact cells. We are developing reagents and methods enabling the first specific studies of EVs produced by commensal bacteria: their biodistribution, cargo and physiological effects. Our research is supported by the EV Core Facility at the University of Helsinki, and we collaborate with EV researchers in the University of Oulu.

We are also collaborating with virologists in order to probe the potential effects of the virome in healthy pregnancies, by utilizing deep sequencing and advanced data analysis pipelines enabling the detection of previously unknown viruses.

In addition to in vitro and murine models, we investigate the early host-microbe interactions in large mammals living in naturally diverse microbiological environments. This is essential in the extrapolation of the murine studies of fetal immune system development to humans, as in mice the maturation occurs largely after birth, and the microbial exposures of laboratory animals are narrow. Here, we have active ongoing collaborations with production animal researchers at University of Helsinki, Estonian University of Life Sciences, and Ghent University.

The research will help curb the high mortality of young production animals in intestinal infections, and sheds light on the origins of pathological breakdown of immunological tolerance also in the human gut. Importantly, the immunomodulatory molecules identified in the project may be used to prevent or treat immunopathologies across species. We collaborate with human early microbiota researchers, neonatologists, animal producers and private companies developing and producing animal feeds and feed additives.

The research project recently received funding from the Academy of Finland, with top scores from the international evaluation panel. “This is a very relevant research topic with high societal, health and medical impact.”