Pregnancy as a perturbation principle of the intestinal microbiota: impact on intestinal inflammation and inflammation-associated cancer

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Pregnancy is an important transient physiological state that has been shown to cause dysbiotic alterations in the intestinal microbiota, which may exert local pro-inflammatory effects in the third trimester. This may contribute to metabolic alterations such as insulin resistance, which in turn might be favourable for fetal development. The mechanism how a maternal host is in control of pregnancy-associated changes in the microbiome is only poorly understood. Dysbiotic gut microbiota and lack of their resilience capacity are also established features of human IBD that often manifests in younger individuals, and as such affects females most often in their reproductive span of life. Several studies have shown a complex impact of pregnancies on the individual disease course, e.g. pregnant women with ulcerative colitis (UC) as compared to nonpregnant UC women are more likely to relapse both during pregnancy and postpartum. We here hypothesize that the microbial alterations and/or the host physiological response to microbiota shifts may contribute to the modulation of disease course and that understanding altered host-microbe interplay during and after pregnancy may help to identify novel therapeutic principles aiming at the intestinal microbiome as a target.Thus, we here ask the fundamental question how changes of composition and metabolic properties of luminal and mucosa-associated microbiota are controlled during pregnancy. We hypothesize that context-dependent signals act on the function of intestinal epithelial cells, which specifically select for the microbe shifts observed in pregnancy. (i) We will functionally relate these shifts to susceptibility to intestinal inflammation (e.g. acute vs. chronic DSS colitis, oxazolone colitis and the TNFdeltaARE genetic model) as well as inflammation-induced (AOM/DSS) cancer in WT mice. (ii) In a second step, we will use mice carrying intestinal epithelial cell (IEC)-specific knockouts of IBD susceptibility genes (NOD2, Atg16L1) to study the effects of such genes on pregnancy-related host and microbial dysbiosis and rebiosis processes. (iii) A human IBD – pregnancy cohort will be recruited and analyzed as validation of mouse model findings. Detailed patient data (inflammatory clinical parameters, disease activity, serum levels of micronutrients and pregnancy/gestation related information) will be correlated to acquired microbial data and frozen stool specimen will be used in gnotobiotic transfer experiments in order to identify whether the observed effects are transmissible. We hypothesize that understanding the alteration of ecological niches throughout pregnancy might guide us to therapeutically accessible targets for intestinal inflammatory diseases. Furthermore, insights into the modification of the pro-inflammatory tone and microbiota of the mucosa during and after pregnancy may help to improve the management of female IBD patients as a future perspective.