Project Details
Projekt
Pregnancy as a perturbation principle of the intestinal microbiota: impact on intestinal inflammation and inflammation-associated cancer
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426660215
Pregnancy is accompanied by physiological changes in the intestinal microbiota. How the maternal "host" exerts control in this process and what function the change has on the immune system, e.g. in the context of tolerance induction to the semiallogenic fetus, is poorly understood. Studies in IBD patients have shown a complex influence of pregnancy on individual disease progression, with over 30% of patients experiencing an inflammatory episode in the months following childbirth. We are pursuing the hypothesis that these microbial changes contribute to the altered disease course by acting on specific immune cell populations. We have shown in mice, that increased abundance of neutrophil-type myeloid suppressor cells (PMN-MDSC), which persists into lactation, is dependent on the presence of microbial influences. Similarly, we demonstrated that the absence of functional autophagy (due to ablation of ATG16L1 in myeloid cells) similarly leads to increased abundance of PMN-MDSCs and spontaneous inflammation. While the suppressive functions of MDSCs normally dampen immune responses, in IBD recent data suggest that PMN-MDSCs can promote tissue damage and impede the resolution of inflammation. In the present project, we aim to investigate the influence of microbiota-dependent metabolites on the induction and function of PMN-MDSCs in germ-free and conventional mice. 1) We will characterize MDSC cell populations in different tissue compartments functionally and via single cell sequencing in detail. In in vitro models, we will determine how exactly pregnancy-induced microbiota shifts and associated metabolites contribute to the expansion of PMN-MDSCs. In intestinal inflammatory models, we will investigate how these changes relate to increased susceptibility in mice post partum. (2) We will study the functional impact of myeloid ablation of the ATG16L1 risk gene on the development of MDSCs and on pregnancy-induced dysbiosis and re-biosis processes. (3) We will study changes in metabolic networks of the intestinal microbiota in the locally established pregnancy cohort (controls and IBD patients). Here, we will focus on human-associated taxa that may influence MDSC maturation and function. Selected hypotheses from this cohort will be tested by gnotobiotic transfer experiments. A deeper understanding of the complex role of PMN-MDSC in IBD holds promise for the development of targeted therapies to restore immune homeostasis. In addition, insights into pro-inflammatory regulatory networks related to the gut microbiota as markers may help improve the management of IBD patients during and after pregnancy.
DFG Programme
Research Units
