Functional analysis of gut microbiome-host interactions during the postnatal window of opportunity by a multiscale sequencing approach

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Microbial colonization of the neonate gut is a dynamic process that contributes to the establishment of intestinal immunity and tolerance. Failure to reach a homeostatic host-microbial crosstalk during this time window influences the susceptibility to inflammatory, autoimmune, and metabolic diseases throughout life. Although this critical role of the postnatal period has been recognized, knowledge about underlying mechanisms is still scant. Here we join our expertise in microbiome research, phage biology and genomics, intestinal epithelium biology in neonates, and mucosal immunology to determine microbial colonization dynamics in the neonatal gut and the impact on innate and adaptive immune imprinting in mice. We propose a functional approach where colonization patterns and causal effects on the host are studied in gnotobiotic mice reconstituted with defined minimal consortia of cultured bacterial species. Particular emphasis is on characterizing (i) differential features of the neonatal and adult microbiota, and (ii) the effect of flagellated bacteria as part of the microbiota providing a dominant immunogenic antigen and innate immune stimulus. Lytic flagellotropic phages will be studied and use for precise manipulation of bacterial communities. In a multiscale sequencing approach including meta-transcriptomic and phageome analysis of microbiome colonization dynamics, single-cell (sc) RNAseq for tissue maturation and differentiation of intestinal epithelial cell (IEC) lineages, and lymphocyte receptor sequencing, we will provide novel insights into the functional importance of microbial colonization in early life.