The embryo is considered sterile and readily colonized upon birth by environmental microorganisms. Exposure to a diverse microbiota during early life is particularly important for a proper education of the immune system and to avoid developing allergies - the central feature of the hygiene hypothesis. Colonization later in life does not suffice to achieve a full immune maturation. Thus, the concept of a “window of opportunity” early in life was coined, but the underlying molecular factors remained unknown.

A project published in Nature lead by Marcus Fulde of the Berlin University and Mathias Hornef of the RWTH University Hospital Aachen and in collaboration with Felix Sommer and Philip Rosenstiel of the IKMB (Kiel University) together with Fredrik Bäckhed of Gothenburg University and researchers of the Hannover Medical School and Georgia State University uncovered that in mice the TLR5 signaling pathway of intestinal epithelial cells shapes the composition of the gut microbiota and that this selective capability is restricted to the first two weeks of life.

The researchers started off by comparing the expression profiles of intestinal epithelial cells isolated from newborn and older mice and found that newborn mice express high levels of TLR5 whereas expression diminishes sharply starting at 21 days after birth. Using in vitro experiments, they further showed that TLR5 selects against bacteria that carry flagellin, the principal ligand of TLR5 and the main component of bacterial flagella. Mice lacking TLR5 in intestinal epithelial cells harbored an altered microbiota with an expansion of flagellated bacteria. Importantly, when the researchers transplanted the different microbiota of TLR5-deficient and wild-type mice onto neonatal or adult germ-free mice, which are devoid of any microorganisms, they demonstrated that only neonatal wild-type recipient mice could shape the flora upon transfer, whereas adult mice or those lacking TLR5 failed. Together this data therefore demonstrates that TLR5 in neonates drives homeostatic selection of the intestinal microbiota. Thus, this study reports the first molecular pathway contributing to the “window of opportunity” during early development.

The article Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition has been published online in Nature on August 8th.