Early Life Microbiota, Neonatal Immune Maturation and Hematopoiesis

Emerging epidemiologic data supports the hypothesis that early life colonization is a key player in development of a balanced immune system. Events in early life, as birth mode and infant diet, are shown to influence development of immune related diseases, like asthma, diabetes and inflammatory bowl disease, later in life. The intestinal epithelium makes up a physical and biochemical barrier between the bacteria in the gut lumen and the immune cells in the submocusal tissue. This monolayer of intestinal epithelial cells (IEC) makes up an extremely large surface and is highly important for the synergistic coexistence between trillions of bacteria in the gastrointestinal tract and their mammalian hosts. The IEC actively communicate with the microbiota of the gut lumen and tolerance establishment in the intestine is induced as a result of a balanced and controlled communication between IEC and the commensals in the gut. Hematopoietic stem cells from the fetal liver seed the fetal spleen and bone marrow in perinatal phase. Granulocytosis in neonate mice and man just after birth is a natural event of early life hematopoiesis and likely contributes to elevated counts of neutrophil-like cells in the peripheral blood of newborns. Granular myeloid derived suppressor cells (MDSC) have recently been described in human cord blood. MDSC are potential immunosuppressive cells often described in cancer, inflammation and during sepsis. They evolve from immature myeloid cells during hematopoiesis. Several recent studies show a role for various myeloid derived and immune suppressive cellular subsets in the newborn. In the present work we showed the presence of a prominent group of CD11bGr-1 cells in the neonate murine spleen. The presence of these cells were dependent on the colonizing microbiota, as germfree neonate mice held notably fewer of these cells in the spleen. Microscopy of spleens and livers indicated that these cells derived from hematopoietic tissue in the liver of the neonate mouse, and that mobilization and activation of the hematopoietic tissue is promoted by the presence of colonizing microbes. The regulation of epithelial barrier integrity was influenced by the nature of the microbiota, as expression of tight junction (TJ) protein encoding genes showed a faster and more tightly regulated rate in the murine ileum of conventionally colonized mice compared to the GF ileum. The conventional microbiota furthermore promotes the expression of genes involved in mucin secretion, TLR signaling pathways and cytokine production in the intestine, while downregulating genes encoding chemokines in the epithelial tissue. Newly published studies indicate that the prominent CD11bGr-1 cell group may have a role in early life immune regulation. This is however not proven by the data of present study.