An association of early-life antibiotic use and altered immune ontogeny is suggested by findings in mouse models where mice exposed to antibiotics prenatally and shortly after birth had increased susceptibility to Vaccinia virus infection and altered CD8 T cell responses at 2?weeks of age (115). age. Moreover, sterile fecal waters from such at-risk infants induced a higher proportion of IL-4-secreting compared to IFN-secreting adult CD4+ cells, linking fecal metabolites to possible immune cell alterations that could play a role in increased asthma risk for these children (23). Other studies have linked particular early-life microbiota to variation in immune ontogeny later in infancy. For example, newborns colonized with express lower levels of TLR4 and TLR2 mRNA in their peripheral blood leukocytes at 1?year of age and produce lower levels of inflammatory cytokines (24). However, in another study, infants with a greater abundance of in the microbiota during infancy displayed a higher incidence of inflammatory diseases (25). As these contrasting results involve distinct human populations as well as different strains of is an exception as it provides one of the best studied examples of a human commensal driving immune ontogeny. Specifically, polysaccharide A (PSA), a sphingolipid specific to PSA in particular was shown to play a critical role in neonatal immune development, where colonization with PSA-expressing was necessary for regulatory T cell (Treg) development and invariant NKT cell inhibition in the intestinethe absence of which led to exacerbated inflammation in adulthood (28). Importantly, colonizing adult mice with failed to correct this defect (28), CUDC-907 (Fimepinostat) indicating critical early-life window of susceptibility for the microbiota to educate the immune system (5). This is again reflected on the clinical level, where differences in microbiota at 3?months of age better predict atopic outcome at 1?year than the microbiota collected at 1?year (29), and microbiota at 3?months predict milk allergy resolution at 8?years of age better than microbiota collected at 6C12?months (30). Further evidence for the existence of a critical early-life window was found when studying the effects of early-life microbial exposure on NK cell phenotypes, where conventionalization of germ-free mice at either 1?week or 3?weeks of life resulted in higher splenic IFN-expressing CD4 cells, and higher frequencies of NK and NKT cells compared to conventionally housed mice (31). Immune-regulatory genes were also underexpressed in ileal tissues of the same CUDC-907 (Fimepinostat) mice after conventionalization at 1 or 3?weeks of age (32). Clostridial species (specifically, clusters IV and XIVa) have also been shown to induce Treg accumulation in mouse colons if present during specific early-life periods. Colonizing mice with these bacteria at two weeks of age protects them from colitis in adulthood and lowers their systemic IgE levels (33). On the other hand, exposure to segmented filamentous bacteria (SFB) in early life of mice is uniquely able to induce large numbers of Th17?cells (34) using a mechanism dependent on their adherence to the intestinal epithelium (35). Through induction of Th17?cells, SFB were also shown to exacerbate autoimmune arthritis in colonized germ-free mice (36). While the role of SFB, or similar bacteria in the neonatal period has yet to be defined, one survey of SFB abundance across IL2RA species and ages found SFB to colonize humans by 2?years of age, but could no longer be CUDC-907 (Fimepinostat) found after the third year of life suggesting a possible early-life restricted colonization for these bacteria in humans (37). While much of the necessary detailed knowledge is still amiss, current data clearly support the notion that perturbations of microbiota in the early-life imprint the host immune phenotype for a long time (maybe lifetime) and can manifest as immune-mediated disease later in life. We here extract overarching themes of how pre-, peri-, as well as early postnatal environmental modulators of newborn microbiota associated with changes in immune ontogeny that predispose to disease; given the little data there are on this topic, we focus on those disease states for which existing data suggest this to be a plausible if not reasonable connection. In doing so, CUDC-907 (Fimepinostat) we also begin to CUDC-907 (Fimepinostat) delineate the windows of opportunity, knowledge of which should help guide to target research efforts into mechanisms and interventions. The goal of this review then is to highlight the potential harm as well as.