Interestingly, intestinal colonization with SFB has been observed in humans within the first two years of life, at the time of maturation of the immune system, and this SFB community disappears by the age of 3 years [74]. Some information on the molecular mechanisms by which commensals regulate systemic immunity has been provided by studies in mice that indicate a requirement of the gut microbiota for the initiation of immunity against respiratory virus

infection [21, 25]. In these studies, oral antibiotics treatment Napabucasin was shown to impair the ability of the animals to limit influenza virus replication by reducing the constitutive expression of the pro-IL-1β and pro-IL-18 genes, as well as limiting the ability of immune cells to produce and to respond to IFN [21, 25]. In one of the studies, either pulmonary or systemic administration of TLR ligands rescued the anti-influenza immune response in antibiotic-treated mice [25]. Another study demonstrated the role of IFN responsiveness in the microbiota signal-driven priming of natural killer (NK) cells by nonmucosal myeloid cells [20]. In this study, it was shown that in GF or antibiotic-treated mice, there was a reduced association of histone H3K4me3 around the transcriptional start sites of inflammatory genes, such as Ifnb1, Il6, and Tnf [20]. Treatment of GF mice with TLR ligands failed to induce, in myeloid cells, transcription of these genes and the

recruitment of IRF3 and NF-κB as well as PolII to the their promoter region [20]. These data suggest that signals from Rucaparib molecular weight the microbiota are required in conventionally raised animals to maintain inflammatory genes in a transcriptionally (-)-p-Bromotetramisole Oxalate poised epigenetic configuration. The commensal microbiota has also been shown to induce the expression of cytokines and other biologically active molecules capable of affecting the systemic immune response. In one study, the colonization

of GF mice resulted in the upregulation, in the gut, of cytokines known to influence both the innate and adaptive arms of the immune response, including IL-1, IL-18, IFN-γ, TNF, IL-10, components of complement, serum amyloid A protein [39]. Although there is not yet any direct experimental evidence, it is reasonable to assume that cytokines and other biologically active molecules produced in the gut may diffuse and systemically affect the immune response. Serum amyloid A protein expression has been shown to depend on MyD88-mediated signaling from gut microbiota, and to affect the migratory activity and recruitment of neutrophils to systemic sites [76, 77]. On the other hand, Candida, which can inhabit the gut during antibiotic treatment, has been shown to modulate the immune system via the induction of PGE2, which favors M2 macrophage polarization in the lung, and this subsequently enhances allergic responses, but dampens the protective immune response to respiratory viruses [41].