To further evaluate the influence of antibiotics on allergy

To further evaluate the influence of IC261 on allergy, Russel et al. initiated vancomycin treatment during pregnancy in mice and continued it for several weeks after birth. This resulted in exaggerated OVA-induced allergic inflammation, characterized by higher numbers of lung eosinophils, elevated concentration of serum OVA-specific IgE, and increased airway hyper-responsiveness and total pathology score. By contrast, treatment of adult mice did not confer this effect [89]. In a follow-up study from this group, the authors observed that perinatal but not prenatal exposure to antibiotics recapitulated this phenomenon, indicating that antibiotic exposure from birth until weaning was crucial in this model. Also, the authors found a positive correlation between antibiotic treatment and the increase in IgE titers in serum and IgE expression on basophils, and an inverse correlation with the numbers of Tregs, offering plausible mechanisms that could explain the role of vancomycin in the exacerbation of allergic inflammation [90]. Finally, Hill et al. showed that antibiotic treatment of adult mice (using a mix of ampicillin, gentamicin, metronidazole, neomycin, and vancomycin) resulted in exaggerated Th2-mediated responses in a papain model of allergic airway inflammation. Interestingly, IgE levels directly correlated with the increase in circulating basophils. MyD88 expression in B cells was important to limit IgE titers and maintain low levels of circulating basophils, indicating a causality behind this correlation. Importantly, depletion of basophils with the use of α-FcεRI antibodies resulted in the reduced frequency and numbers of Th2 cells, underlining the importance of basophils in driving the allergic inflammation [91]. Overall, these data, together with the work of Russell et al. [90], point to the possible role of antibiotic administration in the induction of IgE secretion and the subsequent increase in basophil frequency, which contribute to the exaggerated allergic response [91]. In contrast to the studies described above, a handful of reports indicated the ability of antibiotics belonging to the macrolide class to attenuate allergic airway inflammation. In a study by Beigelman and colleagues, azithromycin administration initiated after sensitization to OVA inhibited inflammatory cell recruitment into the airways, mucus cell metaplasia, and production of Th2 cytokines. Interestingly, azithromycin treatment initiated 1h after the last challenge conferred similar protection, underlying the potential use of this antibiotic as a therapeutic for asthma [92]. Properties similar to azithromycin were described for clarithromycin [93] and roxithromycin [94]. The results from these studies match observations made in some clinical trials evaluating macrolide therapy for asthma treatment [95–97]. However, its clinical efficacy is controversial and some recent systematic reviews and meta-analyses point to a lack of sufficient evidence to support this hypothesis [98,99]. Finally, a study using a broad-spectrum antibiotic, enrofloxacin, showed its potential to attenuate trinitrophenyl chloride-induced contact sensitivity (CS). Enrofloxacin-treated mice developed less pronounced disease, which correlated with the increase in Clostridium coccoides, Clostridum coccoides–Eubacterium rectal, Bacteroidetes, and Bifidobacterium spp. and with the induction of regulatory subsets of cells, including Tregs, regulatory B cells, and IL-10-producing γδ T cells. Administration of microbiota from antibiotic-treated donors into naïve recipients partially recapitulated CS suppression. Similarly, reconstitution of antibiotic-treated mice with microbiota from untreated animals rendered them susceptible to CS [100]. It remains to be investigated whether administration of C. coccoides and/or C. coccoides–E. rectal may have therapeutic potential in this model. Given the ability of Clostridium spp. to induce Tregs [22], this appears to be a plausible scenario. Additionally, further delineation of Bacteroidetes and Bifidobacterium spp. contributing to the observed effect in this model will be of interest. Defining molecular pathways triggered by these beneficial bacteria is the next challenge to undertake.