A Case for Antibiotic Perturbation of the Microbiota Leading to Allergy Development

Lisa A Reynolds; B Brett Finlay

Disclosures

Expert Rev Clin Immunol. 2013;9(11):1019-1030. 

In This Article

Antibiotic Disruption Later in Life

Antibiotic treatment in adult mice has also been linked to exacerbations in allergic disease severity. When adult mice (at least 8 weeks old) are treated with a broad-spectrum cocktail of antibiotics, including ampicillin, gentamicin, metronidazole, neomycin and vancomycin for 4 weeks, serum levels of IgE are elevated, along with circulating basophil numbers.[31] IgE appears to regulate basophil numbers in the blood; administration of IgE to Rag1−/- mice (which lack B and T cells) elevates circulating basophil frequencies, and correlations are seen between serum IgE levels and circulating basophil frequencies in human patients with hyperimmunoglobulinemia E syndrome.[31] Antibiotic cocktail treatment also results in increased disease severity to two allergens: after intranasal exposure to extract from the house dust mite Dermatophagoides pteronyssinus, antibiotic cocktail-treated mice had greater eosinophilia in BALF and lungs, increased alveolar infiltrates and exaggerated Th2 responses in their mediastinal lymph nodes compared with untreated mice.[31] Additionally, following footpad injection of the cysteine protease papain, antibiotic cocktail- treated mice developed amplified Th2 responses in their popliteal lymph nodes,[31] suggesting that the exaggerated allergic responses following this antibiotic treatment regime are not limited to mucosal surfaces.

Following broad-spectrum antibiotic treatment of adult mice, increased trafficking of non-invasive bacteria to the mesenteric lymph nodes by CX3CR1hi mononuclear phagocytes is seen, suggesting that under normal conditions, the microbiota function to inhibit the migration of these cells.[59] This may be a mechanism by which increased sensitivity to dietary antigens occurs after antibiotic administration, and it will be important for future work to directly test whether this is the case.

Similar to the broad-spectrum antibiotic treated animals, mice lacking MyD88 expression only on B cells also exhibit high serum IgE and basophil levels.[31] Together, these data suggest that signals from the microbiota, mediated by MyD88 on B cells, limit IgE production in adult mice. After broad-spectrum treatment to drastically reduce intestinal bacteria numbers, the inhibition of IgE is reduced, and exaggerated allergic responses ensue. Whether the effects of antibiotic treatment in adults on allergic disease development are persistent after antibiotic administration is stopped, as they appear to be after early-life antibiotic treatment,[58] or are limited to the period of antibiotic exposure, perhaps by enhancing susceptibility to infections, has yet to be explored (Figure 2).

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