Commensal Microbiota Regulates IgE Production in Response to Food Antigens

IgE is one of the key modulators in the pathogenesis of allergy by inducing FcR-mediated activation of mast cells and basophils. Production of IgE is regulated by commensal microbiota, as it is normally undetectable in conventional SPF mice, but highly elevated in microbiota-deprived mice such as germ-free mice and antibiotics-treated mice. The mechanism of IgE production in microbiota-deprived mice is poorly understood, but could be a consequence of dysregulated immune responses to exogenous antigens, especially food antigens. To address this idea, germ-free mouse pups were weaned into an antigen-free elemental diet comprised of essential amino acids, vitamins and minerals. Interestingly, neither these mice nor their offspring, designated as antigen-free mice, possessed very low levels of serum IgE compared to germ-free mice. Moreover, feeding adult germ-free mice with antigen-free diet showed no increase of serum IgE compared to mice with normal solid diet. Reversely, antigen-free mice weaned onto normal solid food diet produced high levels of IgE within a few weeks.  The results seen in antigen-free mice study indicate that IgE is elevated in response to food antigens in the absence of commensal microbes. Due to the importance of CD4 T cells responding to exogenous antigens, CD4 T cells in germ-free mice were analyzed and GATA3-expressing and IL-4 or IL-13-producing T helper (Th) 2 cells were increased in germ-free mice compared to SPF mice. To determine the role of Th2 cells for IgE production in germ-free mice, CD4 T cells were depleted using CD4-depleting antibody. This led to a reduction in IgE production in germ-free mice. Furthermore, IgE was highly elevated in OT-II cells transferred germ-free and antigen-free mice after feeding them with ovalbumin, not in SPF mice. This indicates that food antigen-specific-CD4 T cells and food antigen induced IgE production in microbiota-deprived condition. These results suggest that a perturbation of commensal microbiota can affect the incidence of allergic diseases by inducing the generation of Th2 cells and the production of IgE in response to food antigens.