Escherichia coli-induced gut IL-33 release inhibits lung type 2 allergic responses

BackgroundThe incidence of lung allergies is reduced in countries with higher prevalence of infection and environmental exposure to microbes. However, enteric bacterial infections do not always correlate with lower incidence of allergic disorders and how lung immunity to allergens can be regulated by gut exposure to pathogens and their toxins is not fully understood. ObjectiveWe used mouse models of enterotoxigenic Escherichia coli (ETEC) infection and lung allergy to examine how gut exposure to bacteria, or their related toxins, affects allergic lung inflammation. MethodsNaive C57BL/6 mice were infected with enterotoxigenic Escherichia coli (ETEC) or orally treated with the ETEC LT toxin, to mimic enteric bacterial infections. After two weeks, these mice were treated intranasally with Ovalbumin (OVA) and Papain or IL-33, followed by challenge with OVA, to induce allergic lung inflammation that was assessed using multiple readouts. ResultsGut exposure to ETEC significantly inhibited allergic lung inflammation in a LT-dependent manner, as demonstrated by reduced tissue inflammation, less accumulation of type 2 cytokines, and reduced lung numbers of type 2 immune cells such as type 2 innate lymphoid cells (ILC2) and eosinophils. The anti-allergic capacity of LT was associated with reduced ability of lung ILC2s to recognize IL-33. Counterintuitively, deletion of either IL-33 or ILC2s significantly reverted the LT protective effect, suggesting the LT-mediated protection may occur through gut release and local sensing of IL-33. ConclusionsExposure to ETEC protects hosts against allergic lung inflammation through a negative feedback loop regulated by gut IL-33 release and sensing, suggesting a possible new immunological mechanism for reduced lung allergy incidence observed in areas with enteric bacterial infections. Key Messages- Enteric exposure to enterotoxigenic E. coli (ETEC) bacteria or its toxin LT significantly protects hosts against lung type 2 allergic inflammation. - ETEC and LT downregulate the capacity of lung ILC2s to respond to allergen-induced IL-33. - Deletion of IL-33 or ILC2s significantly impairs the protective effect of ETEC and LT, suggesting the presence of a negative feedback loop driven by toxin-induced gut IL-33 release.