The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease

Abstract

Allergic disease affects millions. Despite many advances in our understanding of the immune system in the past century, the physiologic underpinning for the existence of allergy remains largely mysterious. Food allergies, in particular, have increased dramatically in recent years, adding a new sense of urgency to unraveling this mystery. The concurrence of significant lifestyle changes in Western societies with increasing disease prevalence implies a causal link. Demographic variables that influence the composition and function of the commensal microbiota early in life seem to be most important. Identifying the evolutionary and physiologic foundations of allergic disease and defining what about our modern environment is responsible for its increased incidence will provide insights critical to the development of new approaches to prevention and treatment.

Figure 1. The barrier regulation hypothesis of allergic disease

(A) In healthy individuals, both food allergen specific and bacteria-induced Tregs cooperate with ILC-derived IL-22 dependent effector functions (e.g. mucus secretion, induction of AMPs) to maintain barrier integrity and mucosal homeostasis. Allergy protective bacterial populations residing in the proximal colon may secrete metabolites or influence cellular migration from that site to regulate allergen uptake in the small intestine. (B) In food allergic subjects, the loss of these allergy protective bacterial populations impairs barrier integrity. Increased allergen contact and depletion of metabolites like SCFAs stress the epithelial layer. Both DC and ILC2 are primed by epithelial derived cytokines to induce a Th2 response and CSR to IgE, both locally and in peripheral LN.