The Influence of the Microbiome on Allergic Sensitization to Food

Abstract

The alarming increase in the incidence and severity of food allergies has coincided with lifestyle changes in Western societies, such as dietary modifications and increased antibiotic use. These demographic shifts have profoundly altered the coevolved relationship between host and microbiota, depleting bacterial populations critical for the maintenance of mucosal homeostasis. There is increasing evidence that the dysbiosis associated with sensitization to food fails to stimulate protective tolerogenic pathways, leading to the development of the type 2 immune responses that characterize allergic disease. Defining the role of beneficial allergy-protective members of the microbiota in the regulation of tolerance to food has exciting potential for new interventions to treat dietary allergies by modulation of the microbiota.

Figure 1. Induction of tolerance to food and bacterial antigens in the intestine

Food antigen is taken up by dendritic cells (DCs) in the small intestine which migrate to the proximal mesenteric lymph node (mLN). TGF-β and retinoic acid produced by LN stromal cells and DCs induce differentiation of food antigen specific Tregs (fTregs) and upregulation of gut homing molecules. fTregs migrate back to the small intestine lamina propria where TLR signaling by bacterial products induces production of IL-10 by resident CX3CR1 macrophages and DCs that supports Treg expansion and IL-10 production. Bacterial products are also taken up by colonic DCs that migrate to the distal mLN and caudal LN to induce differentiation of bacterial specific Tregs (bTreg). Although predominant in the colon, bTregs also migrate to the small intestine where they release IL-10 to maintain the tolerogenic immune environment. Fermentation of dietary fiber to short chain fatty acids (SCFAs) may enhance retinoic acid production by DCs and promote Treg differentiation. TLR signaling by bacterial products such as LPS induces a tolerogenic phenotype in colonic and small intestinal DCs that promotes differentiation of Tregs.

Figure 2. The microbiota regulates both protective and pathogenic barrier responses in the intestine

A) A healthy microbiota will induce a barrier protective response in the intestine, in part, through production of SCFAs that are most likely to act on ILC3s to produce IL-22. IL-22 induces antimicrobial peptide (AMP) production by Paneth cells and mucus production by goblet cells to reinforce barrier function, controlling the location and composition of the microbiota. This barrier protective function prevents uncontrolled access to the lamina propria by food antigens to prevent allergic sensitization. B) Dysbiosis fails to induce these protective pathways. Dysregulated epithelial barrier function and a compromised mucus layer allow increased permeability to food antigens. Damaged or stressed epithelial cells release the alarmins IL-25, IL-33 and TSLP that activate ILC2s to produce IL-4 and IL-13 which promotes the development of allergic sensitization to food antigens through the generation of food antigen specific Th2 cells (fTh2).