The microbial origins of food allergy

Abstract

Food allergy (FA) is a significant public health issue, propelled by its rapidly increasing prevalence. Its sharp rise into prominence has focused attention on causative environmental factors and their interplay with the immune system in disease pathogenesis. In that regard, there is now substantial evidence that alterations in the gut microbiome early in life imprint the host gut mucosal immunity and may play a critical role in precipitating FA. These changes may impact key steps in the development of the infant gut microbiome, including its shaping by maternal factors and upon the introduction of solid food (the weaning reaction). These early-life changes may have long-range effects on host immunity that manifest later in time as disease pathology. Experimental studies have shown that resetting the host intestinal immune responses by treatment with either a healthy fecal microbiota transplantation or defined commensal bacterial taxa can prevent or treat FA. The mechanisms by which these interventions suppress FA include restoration of gut immune regulatory checkpoints, notably the retinoic orphan receptor gamma T⁺ regulatory T cells, the epithelial barrier, and healthy immunoglobulin A responses to the gut commensals. These findings inform human studies currently in progress that evaluate the role of microbial therapies in FA.

Keywords: Food allergy; IgA; IgE; RORγt(+) Treg; dysbiosis; fecal microbiota transplantation; microbiome; microbiota; regulatory T cells.

Figure 1.. Maternal, Dietary, and Microbial factors shape early life oral tolerance.

Schematic representations of post-natal changes in the gut microbiome and the mucosal interface. After birth, the infant gut microbiota is shaped by Immunoglobulin A and other immunological components present in the mother’s milk. Transition to a solid food diet (weaning) expands the diversity of gut microbiota composition with an expansion of Clostridales species. Induction of Tgfb1 in Treg cells by commensals drives the differentiation of long-lived ROR-γt⁺ Treg cells that regulate tolerance to gut content, including bacteria and dietary antigens. Ag: antigen; APC: antigen presenting cells; EC: epithelial cells; EGF: epidermal growth factor; GAPs: goblet cell-associated antigen passages; GC: goblet cells; TLR: toll-like receptors.

Figure 2.. Microbial regulation of oral immune tolerance to food and its breakdown in FA.

Dysbiosis caused by aberrant insults to the gut microbiota early in life impairs the differentiation of ROR-γt⁺ Treg cells. Breakdown in the development of oral tolerance is associated with dysregulated anti-microbial antibody responses to gut commensals that is characterized by a decreased IgA binding and an increased IgE binding to the gut microbiota. Anti-food antigen T follicular helper cell (Tfh) responses develop that promote the generation of high affinity anaphylactic IgE.