Role of genetics, environment, and their interactions in the pathogenesis of eosinophilic esophagitis

Abstract

The rise in incidence and prevalence of eosinophilic esophagitis (EoE) since the 1990s has prompted investigations into its pathogenesis, natural history, and management. Identified genetic variants in FLG, DSG1, CAPN14, SPINK5, and SPINK7 link EoE to epithelial barrier dysfunction, whereas variants in CCL26, POSTN, and TSLP associate EoE with T helper type 2-mediated immunity. Early-life, infectious, and geographic factors have been implicated in promoting esophageal microbial dysbiosis and, subsequently, T helper type 2 immune responses. However, research into environmental factors and their interactions with genetic variants are not as developed as their genetic counterparts. Further research into the subgroups and epigenetics of EoE will likely promote further understanding.

Figure 1.. Genetic and environmental components involved in the pathogenesis of EoE.

Our current understanding of the pathogenesis of EoE involves multiple pathways for epithelial barrier dysfunction and Th2-mediated immune responses. IL-13 downregulates DSG1 and FLG while upregulating CAPN14, which subsequently downregulates DSG1, while SPINK7 dysregulation has been found to be sufficient for epithelial barrier dysfunction as well. IL-13 also induces CCL26 (eosinophil chemotaxis), POSTN (eosinophil adherence), and TSLP (dendritic cell chemotaxis). Multiple environmental factors (absence of furred pet, preterm labor, cesarean delivery, antibiotics in infancy) are hypothesized to lead to microbial dysbiosis and Th2-mediated immunity; however, temporal associations are difficult to prove, and it remains unclear if the observed microbial dysbiosis in the esophagi of patients with EoE is causing or due to the disease. PPI’s are strongly associated with EoE; however, this association suffers from protopathic bias.

Figure 2.. Present Knowledge and Future Directions

Twin studies have shown that the heritability of EoE is a complex issue raising evidence for both genetic and environmental influence. While few studies have examined the interaction between identified genetic variants and environmental factors, further studies are needed. Likewise, epigenetics has the potential to explain gene-environment interactions, identify further risk factors, and advance development of novel therapeutics; however, studies to date are scarce.