Molecular analysis of duodenal eosinophilia

Abstract

Eosinophilic duodenitis (EoD), characterized by nonspecific gastrointestinal symptoms and increased numbers of duodenal eosinophils, may be in the eosinophilic gastrointestinal disease spectrum. However, diagnostic thresholds and pathogenic processes of duodenal tissue eosinophilia are inadequately characterized. We aimed to define an EoD transcriptome and pathologic pathways. RNA sequencing and histologic features of human duodenal biopsy samples were analyzed as a function of duodenal eosinophils levels. For analyses, we defined EoD as more than 52 peak eosinophils/hpf (n= 8), duodenal eosinophilia as 30 to 52 eosinophils/hpf (n= 11), and normal controls as fewer than 30 eosinophils/hpf (n= 8). Associations between gene expression and histologic features were analyzed with Spearman correlation. We identified 382 differentially expressed genes (EoD transcriptome) between EoD and normal controls (>2-fold change [adjusted P< .05]). The EoD transcriptome distinguished EoD from controls (duodenal eosinophilia and normal controls). The duodenal eosinophil count was correlated with a distinct EoD transcriptome when 50 to 60 peak eosinophils/hpf were present. The EoD transcriptome was enriched in genes involved in IL-4/IL-13 signaling, mast cells, and myeloid progenitor cells. Among duodenal histologic features, lamina propria eosinophil sheets was the most associated with transcriptomic changes (r= 0.66; P< .01). EoD gene signatures were shared with eosinophilic esophagitis and eosinophilic gastritis but not with eosinophilic colitis or celiac disease. We have identified an EoD transcriptomic signature that emerges at 50 to 60 peak eosinophils/hpf and established EoD as part of a spectrum of upper eosinophilic gastrointestinal disorder associated with type 2 immunity and distinct from eosinophilic colitis and celiac disease. These findings provide a basis for improving diagnosis and treatment.