BACKGROUND: A causal relationship between Crohn's disease (CD) and asthma is reported, but the underlying mechanisms are not fully understood. We sought to investigate the role of IgE and IgE-mediated pathways in the pathophysiology of CD. METHODS: 20 CD patients, 10 allergic patients without inflammatory bowel disease, and 10 healthy donors (HD) were included in the study. Total serum IgE was quantified by ELISA. Circulating IgE(+) and FcepsilonRIalpha(+) immune cells, as well as specific CD4(+) T cell populations, were determined by flow cytometry. Gene set enrichment signatures from available single-cell (sc)RNAseq datasets of the intestine from CD patients were analyzed. Purified plasmacytoid dendritic cells (pDCs) from CD patients were cocultured with naive CD4(+) T cells to assess Tregs generation. RESULTS: CD patients, similar to allergic non-CD patients, displayed significantly higher numbers of circulating IgE(+) or FcepsilonRIalpha(+) immune cells than HD. The percentage of blood IgE(+) or FcepsilonRIalpha(+) pDCs was significantly higher in CD than HD and similar to allergic non-CD patients. CD patients showed significantly higher numbers of effector memory CD4(+) T cells and lower numbers of FOXP3(+) Tregs than HD. scRNAseq data from CD patients confirmed that Tregs imbalance and overactivation of IgE-mediated pathways take place also in gut tissues of children and adults, suggesting IgE could interfere in the pDC-Tregs axis. In vitro functional experiments demonstrated that IgE-crosslinking on pDCs from CD patients impairs Treg generation, which was restored by the anti-IgE mAb omalizumab. CONCLUSIONS: IgE might play an unprecedented role in CD by impairing the capacity of pDCs to generate Tregs, which could represent a novel mechanism contributing to CD to be exploited for alternative therapeutic interventions.