SEARCHCROSS-SECTIONALgastroenterology, allergy/immunology

cross-sectional·gastroenterology, allergy/immunology, pediatrics, pathology·PMC10050742

Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches

Frontiers in Immunology · 15 authors, 8 centres

AI SUMMARY

FIDELITY 100%

POPULATIONFrench children with EoE (n=17) and control subjects with GERD/abdominal pain/dysphagia (n=15); median age 10.9 years (EoE) vs 7.7 years (controls)

INTERVENTIONMulti-omics profiling (transcriptomics, flow cytometry, cytokine/chemokine panels, untargeted metabolomics) of oesophageal biopsies and blood

COMPARISONChildren with EoE (>15 eosinophils/HPF) vs control subjects (<15 eosinophils/HPF)

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This study used multi-omics approaches (transcriptomics, immunology, metabolomics) to characterize eosinophilic esophagitis (EoE) in 17 French children compared to 15 controls. The authors confirmed that EoE involves dysregulation beyond type 2 immunity, including epithelial barrier dysfunction and altered vitamin B6 and amino acid metabolism. As a proof of concept, combining plasma metabolomics and cytokine data yielded a potential non-invasive biomarker panel for EoE diagnosis, though validation in larger cohorts is needed.

Full summary

3,743 CHARS

**Background:** Eosinophilic oesophagitis (EoE) is a chronic food allergic disorder limited to the oesophageal mucosa. Its pathogenesis is incompletely understood, and diagnosis/monitoring require repeated endoscopies due to the lack of validated non-invasive biomarkers. The authors aimed to comprehensively describe local immunological and molecular components of EoE in well-phenotyped children and identify potential circulating biomarkers.

**Methods:** Blood and oesophageal biopsies were collected simultaneously from 17 French children with EoE (median age 10.9 years, 70.6% male) and 15 control subjects (median age 7.7 years, 80% male). Untargeted transcriptomics (Agilent 8x60K microarrays) was performed on biopsy mRNA. Comprehensive immune analysis of biopsies and blood used flow cytometry (40 cell subtypes in blood, 14 in biopsies) and multiplex assays (79 detectable cytokines/chemokines in plasma, 46 in biopsy supernatants). Untargeted plasma metabolomics used LC-HRMS with C18 and HILIC columns, annotating 125 metabolites. Uni/multivariate analyses (PCA, PLS-DA, Mann-Whitney) identified significant discriminant components. Multi-block integration (DIABLO) combined transcriptomics, cytokines, immunoglobulins, and metabolomics data from 10 EoE and 10 control subjects with clear transcriptomic signatures.

**Key Results:** The EoE transcriptomic signature in French children strongly correlated with that previously reported in US patients (ρ=0.93). Among 24 evaluable biopsies (after excluding 4 outliers), 4,767 genes were differentially expressed (8.3% of 57,409 genes/lncRNAs). Top upregulated genes included TNFAIP6, CCL26 (eotaxin-3), ALOX15, POSTN, and CPA3. Top downregulated genes involved epithelial barrier function (SPINK6/7/8, SFTA2, EPGN, TGM3, SLURP1, ENDOU, MUC22, MUC21). GSEA identified 19 significantly enriched pathways, and IPA identified 90 enriched canonical pathways, predominantly immune-related. In biopsies, children with EoE had higher ILC counts, ILC2 frequency, activated ILC1 (IFNγ+), IgE, MMP1, MMP2, and multiple cytokines/chemokines (IFNβ, IFNγ, IL-10, IL-16, IL-26, IL-32, pentraxin-3, CCL24, CCL26, CCL1, CCL13, CCL22, CXCL1, CXCL2, CXCL6, CXCL12). In plasma, EoE patients had higher total IgE and CXCL12, and lower IgG1, CXCL8, CXCL9, CXCL16, CCL15, CCL19, IL-17A, IL-28A, LIGHT, and sTNFR1. Untargeted metabolomics in patients not on PPI (9 EoE, 8 controls) yielded a highly predictive model (R²Ycum=0.905, R²Xcum=0.333, AUC=1, 100% sensitivity and specificity). Significantly elevated metabolites in EoE included pyridoxic acid, pyridoxine, methionine/S-ethyl-L-cysteine/D-penicillamine, N-acetyl-DL-tryptophan, L-homoserine/threonine, and thymine. Multi-block integration showed strong correlation between local DE genes and plasma metabolites (ρ=0.79) and cytokines (ρ=0.75). A combined PLS-DA model using 12 selected plasma markers (IgE, IgG4, CXCL12, sTNFR1, pyridoxine, 4-pyridoxic acid, N-acetyl-DL-tryptophan, thymine, 3-hydroxybutyric acid, gamma-butyrolactone, hexanoylcarnitine, alanine) achieved AUC=0.929, specificity 93.3%, sensitivity 87.5%.

**Clinical Implications:** This study confirms that EoE involves complex immune dysregulation beyond type 2 inflammation, with significant epithelial barrier dysfunction. The identification of a plasma signature combining metabolomics and immune markers offers promise for non-invasive EoE diagnosis and monitoring, potentially reducing the need for repeated endoscopies. The novel finding of altered vitamin B6 metabolism in EoE warrants further investigation into its role in pathogenesis and as a potential biomarker. However, these findings require validation in larger, independent cohorts before clinical translation.

PICO

PPOPULATION

French children with EoE (n=17) and control subjects with GERD/abdominal pain/dysphagia (n=15); median age 10.9 years (EoE) vs 7.7 years (controls)

IINTERVENTION

Multi-omics profiling (transcriptomics, flow cytometry, cytokine/chemokine panels, untargeted metabolomics) of oesophageal biopsies and blood

OOUTCOME

Differentially expressed genes, immune cell frequencies, cytokine/chemokine concentrations, and metabolite levels distinguishing EoE from controls; multi-block integration for plasma signature

STUDY TYPE

cross-sectional

SPECIALTY

gastroenterology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10050742

Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches

Frontiers in Immunology

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Background Eosinophilic oesophagitis (EoE) is a chronic food allergic disorder limited to oesophageal mucosa whose pathogenesis is still only partially understood. Moreover, its diagnosis and follow-up need repeated endoscopies due to absence of non-invasive validated biomarkers. In the present study, we aimed to deeply describe local immunological and molecular components of EoE in well-phenotyped children, and to identify potential circulating EoE-biomarkers. Methods Blood and oesophageal biopsies were collected simultaneously from French children with EoE (n=17) and from control subjects (n=15). Untargeted transcriptomics analysis was performed on mRNA extracted from biopsies using microarrays. In parallel, we performed a comprehensive analysis of immune components on both cellular and soluble extracts obtained from both biopsies and blood, using flow cytometry. Finally, we performed non-targeted plasma metabolomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Uni/multivariate supervised and non-supervised statistical analyses were then conducted to identify significant and discriminant components associated with EoE within local and/or systemic transcriptomics, immunologic and metabolomics datasets. As a proof of concept, we conducted multi-omics data integration to identify a plasmatic signature of EoE. Results French children with EoE shared the same transcriptomic signature as US patients. Network visualization of differentially expressed (DE) genes highlighted the major dysregulation of innate and adaptive immune processes, but also of pathways involved in epithelial cells and barrier functions, and in perception of chemical stimuli. Immune analysis of biopsies highlighted EoE is associated with dysregulation of both type (T) 1, T2 and T3 innate and adaptive immunity, in a highly inflammatory milieu. Although an immune signature of EoE was found in blood, untargeted metabolomics more efficiently discriminated children with EoE from control subjects, with dysregulation of vitamin B6 and various amino acids metabolisms. Multi-blocks integration suggested that an EoE plasma signature may be identified by combining metabolomics and cytokines datasets. Conclusions Our study strengthens the evidence that EoE results from alterations of the oesophageal epithelium associated with altered immune responses far beyond a simplistic T2 dysregulation. As a proof of concept, combining metabolomics and cytokines data may provide a set of potential plasma biomarkers for EoE diagnosis, which needs to be confirmed on a larger and independent cohort.

CITATION EXPORT

Karine Adel-Patient, Florence Campeotto, Marta Grauso et al.. Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches. Frontiers in Immunology. (2023). https://doi.org/10.3389/fimmu.2023.1108895

AUTHORS

15 · 8 CENTRES

Karine Adel-Patient, Florence Campeotto, Marta Grauso, Blanche Guillon, Marco Moroldo, Eric Venot, Céline Dietrich, François Machavoine, Florence A. Castelli, François Fenaille, Thierry Jo Molina, Patrick Barbet, Christophe Delacourt, Maria Leite-de-Moraes, Guillaume Lezmi

1 Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), Gif-sur-Yvette, France
2 AP-HP, Hôpital Necker-Enfants Malades, Service de Gastro-Entérologie et Nutrition Pédiatriques, Paris, France
3 Université de Paris Cité, INSERM UMR1139, Laboratoire de Microbiologie, Faculté de Pharmacie, Paris, France
4 Université Paris Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas, France
5 Université Paris Cité, CNRS UMR 8253, Inserm UMR 1151, Institut Necker Enfants Malades, Equipe Immunorégulation et Immunopathologie, Paris, France
6 Université de Paris, UMRS 1138, INSERM, Sorbonne Paris-Cité, Paris, France
7 AP-HP, Centre-Université de Paris, hôpital Necker-Enfant-Malades, Service d'Anatomie et Cytologie Pathologiques, Paris, France
8 AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques, Paris, France