Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis

Seung Kim¹, Netali Ben-Baruch Morgenstern¹, Kasumi Osonoi¹, Seema S Aceves², Nicoleta C Arva³, Mirna Chehade⁴, Margaret H Collins⁵, Evan S Dellon⁶, Gary W Falk⁷, Glenn T Furuta⁸, Nirmala P Gonsalves⁹, Sandeep K Gupta¹⁰, Ikuo Hirano⁹, Girish Hiremath¹¹, David A Katzka¹², Paneez Khoury¹³, John Leung¹⁴, Robbie Pesek¹⁵, Kathryn A Peterson¹⁶, Maria A Pletneva¹⁷, Jonathan M Spergel¹⁸, Joshua B Wechsler¹⁹, Guang-Yu Yang²⁰, Marc E Rothenberg¹, Tetsuo Shoda²¹

Affiliations

¹ Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
² Division of Allergy Immunology, Department of Pediatrics and Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, Calif.
³ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
⁴ Departments of Pediatrics and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
⁵ Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁷ Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
⁸ Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colo.
⁹ Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
¹⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Birmingham, Ala.
¹¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tenn.
¹² Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY.
¹³ National Institutes of Health, Bethesda, Md.
¹⁴ Boston Specialists, Boston, Mass.
¹⁵ Division of Allergy and Immunology, Department of Pediatrics, Arkansas Children's Hospital, University of Arkansas for Medical Science, Little Rock, Ark.
¹⁶ Division of Gastroenterology, University of Utah Health, Salt Lake City, Utah.
¹⁷ Department of Pathology, University of Utah Health, Salt Lake City, Utah.
¹⁸ Division of Allergy-Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pa.
¹⁹ Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.
²⁰ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
²¹ Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Tetsuo.Shoda@cchmc.org.

PMID: 38768900
PMCID: PMC11570700 (available on 2025-12-01)
DOI: 10.1016/j.jaip.2024.05.015

Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis

Seung Kim et al. J Allergy Clin Immunol Pract. 2024 Dec.

. 2024 Dec;12(12):3346-3355.e1.

doi: 10.1016/j.jaip.2024.05.015. Epub 2024 May 18.

Authors

Affiliations

¹ Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
² Division of Allergy Immunology, Department of Pediatrics and Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, Calif.
³ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
⁴ Departments of Pediatrics and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
⁵ Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁷ Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
⁸ Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colo.
⁹ Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
¹⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Birmingham, Ala.
¹¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tenn.
¹² Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY.
¹³ National Institutes of Health, Bethesda, Md.
¹⁴ Boston Specialists, Boston, Mass.
¹⁵ Division of Allergy and Immunology, Department of Pediatrics, Arkansas Children's Hospital, University of Arkansas for Medical Science, Little Rock, Ark.
¹⁶ Division of Gastroenterology, University of Utah Health, Salt Lake City, Utah.
¹⁷ Department of Pathology, University of Utah Health, Salt Lake City, Utah.
¹⁸ Division of Allergy-Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pa.
¹⁹ Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.
²⁰ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
²¹ Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Tetsuo.Shoda@cchmc.org.

PMID: 38768900
PMCID: PMC11570700 (available on 2025-12-01)
DOI: 10.1016/j.jaip.2024.05.015

Abstract

Background: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood.

Objective: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis.

Methods: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms.

Results: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden.

Conclusion: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity.

Keywords: EoE transcriptome; Eosinophilic esophagitis; Eosinophilic gastrointestinal diseases; Molecular diagnostics.

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Conflict of interest statement

Conflict of Interest

S.S.A. is a consultant for AstraZeneca, Bristol Meyers Squibb (BMS), and Regeneron/Sanofi; speaker for Regeneron/Sanofi; co-inventor of the oral viscous budesonide UCSD patent, Takeda license; and receives funding from Implicit Biosciences. M.C. received consulting fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, BMS, Recludix Pharma, Allakos, Shire/Takeda, and Phathom and research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. M.H.C. is a consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline (GSK), Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc./Alimentiv, Inc., and Shire/ Takeda. E.S.D. is a consultant of Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and received educational grants from Allakos, Holoclara, and Invea. G.W.F. is a consultant for Adare/Ellodi, Allakos, BMS/Celgene, Lucid, Nexstone, Phathom, Regeneron/Sanofi, Shire/Takeda, and Upstream Bio and receives research funding from Adare/Ellodi, Allakos, Arena/Pfizer, BMS/Celgene, Lucid, Nexteos, Regeneron/Sanofi, and Shire/Takeda. I.H. is a consultant for Ellodi/Adare Pharma, Allakos, Pfizer/Arena Pharmaceuticals, AstraZeneca, Dermavant, Eli Lilly, EsoCap, GSK, Gossamer Bio, Nexstone, Calyx/Parexel, Phathom, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., and Shire/Takeda and receives research funding from Ellodi/Adare Pharma Solutions, Allakos, AstraZeneca, Pfizer/Arena, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., and Shire/Takeda. G.H. is supported by the National Institutes of Health (NIH) 1K23DK131341. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M.P. is a consultant for Allakos. J.M.S. is a consultant for Regeneron Pharmaceutical, Sanofi, and Readysetfood and receives royalties from Uptodate and grant support from the NIH, Regeneron/Sanofi, and Novartis. J.B.W. is a consultant for Allakos, AstraZeneca, BMS, Ellodi Pharma, and Regeneron/Sanofi. M.E.R. is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, BMS, Astra Zeneca, Ellodi Pharma, GSK, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first seven listed; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. T.S. is a co-inventor of patents owned by Cincinnati Children’s Hospital Medical Center. All other authors declare that they have no competing interests.

References

1. Dellon ES, Liacouras CA, Molina-Infante J, Furuta GT, Spergel JM, Zevit N, et al. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology 2018; 155:1022–33.e10. - PMC - PubMed
1. Muir AB, Brown-Whitehorn T, Godwin B, Cianferoni A. Eosinophilic esophagitis: early diagnosis is the key. Clin Exp Gastroenterol 2019; 12:391–9. - PMC - PubMed
1. Lucendo AJ, Arias-González L, Molina-Infante J, Arias Á. Determinant factors of quality of life in adult patients with eosinophilic esophagitis. United European Gastroenterol J 2018; 6:38–45. - PMC - PubMed
1. Fox VL, Nurko S, Teitelbaum JE, Badizadegan K, Furuta GT. High-resolution EUS in children with eosinophilic "allergic" esophagitis. Gastrointest Endosc 2003; 57:30–6. - PubMed
1. Muir A, Falk GW. Eosinophilic Esophagitis: A Review. Jama 2021; 326:1310–8. - PMC - PubMed

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Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis

Affiliations

Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical