Tetsuo Shoda1, Margaret H Collins2, Mark Rochman1, Ting Wen3, Julie M Caldwell1, Lydia E Mack1, Garrett A Osswald1, John A Besse1, Yael Haberman4, Seema S Aceves5, Nicoleta C Arva6, Kelley E Capocelli7, Mirna Chehade8, Carla M Davis9, Evan S Dellon10, Gary W Falk11, Nirmala Gonsalves12, Sandeep K Gupta13, Ikuo Hirano12, Paneez Khoury14, Amy Klion14, Calies Menard-Katcher15, John Leung16, Vincent A Mukkada17, Philip E Putnam17, Jonathan M Spergel18, Joshua B Wechsler19, Guang-Yu Yang20, Glenn T Furuta15, Lee A Denson17, Marc E Rothenberg21. 1. Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. Division of Pathology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, Utah. 4. Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Israel. 5. Division of Allergy Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, California. 6. Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 7. Department of Pathology, Children's Hospital Colorado, Aurora, Colorado. 8. Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Section of Immunology, Allergy and Retrovirology, Baylor College of Medicine & Texas Children's Hospital, Houston, Texas. 10. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 11. Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 12. Division of Gastroenterology & Hepatology, Northwestern University, Chicago, Illinois. 13. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children/Indiana University, and Community Health Network, Indianapolis, Indiana. 14. Human Eosinophil Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 15. Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado. 16. Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts. 17. Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 18. Division of Allergy and Immunology, University of Pennsylvania Perelman School of Medicine/Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 19. Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 20. Department of Pathology and Laboratory Medicine, Northwestern University, Chicago, Illinois. 21. Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: rothenberg@cchmc.org.
Abstract
BACKGROUND & AIMS: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined. METHODS: Subjects with EoC (n = 27) and controls (normal [NL, n = 20], Crohn's disease [CD, n = 14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived. RESULTS: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r = 0.78 and 0.77, P < .0001). Among EoC and other EGIDs, there was minimal transcriptomic overlap and minimal evidence of a strong allergic type 2 immune response in EoC compared with other EGIDs. Decreased cell cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001). CONCLUSIONS: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.
BACKGROUND & AIMS: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined. METHODS: Subjects with EoC (n = 27) and controls (normal [NL, n = 20], Crohn's disease [CD, n = 14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived. RESULTS: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r = 0.78 and 0.77, P < .0001). Among EoC and other EGIDs, there was minimal transcriptomic overlap and minimal evidence of a strong allergic type 2 immune response in EoC compared with other EGIDs. Decreased cell cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001). CONCLUSIONS: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.
Authors: Emma K Persson; Kenneth Verstraete; Ines Heyndrickx; Elien Gevaert; Helena Aegerter; Jean-Michel Percier; Kim Deswarte; Koen H G Verschueren; Ann Dansercoer; Delphine Gras; Pascal Chanez; Claus Bachert; Amanda Gonçalves; Hanne Van Gorp; Hans De Haard; Christophe Blanchetot; Michael Saunders; Hamida Hammad; Savvas N Savvides; Bart N Lambrecht Journal: Science Date: 2019-05-24 Impact factor: 47.728
Authors: Jacob Mark; Shahan D Fernando; Joanne C Masterson; Zhaoxing Pan; Kelley E Capocelli; Glenn T Furuta; Edwin F de Zoeten Journal: J Pediatr Gastroenterol Nutr Date: 2018-05 Impact factor: 2.839
Authors: Julie M Caldwell; Margaret H Collins; Emily M Stucke; Philip E Putnam; James P Franciosi; Jonathan P Kushner; J Pablo Abonia; Marc E Rothenberg Journal: J Allergy Clin Immunol Date: 2014-09-15 Impact factor: 10.793
Authors: Tetsuo Shoda; Ting Wen; Julie M Caldwell; Margaret H Collins; John A Besse; Garrett A Osswald; J Pablo Abonia; Nicoleta C Arva; Dan Atkins; Kelley E Capocelli; Evan S Dellon; Gary W Falk; Nirmala Gonsalves; Sandeep K Gupta; Ikuo Hirano; Vincent A Mukkada; Philip E Putnam; Rachel M Sheridan; Amanda K Rudman Spergel; Jonathan M Spergel; Joshua B Wechsler; Guang-Yu Yang; Seema S Aceves; Glenn T Furuta; Marc E Rothenberg Journal: J Allergy Clin Immunol Date: 2019-11-16 Impact factor: 10.793
Authors: Ting Wen; Emily M Stucke; Tommie M Grotjan; Katherine A Kemme; J Pablo Abonia; Philip E Putnam; James P Franciosi; Jose M Garza; Ajay Kaul; Eileen C King; Margaret H Collins; Jonathan P Kushner; Marc E Rothenberg Journal: Gastroenterology Date: 2013-08-23 Impact factor: 22.682
Authors: Zoltán Kiss; Nóra Judit Béres; Erna Sziksz; Bálint Tél; Katalin Borka; András Arató; Attila J Szabó; Gábor Veres Journal: Int J Mol Sci Date: 2017-05-12 Impact factor: 5.923
Authors: Tetsuo Shoda; Kenneth M Kaufman; Ting Wen; Julie M Caldwell; Garrett A Osswald; Pathre Purnima; Nives Zimmermann; Margaret H Collins; Kira Rehn; Heather Foote; Michael D Eby; Wenying Zhang; Netali Ben-Baruch Morgenstern; Adina Y Ballaban; Jeff E Habel; Leah C Kottyan; J Pablo Abonia; Vincent A Mukkada; Philip E Putnam; Lisa J Martin; Marc E Rothenberg Journal: Nat Commun Date: 2021-11-23 Impact factor: 17.694