Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR)

doi:10.1053/j.gastro.2022.01.022

Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR)

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1635-1649
Number of pages	15
Journal	Gastroenterology
Volume	162
Issue number	6
DOIs	https://doi.org/10.1053/j.gastro.2022.01.022
State	Published - May 2022

Funding

The authors thank all patients who participated in the study. The authors are also grateful to their colleagues and clinical support staff for procuring biopsies, blood samples, and clinical data. Shawna Hottinger provided editorial assistance as a medical writer funded by Cincinnati Children's Hospital Medical Center. Order of Authors (with Contributor Roles):, Tetsuo Shoda, MD, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Supervision: Lead; Validation: Lead; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Margaret H. Collins, MD (Data curation: Supporting; Project administration: Supporting; Supervision: Supporting; Validation: Supporting; Writing – review & editing: Supporting), Mark Rochman, PhD (Data curation: Supporting; Formal analysis: Supporting; Software: Supporting; Writing – review & editing: Supporting), Ting Wen, MD, PhD (Data curation: Supporting; Resources: Supporting; Supervision: Supporting; Writing – review & editing: Supporting), Julie M. Caldwell, PhD (Project administration: Supporting; Resources: Supporting), Lydia E. Mack, MS (Data curation: Supporting; Resources: Supporting), Garrett A. Osswald, BS (Data curation: Supporting; Resources: Supporting), John A. Besse, BS (Project administration: Supporting), Yael Haberman, MD, PhD (Resources: Supporting; Writing – review & editing:, Supporting), Seema S. Aceves, MD, PhD (Project administration: Supporting; Writing – review & editing: Supporting), Nicoleta C. Arva, MD, PhD (Project administration: Supporting; Writing – review & editing: Supporting), Kelley E. Capocelli, MD (Project administration: Supporting; Writing – review & editing: Supporting), Mirna Chehade, MD, MPH (Project administration: Supporting; Writing – review & editing: Supporting), Carla M. Davis, MD (Project administration: Supporting; Writing – review & editing: Supporting), Evan S. Dellon, MD, MPH (Project administration: Supporting; Writing – review & editing: Supporting), Gary W. Falk, MD, MS (Project administration: Supporting; Writing – review & editing: Supporting), Nirmala Gonsalves, MD (Project administration: Supporting; Writing – review & editing: Supporting), Sandeep K. Gupta, MD (Project administration: Supporting; Writing – review & editing: Supporting), Ikuo Hirano, MD (Project administration: Supporting; Writing – review & editing: Supporting), Paneez Khoury, MD (Project administration: Supporting; Writing – review & editing: Supporting), Amy Klion, MD (Project administration: Supporting; Writing – review & editing: Supporting), Calies Menard-Katcher, MD (Project administration: Supporting; Writing – review & editing: Supporting), John Leung, MD (Project administration: Supporting; Writing – review & editing: Supporting), Vincent Mukkada, MD (Project administration: Supporting; Writing – review & editing: Supporting), Philip E. Putnam, MD (Project administration: Supporting; Writing – review & editing: Supporting), Jonathan M. Spergel, MD, PhD (Project administration: Supporting; Writing – review & editing: Supporting), Joshua B. Wechsler, MD, MS (Project administration: Supporting; Writing – review & editing: Supporting), Guang-Yu Yang, MD (Project administration: Supporting; Writing – review & editing: Supporting), Glenn T. Furuta, MD (Project administration: Supporting; Writing – review & editing: Supporting), Lee A. Denson, MD (Project administration: Supporting; Supervision: Supporting; Writing – review & editing: Supporting), Marc E. Rothenberg, MD, PhD (Conceptualization: Lead; Funding acquisition: Lead; Project administration: Lead; Supervision: Lead; Writing – original draft: Lead; Writing – review & editing: Lead) Funding This study was supported by National Institutes of Health (NIH) grant K99/R00 AI158660 (to Tetsuo Shoda) and CEGIR (U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and the Intramural Research Program of the NIH. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). This project was supported in part by NIH P30 DK078392 (Gene Expression Core, Pathology Research Core, and Confocal Imaging Core) of the Digestive Diseases Research Core Center in Cincinnati.

Keywords

Colitis
Eosinophil
Eosinophilic Colitis
Inflammatory Bowel Disease
Transcriptome

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2022.01.022

Cite this

@article{167fe392071d4f818701d82920ae7922,

title = "Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study",

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.",

keywords = "Colitis, Eosinophil, Eosinophilic Colitis, Inflammatory Bowel Disease, Transcriptome",

author = "{Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR)} and Tetsuo Shoda and Collins, {Margaret H.} and Mark Rochman and Ting Wen and Caldwell, {Julie M.} and Mack, {Lydia E.} and Osswald, {Garrett A.} and Besse, {John A.} and Yael Haberman and Aceves, {Seema S.} and Arva, {Nicoleta C.} and Capocelli, {Kelley E.} and Mirna Chehade and Davis, {Carla M.} and Dellon, {Evan S.} and Falk, {Gary W.} and Nirmala Gonsalves and Gupta, {Sandeep K.} and Ikuo Hirano and Paneez Khoury and Amy Klion and Calies Menard-Katcher and John Leung and Mukkada, {Vincent A.} and Putnam, {Philip E.} and Spergel, {Jonathan M.} and Wechsler, {Joshua B.} and Yang, {Guang Yu} and Furuta, {Glenn T.} and Denson, {Lee A.} and Rothenberg, {Marc E.} and {Pablo Abonia}, J. and Seema Aceves and Samuel Almonte and Rachel Andrews and Sara Anvari and Ashley Arrington and Nicoleta Arva and Fred Atkins and Dominique Bailey and Alexis Berry and Bridget Besl and Scott Bolton and Peter Bonis and Wendy Book and Kimberly Bray and Teresa Brown and Cassandra Burger and Amir Kagalwalla and Barry Wershil",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = may,

doi = "10.1053/j.gastro.2022.01.022",

language = "English (US)",

volume = "162",

pages = "1635--1649",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "6",

}

TY - JOUR

T1 - Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles

T2 - A Multi-Site Study

AU - Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR)

AU - Shoda, Tetsuo

AU - Collins, Margaret H.

AU - Rochman, Mark

AU - Wen, Ting

AU - Caldwell, Julie M.

AU - Mack, Lydia E.

AU - Osswald, Garrett A.

AU - Besse, John A.

AU - Haberman, Yael

AU - Aceves, Seema S.

AU - Arva, Nicoleta C.

AU - Capocelli, Kelley E.

AU - Chehade, Mirna

AU - Davis, Carla M.

AU - Dellon, Evan S.

AU - Falk, Gary W.

AU - Gonsalves, Nirmala

AU - Gupta, Sandeep K.

AU - Hirano, Ikuo

AU - Khoury, Paneez

AU - Klion, Amy

AU - Menard-Katcher, Calies

AU - Leung, John

AU - Mukkada, Vincent A.

AU - Putnam, Philip E.

AU - Spergel, Jonathan M.

AU - Wechsler, Joshua B.

AU - Yang, Guang Yu

AU - Furuta, Glenn T.

AU - Denson, Lee A.

AU - Rothenberg, Marc E.

AU - Pablo Abonia, J.

AU - Aceves, Seema

AU - Almonte, Samuel

AU - Andrews, Rachel

AU - Anvari, Sara

AU - Arrington, Ashley

AU - Arva, Nicoleta

AU - Atkins, Fred

AU - Bailey, Dominique

AU - Berry, Alexis

AU - Besl, Bridget

AU - Bolton, Scott

AU - Bonis, Peter

AU - Book, Wendy

AU - Bray, Kimberly

AU - Brown, Teresa

AU - Burger, Cassandra

AU - Kagalwalla, Amir

AU - Wershil, Barry

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - Colitis

KW - Eosinophil

KW - Eosinophilic Colitis

KW - Inflammatory Bowel Disease

KW - Transcriptome

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Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

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