Browsing by Author "Rochman, Mark"

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    Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study
    (Elsevier, 2022) Shoda, Tetsuo; Collins, Margaret H.; Rochman, Mark; Wen, Ting; Caldwell, Julie M.; Mack, Lydia E.; Osswald, Garrett A.; Besse, John A.; Haberman, Yael; Aceves, Seema S.; Arva, Nicoleta C.; Capocelli, Kelley E.; Chehade, Mirna; Davis, Carla M.; Dellon, Evan S.; Falk, Gary W.; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Khoury, Paneez; Klion, Amy; Menard-Katcher, Calies; Leung, John; Mukkada, Vincent; Putnam, Philip E.; Spergel, Jonathan M.; Wechsler, Joshua B.; Yang, Guang-Yu; Furuta, Glenn T.; Denson, Lee A.; Rothenberg, Marc E.; Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR); Pediatrics, School of Medicine
    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.
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    Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk
    (AGA, 2022-02) Shoda, Tetsuo; Wen, Ting; Caldwell, Julie M.; Morgenstern, Netali Ben-Baruch; Osswald, Garrett A.; Rochman, Mark; Mack, Lydia E.; Felton, Jennifer M.; Abonia, J. Pablo; Arva, Nicoleta C.; Atkina, Dan; Bonis, Peter A.; Capocelli, Kelley E.; Collins, Margaret H.; Dellon, Evan S.; Falk, Gary W.; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Leung, John; Menard-Katcher, Paul A.; Mukkada, Vincent A.; Putnam, Philip E.; Rudman Spergel, Amanda K.; Spergel, Jonathan M.; Wechsler, Joshua B.; Yang, Guang-Yu; Aceves, Seema S.; Furuta, Glenn T.; Rothenberg, Marc E.; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group; Medicine, School of Medicine
    Background & Aims Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. Methods Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) sites (n = 311) and two independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE endoscopic reference score (EREFS), EoE Histology Scoring System (HSS), EoE Diagnostic Panel (EDP), and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. Results TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EREFS, EDP, and HSS (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle–related pathways. IL-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix (ECM) pathways. Endothelial cell–fibroblast crosstalk induced ECM changes relevant to esophageal remodeling. Conclusions Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.