Postoperative Ileum Transcriptomics Implicate Sex-Biased Mechanisms in Crohn's Disease Recurrence

Kyle Gettler; Sini Nagpal; Savannah Washburn; Christopher Tastad; Jiayu Zhang; Ksenija Sabic; Mark Lazarev; Alain Bitton; Rita Cohen; Marc B Schwartz; Arthur Barrie; Philip Gu; Philip Fleshner; Michelle Bao; Cristian Hernández-Rocha; Jacob McCauley; Maria Abreu; Subra Kugathasan; Dermot P McGovern; Steven R Brant; Richard H Duerr; Mark S Silverberg; John D Rioux; Greg Gibson; Judy H Cho

doi:10.1053/j.gastro.2025.08.038

Postoperative Ileum Transcriptomics Implicate Sex-Biased Mechanisms in Crohn's Disease Recurrence

Gastroenterology. 2025 Nov 18:S0016-5085(25)05983-9. doi: 10.1053/j.gastro.2025.08.038. Online ahead of print.

Authors

Kyle Gettler¹, Sini Nagpal², Savannah Washburn², Christopher Tastad¹, Jiayu Zhang¹, Ksenija Sabic¹, Mark Lazarev³, Alain Bitton⁴, Rita Cohen⁴, Marc B Schwartz⁵, Arthur Barrie⁵, Philip Gu⁶, Philip Fleshner⁶, Michelle Bao⁷, Cristian Hernández-Rocha⁸, Jacob McCauley⁹, Maria Abreu¹⁰, Subra Kugathasan¹¹, Dermot P McGovern⁶, Steven R Brant¹², Richard H Duerr¹³, Mark S Silverberg¹⁴, John D Rioux¹⁵, Greg Gibson², Judy H Cho¹⁶

Affiliations

¹ Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
² School of Biological Sciences, and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, Georgia.
³ Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁴ McGill University Health Centre, Division of Gastroenterology, Montreal, Quebec, Canada.
⁵ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
⁶ F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California.
⁷ Division of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
⁸ Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Catolica of Chile, Santiago, Chile.
⁹ John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida; Dr. John T. Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida.
¹⁰ Crohn's and Colitis Center, University of Miami, Miller School of Medicine, Miami, Florida.
¹¹ Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
¹² Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Crohn's and Colitis Center of New Jersey, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; Department of Genetics, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania.
¹⁴ Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Division of Gastroenterology, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Montreal Heart Institute Research Center, Montreal, Quebec, Canada Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada.
¹⁶ Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: Judy.Cho@mssm.edu.

PMID: 41251630
DOI: 10.1053/j.gastro.2025.08.038

Abstract

Background & aims: Despite widespread biologic use, more than 70% of patients with Crohn's disease require resectional surgery, most commonly of the terminal ileum. Gene expression and genetics of the neoterminal ileum at postoperative, surveillance colonoscopies highlight pathways of disease recurrence. Postoperative colonoscopy transcriptomes were interrogated to evaluate the hypothesis that specific molecular mechanisms contribute to recurrent Crohn's pathophysiology.

Methods: Ribo-depleted, paired-end sequencing was run on 339 neoterminal ileal pinch biopsies from 267 patients with (Rutgeerts i2b+) and without (Rutgeerts i2a or lower) recurrent disease. Differential gene and transcript usage were assessed. Expression quantitative trait loci link genetic variation with gene expression. Serial sampling was performed on 70 patients.

Results: At colonoscopy, 4171 genes increased and 3579 genes decreased in recurring vs nonrecurring patients. Although gene expression was highly correlated (r = 0.71), we observed and replicated higher dynamic ranges of gene expression in male compared with female patients. Activation of both pro- (tumor necrosis factor, interferon gamma) and anti-inflammatory (transforming growth factor beta) pathways was observed; importantly, multiple nuclear hormone receptor pathways demonstrated activation, including both estrogen and dihydrotestosterone pathways, whereas progesterone was inhibited. We observed sex-specific expression quantitative trait loci driven by recurrent samples and differential transcript usage related to lipid metabolism, membrane trafficking, and the extracellular matrix.

Conclusions: In recurrent disease of the postoperative neoterminal ileum, markedly greater dynamic ranges of gene expression occur in male compared with female patients. Pathway analyses implicate numerous nuclear hormone pathways, highlighting new mechanisms for therapeutic targeting beyond pro-inflammatory cytokine blockade. This study identifies key covariates and pathways of disease recurrence, many of which are distinct from drivers of initial disease susceptibility.

Keywords: Crohn’s Disease; Genomics; Inflammatory Bowel Disease; RNA-Seq; Single Cell.