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. 2025 Feb;37(2):e14980.
doi: 10.1111/nmo.14980. Epub 2024 Dec 13.

Genome-Wide DNA Methylation Identifies Potential Disease-Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease

Swapna Mahurkar-Joshi  1   2   3 , Mike Thompson  4 , Elizza Villarruel  3 , James D Lewis  5 , Lisa D Lin  2   3 , Mary Farid  2   3 , Hamed Nayeb-Hashemi  2   3 , Tina Storage  2   3 , Guy A Weiss  2   3   6 , Berkeley N Limketkai  2   3 , Jenny S Sauk  2   3 , Emeran A Mayer  1   2   3 , Lin Chang  1   2   3
Affiliations

Genome-Wide DNA Methylation Identifies Potential Disease-Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease

Swapna Mahurkar-Joshi et al. Neurogastroenterol Motil. 2025 Feb.

Abstract

Background and aims: Irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease (CeD) present with similar gastrointestinal (GI) symptoms. DNA methylation-based biomarkers have not been investigated as diagnostic biomarkers to classify these disorders. We aimed to study DNA methylation profiles of IBS, IBD, CeD, and healthy controls (HC), develop machine learning-based classifiers, and identify associated gene ontology (GO) terms.

Methods: Genome-wide DNA methylation of peripheral blood mononuclear cells from 315 patients with IBS, IBD, CeD, and HC was measured using Illumina's 450K or EPIC arrays. A methylation dataset on 304 IBD and HC samples was used for external validation. Differential methylation was measured using general linear models. Classifiers were developed using penalized generalized linear models using double cross-validation controlling for confounders. Functional enrichment was assessed using GO.

Results: Three hundred and fifteen participants (148 IBS, 47 IBD, 34 CeD, and 86 HC) had DNA methylation data. IBS-IBD and IBD-CeD showed the highest number of differentially methylated CpG sites followed by IBD-HC, CeD-HC, and IBS-HC. IBS-associated genes were enriched in cell adhesion and neuronal pathways, while IBD- and CeD-associated markers were enriched in inflammation and MHC class II pathways, respectively (p < 0.05). Classification performances assessed using area under the receiver operating characteristic curves (AUC) for IBS-IBD, IBS-CeD, and IBD-CeD were 0.80 (95% CI = 0.7-0.87, p = 6.75E-10), 0.78 (95% CI = 0.68-0.86, p = 4.57E-10), and 0.73 (95% CI = 0.62-0.83, p = 0.03), respectively. The performance of IBD-HC was successfully validated using external data (AUC = 0.74 [95% CI = 68-0.80, p < 0.001]).

Conclusions: Blood-based DNA methylation biomarkers can potentially distinguish chronic GI disorders that present with similar symptoms. GO suggested functional significance of the classifiers in disease-specific pathology.

Keywords: Celiac Disease; DNA Methylation‐Based Biomarkers; Inflammatory Bowel Disease; Irritable Bowel Syndrome; Machine Learning.

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Conflict of interest statement

Dr. Sauk has consulted for CorEvitas, Prometheus, and Abbvie. Dr. Weiss has consulted for Guidepoint, Regeneron, and EverlyHealth. Dr. Chang has served as a member of the scientific advisory board or consultant for Alfasigma, Ardelyx, Arena, Atmo, Bausch Health, Food Marble, GlaxoSmithKline, Ironwood, and Trellus Health. She has received research support from the National Institute of Health, Arena, AnX Robotica, and Ironwood Pharmaceuticals. She has stock options with Food Marble, ModifyHealth, and Trellus Health. Drs. Chang and Mahurkar‐Joshi have two related patents.

Figures

FIGURE 1
FIGURE 1
The receiver operating characteristic (ROC) curves and the area under the ROC curves (AUC) for IBS versus IBD, IBS versus celiac disease, and IBD versus celiac disease comparisons. The x‐axis represents the sensitivity, and y‐axis represents the specificity, and each point on the ROC curve represents a sensitivity/specificity pair corresponding to a particular decision threshold. The AUC values for IBS versus IBD, IBS versus celiac disease, and IBD versus celiac disease classifiers were 0.85, 0.82, and 0.78.
See this image and copyright information in PMC

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