Abstract Background Metabolites mediate processes linked with gut homeostasis and inflammation. Gut epithelial function is significantly impaired in inflammatory bowel disease (IBD), contributing to increased intestinal permeability and chronic inflammation. We aimed to identify persistent metabolomics signals across IBD cohorts, and to prioritize and test their functional effects on epithelia. Methods Liquid chromatography-mass spectrometry (LC-MS) was used for untargeted metabolomics with a predefined library consisting of 803 predefined metabolites. Multivariable MaAsLin analyses identified differences between control and IBD samples, controlling for age, gender (FDR0.25), and repeated samples from the same subject. across 4 cohorts. Repeated metabolite signals across cohort comparisons were used for prioritization to then test their ability to suppress epithelial inflammation introduced to Caco-2 cells using a mixture of inflammatory triggers (IFNγ+TNFɑ+LPS) or heat-activated fecal content from IBD patients. Results We analyzed 657 fecal samples (515 IBD and 142 controls) from 364 subjects (226 IBD and 138 controls) across four cohorts, where each cohort was analyzed as a separate batch (Fig. 1A). Comparison between IBD and control samples were performed within each cohort using MaAsLin2, identifying metabolites that were significantly different. Cross-cohort comparison highlighted 62 metabolites that were repeatedly significant in at least two cohorts and showed consistent directionality across all four cohorts, with the linear regression coefficients ≥|0.3| (Fig. 1B). Among these, azelate emerged as a particularly compelling candidate, given its existing commercial use for reducing skin inflammation. This prompted us to evaluate if azelate could also modulate IBD-relevant epithelial responses. After confirming that azelate at different concentrations (10-1000 uM) did not affect cellular viability (ATP levels), we tested specifically if azelate could modulate gut epithelial responses to an inflammatory trigger cocktail (IFNγ + TNFɑ + LPS), or heat-inactivated fecal content from healthy individuals, UC patients, and CD patients. We measured CXCL1 and CXCL8 (IL8) mRNA expression and CXCL1 protein secretion, and observed a reduction in the Caco-2 inflammatory response following treatment with100-1000uM azelate (Fig. 2) Conclusion Meta-analyses of gut metabolomics signals across four IBD cohorts highlight robust, consistent signals, prioritizing different metabolites, including azelate, as potential beneficial interventions. Functional analyses support azelate’s ability to suppress gut epithelial inflammatory response in vitro and its potential use as a novel future adjunct intervention. References: 1.Li L, Lu H, Zhang Y, Li Q, Shi S, Liu Y. Effect of Azelaic Acid on Psoriasis Progression Investigated Based on Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (AKT) Signaling Pathway. Clin Cosmet Investig Dermatol Internet. 2022 cited 2025 Feb 11;15:2523–34. Available from https://pubmed.ncbi.nlm.nih.gov/36447569/ Conflict of interest: Naamnh, Raneen: No conflict of interest Levhar, Nina: No conflict of interest Braun, Tzipi: No conflict of interest Efroni, Gilat: No conflict of interest Jessula Levy, David: No conflict of interest Ben Dov, Avia: No conflicts Ben-Horin, Shomron: Grant: Abbvie, Takeda, Janssen, Celltrion, Pfizer, Medtronic, Galmed, OutSense Personal Fees: Advisory board and/or consulting and/or Speaker fees from Abbvie, Takeda, Janssen, Celltrion, Pfizer, GSK, Ferring, Novartis, Roche, Gilead, NeoPharm, EviNature, Galmed, Medial Earlysign, BMS, Pfizer, Falk, Medtronic and Eli Lilly. Options/stocks in Predicta Med, Evinature, Galmed, Alma Therpeautics. Amir, Amnon: No conflict of interest Haberman Ziv, Yael: Grant: ECCO, CCF, ISF, I-Core, Helmsley, ERC, NIH.
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