P1336 Urinary Metabolomics Reveal Microbiome-Inflammation Axis Predicting Crohn’s disease

Abstract Background Early identification of individuals at risk of Crohn’s disease (CD) before symptoms onset could enable preventive strategies. Urinary metabolomics provides a non-invasive method for capturing systemic and gut-derived metabolic changes. We aim to investigate whether urinary metabolomic profiles predict CD development and to explore links with serum metabolites, gut microbiota, and inflammation. Methods Within the GEM Project, a prospective cohort of healthy first-degree relatives (FDRs) of CD patients, we applied a nested case-control design comparing FDRs who later developed CD (pre-CD) with matched control FDRs who remained disease-free. Untargeted urine metabolomics was performed using the Metabolon untargeted panel, and 16S rRNA sequencing characterized microbial composition. Conditional logistic regression assessed urine metabolite associations with future CD. Spearman’s correlation examined associations between urine metabolites, microbial taxa, and inflammatory markers (CRP, fecal calprotectin FCP), and lactulose/mannitol ratio (LMR), a measure of gut barrier function. Mediation analyses explored potential pathways linking metabolites, inflammation, and CD risk. False discovery rate correction was applied (q 0.05). Results Among 302 participants (64 pre-CD, 238 controls), 21 urinary metabolites were significantly associated with future CD, mainly aromatic amino acid-derived microbial products (phenol sulfate, indoxyl, phenylacetyl conjugates) and tryptophan catabolites (indoxyl, quinolinate). Stratification by median time to diagnosis (2.5 years) showed that most associations were confined to the 2.5 years subgroup, indicating significant metabolic alterations closer to CD onset. Twelve of the 21 CD-associated metabolites significantly correlated with gut microbiome composition, predominantly Clostridia lineages (Oscillospirales, Ruminococcaceae) involved in aromatic amino acid fermentation. In the pre-CD group, sixteen, nine, and one of the CD-associated metabolites correlated with FCP, CRP, and LMR, respectively. Mediation analyses suggest that inflammation (measured by CRP or FCP) mediated 15–45% of the effect of 17 urinary metabolites on CD risk, while LMR showed no mediation effect. Conclusion Urinary metabolomic profiling identified a metabolite signature predicting future CD onset, which largely reflects microbial aromatic amino acid metabolism. Inflammation accounted for only part of these associations, suggesting additional non-inflammatory mechanisms. Urine-based metabolomics may offer a promising, non-invasive approach to identify individuals at high risk of developing CD, with potential applications in risk stratification and mechanistic understanding. Conflict of interest: Dr. Sharar Fischler, Tali: No conflict of interest Guevara, Fredy: No conflict of interest Jeong, Sean: No conflict of interest Bharali, Biju: No conflict of interest Chen, Rirong: There is no conflict of interest. Griffiths, Anne: Grant: Abbvie Personal Fees: Abbvie, Alfasigma, Amgen, Janssen, Lilly, Merck, Pfizer, Roche, Takeda Bernstein, Charles: Grant: Abbvie, Celltrion, Ferring, Pfizer, Takeda, Janssen, Organon, Eli Lilly, Sandoz Personal Fees: Abbvie Janssen, Pfizer, Takeda, Eli Lilly, Ferring, Pendopharm, Sandoz, Amgen, Celltrion, Fresenius-Kabi Steinhart, Hillary: No conflict of interest Jacobson, Kevan: Advisory board: Abbvie, McKesson, Janssen, Viatris, Celltrion Speaker’s bureau: Abbvie Panaccione, Remo: Grant: Abbvie, Janssen, Pfizer, Takeda Other: Consultant for: Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, UCB Speaker’s Fees for: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, Ventyx. Lee, Sun-Ho: Grant: Sun-Ho Lee is a recipient of the Imagine/ Canadian Institute of Health Research/ Canadian Association of Gastroenterology Fellowship Award. He is also a recipient of the Mount Sinai Hospital Department of Medicine Fellowship Award. Croitoru, Kenneth: No conflict of interest Turpin, Williams: No conflict of interest