P0510Non-targeted lipidomic profiling reveals distinct molecular signatures in inflammatory bowel disease: Discovery and validation in two inception cohorts

Abstract Background Minimally invasive biomarkers that can reliably distinguish adults with inflammatory bowel disease (IBD) from symptomatic controls are still lacking. We investigated whether serum lipidomics can provide a reproducible diagnostic signature for IBD and how such a signature performs in relation to relevant inflammatory markers. Methods Untargeted lipidomic profiling was conducted on serum from the Swedish SIC-IBD inception cohort, comprising adults referred for suspected IBD, symptomatic controls, as well as healthy controls. Candidate diagnostic lipids were identified using supervised machine-learning models in the discovery cohort and then evaluated in the independent, population-based Norwegian IBSEN III inception cohort of treatment-naïve adults. We examined the diagnostic performance of the lipidomic signature in combination with high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP). Results The discovery cohort included 96 IBD patients, 66 non-IBD symptomatic controls, and 48 healthy controls, whereas the validation cohort comprised 349 patients with IBD and 198 symptomatic controls (Table 1). In the discovery cohort, a serum signature of hs-CRP and the two top lipids, lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (O-44:5), demonstrated a high diagnostic performance (area under the curve AUC 0.80, 95% CI 0.73-0.87) compared with hs-CRP alone (AUC 0.70, 95% CI 0.63-0.79). When applied to the validation cohort, hs-CRP combined with the serum lipid signature significantly enhanced discrimination between IBD and symptomatic controls (AUC 0.79, 95% CI 0.75-0.83) compared with hs-CRP alone (AUC 0.68, 95% CI 0.64-0.73; P 0.0001). As illustrated in Figure 1, among patients with available stool samples, combining FCP with hs-CRP and the lipid signature numerically improved diagnostic accuracy (AUC 0.89, 95% CI 0.86-0.92) compared with FCP alone (AUC 0.86, 95% CI 0.83–0.90). Conclusion We identified and externally validated a serum lipidomic signature that improves the diagnostic prediction of IBD when combined with hs-CRP. Although the blood-based model of hs-CRP, lactosyl ceramide (d18:1/16:0), and phosphatidylcholine (O-44:5) did not outperform FCP alone, it approached its diagnostic performance and further enhanced accuracy when integrated with FCP. These findings support added value these lipids and may offer insights into lipid-related pathways underlying IBD pathogenesis. Conflict of interest: Salihovic, Samira: No conflict of interest Øyås, Ove: No conflict of interest Hyll Hansen, Simen: No conflict of interest Salomon, Benita: No conflict of interest Bergemalm, Daniel: No conflict of interest Hjortswang, Henrik: No conflict of interest Grännö, Olle: No conflict of interest Hedin, Charlotte Rose: Grant: C. R. H. Hedin has received specific project grants from Takeda and Tillotts. Personal Fees: C. R. H. Hedin served as a speaker and/or advisory board member for AstraZeneca, Abbvie, Dr Falk Pharma and the Falk Foundation, Galapagos, Janssen, Lilly, Pfizer, Ferring, Takeda, Tillotts Pharma, and received grant support from Tillotts and Takeda. These fees are invoiced by her employer. Eriksson, Carl: Carl Eriksson received grant support, lecture fees, and served on an advisory board for BMS, Takeda, Janssen Cilag, Pfizer, and AbbVie. Holm, Kristian: No conflict of interest Aabrekk, Tone Bergene: No conflict of interest D’Amato, Mauro: No conflict of interest Orešič, Matej: No conflict of interest Detlie, Trond Espen: No conflict of interest Kristensen, Vendel: No conflict of interest Keita, Åsa: No conflict of interest Lindqvist, Carl M.: No conflict of interest Öhman, Lena: No conflict of interest Carlson, Marie: No conflict of interest Söderholm, Johan D.: No conflict of interest Repsilber, Dirk: No conflicts Kruse, Robert: No conflict of interest Hov, Johannes Espolin Roksund: Personal Fees: Received grants from Biogen. Lecture honoraria from Amgen, Roche, Novartis. Hyötyläinen, Tuulia: No conflict of interest Høivik, Marte: No conflict of interest Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova ( 2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp & Dohme and Takeda.