P1340 Microbially conjugated bile acids and their microbial functional pathways are predictors of dietary therapy outcomes in paediatric Crohn’s disease.

Abstract Background Crohn’s Disease (CD) Exclusion Diet with Partial Enteral Nutrition (CDED+PEN) effectively induces remission in mild-to-moderate paediatric CD. Microbial biotransformation of bile acids (BAs) has gained attention, with three novel microbially-conjugated bile acids (MCBAs) reported in higher concentrations in CD.1 We aimed to investigate changes in these MCBAs, specifically Phenylalanocholic acid (Phe-CA), Tyrosocholic acid (Tyr-CA), and Leucocholic acid (Leu-CA), associated with dietary therapies in paediatric CD and integrate these with microbiome and metagenome data. Methods Faecal BA and MCBA concentrations were quantified by high performance liquid chromatography in available samples from 12 treatment-naive mild-to-moderate-paediatric CD patients receiving CDED+PEN in a prior RCT NCT017288702 at baseline and week 6 (W6). Clinical remission was defined as Paediatric Crohn’s Disease Activity Index (PCDAI) score ≤10. Baseline metabolites were compared between responders and non-responders to identify predictive BAs. Functional gene (KO) correlations were assessed to explore microbial pathways. Results At W6, 9/12 patients achieved remission. Phe-CA was the only consistently detected MCBA, whereas Tyr-CA was undetectable and Leu-CA present in one sample. Baseline Phe-CA was significantly higher in patients who failed to achieve remission (p 0.0001) and strongly tracked a broader non-remission BA signature characterised by increased primary BA and UDCA/GUDC levels. Metagenomic profiling revealed that Phe-CA showed a strong positive correlation with K00797 (spermidine synthase), aligning it with the polyamine biosynthesis module, a pathway linked to microbial stress responses and altered amino-acid turnover. Additional BA-linked modules in non-remission included DAHP synthase (aromatic amino-acid biosynthesis; K03856), hydrogenase maturation proteins HypE/HypF (redox/energy metabolism), OmpX-family envelope proteins, and several uncharacterised KOs, suggesting coordinated shifts in microbial redox state, translational capacity, and cell-envelope/transport functions that parallel MCBA and BA patterns. Conclusion Baseline faecal Phe-CA appears to mark a broader dysbiotic microbial state, characterised by increased polyamine metabolism, altered redox/energy pathways, and amino-acid biosynthesis, that predicts poor response to CDED+PEN. These findings position Phe-CA as a potential biomarker of non-remission and link MCBA formation to distinctive microbial functional signatures. Validation in larger prospective cohorts is warranted to clarify mechanistic relationships between MCBAs, microbial metabolism, and dietary therapy outcomes in paediatric CD. References: 1. Quinn RA, Melnik AV, Vrbanac A, et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature. 2020;579(7797):123-129. doi:10.1038/s41586-020-2047-9 2. Levine A, Wine E, Assa A, et al. Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial. Gastroenterology. 2019;157(2):440-450.e8. doi:10.1053/j.gastro.2019.04.021 Conflict of interest: Van Der Kruk, Nikki: No conflict of interest Ghiboub, Mohammed: No conflict of interest de Haas, Irina: No conflict of interest de Waart, Rudi: No conflict of interest Sigall-Boneh, Rotem: Personal Fees: Speaker fees- Nestlé Health Science, Takeda and Megapharm, Janssen Consulting- Nestlé Health Science Advisory board- Evinature Writing -Tnuva De Meij, Tim: No conflict of interest Wine, Eytan: Personal Fees: Janssen, AbbVie, Nestle Health Sciences, Mead Johnson Nutrition, Pfizer, BioJamp De Jonge, Wouter: No conflict of interest D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx van de Graaf, Stan: No conflict of interest Van Limbergen, Johan: Grant: Nestle Health Sciences, Janssen Personal Fees: Abbvie, Nestle Health Sciences, Janssen, Pfizer Non-financial Support: Nestle Health Sciences Other: Novalac