P0056The gastrointestinal microbiome is associated with endoscopic disease activity in newly-diagnosed Crohn’s Disease: Results from the PROFILE trial

Abstract Background The gastrointestinal microbiome of Crohn’s disease has been explored previously, with studies demonstrating differences between disease associated microbiomes and healthy controls1. Within diagnosed patients however, there is limited evidence to assess how the microbiota is associated with current or future disease activity. Methods The PROFILE trial enrolled adults newly diagnosed with Crohn’s disease, randomised to receive either accelerated step-up or top-down therapy2. Stool samples were collected from participants at baseline and follow-up (after 48 weeks). Using metagenomic sequencing we explored associations between the gastrointestinal microbiome and symptomatic, endoscopic and biochemical measures of disease activity in all PROFILE participants using a combination of uni- and multi-variate statistical methods. Results A total of 699 stool samples from 456 participants were sequenced, yielding a median of 3.8x107 microbial reads per sample (IQR 3.3x107 – 4.3x107). Measures of disease activity included patient reported outcomes (stool frequency (SF), abdominal pain (AP), Harvey-Brashaw Index); endoscopy (SES-CD) and commonly used clinical biomarkers (C-reactive protein (CRP), faecal calprotectin, serum albumin). All measures of disease activity were significantly improved by week 48 (P 0.05) consistent with impact of treatment. Microbial richness and diversity were significantly lower in participants with greater SF (P 0.005) when correcting for study timepoint, participant age, sex and BMI. Microbial richness was also lower in participants with greater SES-CD scores (P = 0.03). Community structure but not dispersal differed significantly between Montreal disease location (PERMANOVA: P = 0.001, R2=0.01, F = 2.04). Compared to exclusively colonic disease, abundance and prevalence of Ruminococcus torques, Enterocloster spp. and Mediterraneibacter spp. were greater in Ileal and Ileocolonic disease, offset by reduced Bifidobacterium longum and Clostridiaceae spp. Microbiome structure was significantly associated with SF in colonic disease (P = 0.02, R2=0.02) and Montreal disease behaviour in Ileal disease (P = 0.05, R2=0.02). Conclusion These results suggest that bacterial features in Crohn’s disease are more associated with endoscopic disease activity and stool frequency rather than with CRP or faecal calprotectin. Future work will benefit from evaluating microbial signatures of disease activity stratified by anatomical disease location. References: 1.Zheng J, Sun Q, Zhang M, et al. Noninvasive, microbiome-based diagnosis of inflammatory bowel disease. Nature Medicine 2024 30:12. 2024-10-04;30(12)doi:10.1038/s41591-024-03280-4 2.Noor NM, Lee JC, Bond S, et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. The Lancet Gastroenterology 9(5):415-427. doi:10.1016/s2468-1253(24)00034-7 Conflict of interest: Dr. Young, Greg: GRY is supported by the National Institute of Health Research (NIHR) Newcastle Noor, Nurulamin: Grant: NMN reports grants from Celltrion, Dr Falk Pharma, Pfizer, Pharmacosmos, Tillotts. Personal Fees: NMN reports personal fees from AbbVie, BMS, Celltrion, Ferring, J & J, Lilly, Pharmacosmos, Takeda. Beck, Lauren: No conflict of interest Sharip, Mohmmed Tauseef: Consultancy fees from Teva and Dr Falk Pharma. Watson, Hannah: No conflict of interest Mulligan, Robert: Robert J. Mulligan acknowledges research support from Open Targets, Wellcome Trust, European Bioinformatics Institute (EMBL-EBI), Genentech, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer, and Sanofi and support for educational meeting attendance from Ferring. Marchesi, Julian: No conflict of interest Jostins-Dean, Luke: No conflict of interest Stewart, Christopher: No conflict of interest Lyons, Paul: No conflict of interest Parkes, Miles: Grant: Gilead, Pfizer, AstraZeneca, Galapagos, Lilly, Takeda Lamb, Christopher Andrew: Grant: In the last 5 years I have undertaken research supported by grants from the following: Genentech, Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Roche, UCB Biopharma, Sanofi Aventis, Biogen IDEC, Orion OYJ and AstraZeneca. Personal Fees: In the last 5 years I have received honoraria for speaking at educational events from Takeda, Janssen, Dr Falk, Ferring and Nordic pharma. Other: The following companies were corporate sponsors of an educational event, IBD Newcastle 2023, I convened at Newcastle University on 29th November 2023 Amgen, Celltrion Healthcare, Janssen, Tillotts Pharma, Pharmacosmos, Dr Falk Pharma, Galapagos, Ferring, AbbVie, Takeda, Eli Lilly and Bristol Myers Squibb.