P060 Increased metabolic activity of faecal Sutterella Wadsworthensis at IBD onset is associated with an increased risk of escalation to biologic therapies - Results from the Birimingham Inception Cohort Study

Abstract

Abstract Background Gut microbiome disruption is an established characteristic of IBD. The lack of treatment naïve longitudinal microbiome data makes it challenging to separate the influence of potential confounders. We present detailed stool metagenomics analysis from a treatment naïve cohort of IBD patients seen in our rapid-access IBD inception clinic. Methods Stool collected in DNA Genotek OM-200 kits was collected pre-diagnosis, alongside a faecal calprotectin (FCP). Microbial DNA was extracted. Libraries were prepared using NEBNext Ultra II FS DNA Library Prep Kit, NEBNext Multiplex Oligos and sequenced using an Illumina NextSeq550. Data processing was undertaken using the HUMAnN 3.0 workflow. After quality control, a median of 3.6 million reads per sample were obtained. Abundance was mapped to the ChocoPhlAn database and functional pathways derived from MetaCyc. Diversity analysis was undertaken in Vegan, with MaAsLin2 for taxa differences. A False discovery Rate (FDR) <0.2 was considered relevant, <0.05 highly significant. Results A total of 45 CD and 33 UC inception patients were included. There was no significant difference in alpha diversity (Shannon; UC median 2.58[IQR 0.8], CD 2.69[1.04] p=0.36) or differential clustering for beta diversity. Shannon alpha diversity significantly associated with FCP across IBD (n=74, Spearman’s Rho [SR] -0.33 p=0.004) and endoscopic severity in both IBD subtypes (UCEIS n=30 SR -0.37 p=0.047, SESCD n=44 SR -0.35 p=0.016). Across IBD, patients going on to require biologic therapy had a significantly lower baseline Shannon (BioYes 2.26[0.98], BioNo 2.77[0.88] p=0.02, split by IBD subtype in Figure 1). Across IBD, increased FCP associated with depletion of two strains of Faecalibacterium Prausnitzii (SGB15318, log2 fold change[L2FC] -1.2 FDR 0.09; SGB15342 L2FC -1.1 FDR 0.15) alongside Roseburia Intestinalis (SGB4951 L2FC -0.7 FDR 0.09). R.Intestinalis also negatively correlated with Harvey Bradshaw Index (L2FC -0.93 FDR 0.02), whilst F.Prausnitzii (SGB15342) did with UCEIS (L2FC -2.3 FDR 0.05). 82 metabolic pathways correlated with UCEIS (FDR <0.2, 8 <0.05), with 89 for SESCD (6 <0.05). Increased activity of Sutterella Wadsworthensis associated positively with UCEIS (5 pathways). On initial comparison across IBD, no significant signal was seen for future biologic utilisation. However, if analyses were corrected for baseline inflammation (derived by FCP), increased activity of S.Wadsworthensis was again seen (Table 1). Conclusion Reduced alpha diversity at IBD onset associated with increased disease severity and future utilisation of biologic treatment. Increased activity of S.Wadsworthensis associated with an increased risk of future biologic requirement above that explained by mucosal inflammation alone.