P198 An inflammatory serum metabolomic signature predicts response to vedolizumab treatment in people with Crohn’s Disease

Abstract

Abstract Background While Vedolizumab (VDZ) is an established treatment for Crohn’s disease (CD), primary non-response is well-recognised – there is an urgent clinical need for biomarkers that predict response, before initiation of treatment. Metabolomic profiling is a rapidly growing field in biomarker discovery and can distinguish between active and quiescent inflammatory bowel diseases. Here, we sought to identify a metabolic signature able to predict response to VDZ. Methods Prospective serum samples from 62 CD patients before (baseline) and post-treatment follow-up (FU) (median 30 weeks, IQR 27–35) were analyzed. Patients were stratified into n=35 responders (R) and n=27 non-responders (NR) using endoscopic (≥50% reduction in SES-CD score), clinical (≥3 point drop in HBI or HBI ≤4, no systemic steroids), and/or biochemical assessments (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin (fCal) or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Untargeted metabolomic profiling was carried out using high-resolution nuclear magnetic resonance (NMR) spectroscopy. Significant differences in metabolite signatures were identified by orthogonal partial least squares discriminant analysis (OPLS-DA). Model accuracy (acc.) was assessed by external 10-fold cross-validation (CV), permutation testing, and validated on an independent test set. Results We first demonstrate that bowel preparation required for endoscopy had a significant impact on the serum metabolite profile (CV acc. 77±4%, acc. n=10 independent test set 80%, KS test p-value < 0.001) and samples taken from patients at colonoscopy were excluded from further analysis. This reduced the cohort size; 19 baseline (12R/7NR) and 25 FU (16R/9NR). No significant difference in baseline fCal or CRP was observed between R and NR (t-test p-value >0.05). The metabolite profiles at baseline and FU were indistinguishable (KS test p-value > 0.05) suggesting the metabolome was stable. However, high (>300 µg/g) fCal values were associated with elevated N-acetyl-glycoprotein (GlycA), a known inflammatory marker, elevated serum glucose along with decreased lipoprotein and lactate levels (CV acc. 74±3%, acc. n=10 independent test set 100%, KS test p-value < 0.001). This same metabolite signature predicts response (CV acc. 61±5%, acc. n=6 independent test set 83%, KS test p-value < 0.001) with responders exhibiting increased metabolic inflammation at baseline. Conclusion Here, we identify an inflammatory metabolic signature which predicts response to VDZ. Work to confirm these findings in a larger cohort and extend this method to investigate infliximab, adalimumab and ustekinumab treated patients, as part of the EPIC Pioneer study, is ongoing.