Evidence of a genetically driven metabolomic signature in actively inflamed Crohn's disease.

Crohn's disease (CD) is characterised by chronic inflammation. We aimed to identify a relationship between plasma inflammatory metabolomic signature and genomic data in CD using blood plasma metabolic profiles. Proton NMR spectroscopy were achieved for 228 paediatric CD patients. Regression (OPLS) modelling and machine learning (ML) approaches were independently applied to establish the metabolic inflammatory signature, which was correlated against gene-level pathogenicity scores generated for all patients and functional enrichment was analysed. OPLS modelling of metabolomic spectra from unfasted patients revealed distinctive shifts in plasma metabolites corresponding to regions of the spectrum assigned to N-acetyl glycoprotein, glycerol and phenylalanine that were highly correlated (R2 = 0.62) with C-reactive protein levels. The same metabolomic signature was independently identified using ML to predict patient inflammation status. Correlation of the individual peaks comprising this metabolomic signature of inflammation with pathogenic burden across 15,854 unselected genes identified significant enrichment for genes functioning within 'intrinsic component of membrane' (p = 0.003) and 'inflammatory bowel disease (IBD)' (p = 0.003). The seven genes contributing IBD enrichment are critical regulators of pro-inflammatory signaling. Overall, a metabolomic signature of inflammation can be detected from blood plasma in CD. This signal is correlated with pathogenic mutation in pro-inflammatory immune response genes.

Analysis and Hierarchical Clustering of Blood Results Before Diagnosis in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Pediatric inflammatory bowel disease (PIBD) is associated with a diagnostic delay. Blood tests are a routine part of the work-up in children with chronic abdominal symptoms (pain, diarrhea). Normal blood tests cannot exclude PIBD. We analyzed blood results at diagnosis over a 5-year period. METHODS: Patients diagnosed from 2013 to 2017 were identified from the Southampton-PIBD database. Results were obtained up to 100 days before diagnostic endoscopy. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, hemoglobin, platelets, packed cell volume (PCV), white cell count (WCC), and alanine transferase (ALT) were analyzed. Hierarchical clustering was applied to normalized results. RESULTS: Two hundred fifty-six patients were included (Crohn's disease [CD], 151; ulcerative colitis [UC], 95; IBD-unclassified, 10; median age, 13.48 years; 36.7% female). Hierarchical clustering of patients revealed novel groupings enriched for CD and UC, characterized by specific patterns of results. In PIBD, 9% presented with all normal blood tests, 21.9% with normal CRP and ESR. Abnormal results were seen in all tests (ESR, 56.4% of patients; CRP, 53.4%; albumin, 28%; hemoglobin, 61.9%; platelets, 55.6%; PCV, 64.6%; WCC, 22.7%; and ALT, 7.2%). Normal inflammatory markers were more common in UC compared with CD (UC, 34%; CD, 15.8%; P = 0.0035). UC (14.4% normal) presented with all normal results more frequently than CD (CD, 5.3%; P = 0.02). CRP, ESR, and platelets were significantly higher in CD compared with UC. Albumin and hemoglobin were significantly lower. CONCLUSIONS: Most cases of PIBD present with >1 abnormal blood result, although 1/11 patients presents with normal blood tests and 1/5 present with normal inflammatory markers. Hierarchical clustering offers the potential to produce novel groupings to inform disease categorization and best management.

Increased prevalence of anti-TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood.

BACKGROUND: Anti-tumour necrosis factor-α (anti-TNF) therapy use has risen in paediatric-onset inflammatory bowel disease (PIBD). Whether this has translated into preventing/delaying childhood surgery is uncertain. The Wessex PIBD cohort was analysed for trends in anti-TNF-therapy and surgery. AIM: To assess patients diagnosed with PIBD within Wessex from 1997 to 2017. The prevalence of anti-TNF-therapy and yearly surgery rates (resection and perianal) during childhood (<18 years) were analysed (Pearson's correlation, multivariate regression, Fisher's exact). RESULTS: Eight-hundred-and-twenty-five children were included (498 Crohn's disease, 272 ulcerative colitis, 55 IBD-unclassified), mean age at diagnosis 13.6 years (1.6-17.6), 39.6% female. The prevalence of anti-TNF-treated patients increased from 5.1% to 27.1% (2007-2017), P = 0.0001. Surgical resection-rate fell (7.1%-1.5%, P = 0.001), driven by a decrease in Crohn's disease resections (8.9%-2.3%, P = 0.001). Perianal surgery and ulcerative colitis resection-rates were unchanged. Time from diagnosis to resection increased (1.6-2.8 years, P = 0.028) but mean age at resection was unchanged. Patients undergoing resections during childhood were diagnosed at a younger age in the most recent 5 years (2007-2011 = 13.1 years, 2013-2017 = 11.9 years, P = 0.014). Resection-rate in anti-TNF-therapy treated (16.1%) or untreated (12.2%) was no different (P = 0.25). Patients started on anti-TNF-therapy <3 years post-diagnosis (11.6%) vs later (28.6%) had a reduction in resections, P = 0.047. Anti-TNF-therapy prevalence was the only significant predictor of resection-rate using multivariate regression (P = 0.011). CONCLUSIONS: The prevalence of anti-TNF-therapy increased significantly, alongside a decrease in surgical resection-rate. Patients diagnosed at younger ages still underwent surgery during childhood. Anti-TNF-therapy may reduce the need for surgical intervention in childhood, thereby influencing the natural history of PIBD.