To Örebro University

Background: Paediatric inflammatory bowel disease (IBD), comprising the subtypes Crohn’s disease (CD) and ulcerative colitis (UC), is believed to result from an interplay between genetic predisposition and environmental exposures. Examining exposome metabolome may help to identify environmental exposures, including host-derived metabolites, with potential relevance in paediatric IBD.

Methods: Relative concentrations of metabolites were measured in serum samples from treatment-naïve patients with IBD (N = 80) and symptomatic, non-IBD controls (N = 37) included in the IBSENIII cohort (Table 1). Ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS) was performed. Authentic standards or the Human Metabolome Database were used for annotation. Associations with IBD, with CD (N = 53), and with UC including IBD-unclassified (N = 27), were assessed using logistic regression while adjusting for sex, age, and BMI. In addition, correlations with serum proteins (proximity extension assay technology) were examined. A false discovery rate (PFDR) threshold of < 0.1 was applied.

Results: We observed positive association of aryl sulfate (phenol sulfate; PFDR=0.03) with IBD versus symptomatic controls (Figure 1). Within the IBD population, aryl sulfate was positively correlated with several serum proteins, including CCL20 (r = 0.48, PFDR=0.004), MCP-3 (r = 0.47, PFDR=0.004), and TNF-α (r = 0.45, PFDR=0.001). We observed inverse associations of four perfluoroalkyl substances (PFAS); (linear-perfluorooctane sulfonate (PFOS-L), branched-perfluorohexanesulfonate (PFHxS-B), perfluorooctanoate (PFOA), and branched-perfluorooctane sulfonate (PFOS-B)) with IBD, UC, or both. In IBD, PFOA, PFOS-L, PFHxS-B positively correlated with Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) protein levels. The secondary bile acid 6-ketholithocholic acid was inversely associated with UC, while the primary bile acids glycochenodeoxycholic acid-3-O-sulfate, cholic acid and glycocholic acid were positively associated with UC (all PFDR<0.1).

Conclusion: Several metabolites including aryl sulfate were associated with paediatric IBD and correlated with inflammation-related proteins. These findings confirm recent results from preclinical Crohn’s disease1 and may point towards a role of aryl sulfate at IBD diagnosis.