Integrative analysis of the Inflammatory Bowel Disease serum metabolome improves our understanding of genetic etiology and points to novel putative therapeutic targets

Abstract Background Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. Methods We measured the levels of 1300 metabolites in the serum of 484 ulcerative colitis (UC) and 464 Crohn's disease (CD) patients and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity as well as IBD phenotype including disease behavior, location and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization (MR) analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. Results We found 173 genetically controlled metabolites (mQTL, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined by clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel mQTL for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through MR; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted causal for CD. Conclusion An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.