Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets.

BACKGROUND & AIMS: 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 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) 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 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 (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus 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 Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.

Plasmalogen status influences docosahexaenoic acid levels in a macrophage cell line. Insights using ether lipid-deficient variants.

Previously, this laboratory reported the isolation of variants, RAW. 12 and RAW.108, from the macrophage-like cell line RAW 264.7 that are defective in plasmalogen biosynthesis [Zoeller, R.A. et al. 1992. J. Biol. Chem. 267: 8299-8306]. Fatty acid analysis showed significant changes in the mutants in the ethanolamine phospholipids (PE), the only phospholipid class in which the plasmalogen species, plasmenylethanolamine, contributes significantly. Within the PE fraction, docosapentaenoic (DPA; 22:5n-3) and docosahexaenoic (DHA; 22:6n-3) acids were reduced by approximately 50% in the variants while the levels of arachidonic acid (AA; 20:4n-6) remained unaffected. The decrease in DHA was accompanied by a 50% decrease in labeling PE with [3H]DHA over a 90-min period. Restoration of plasmenylethanolamine by supplementing the growth medium with sn -1-hexadecylglycerol (HG) completely reversed these changes in RAW. 108. Pre-existing pools of plasmenylethanolamine were not required for restoration of normal [3H]DHA labeling; addition of HG only during the labeling period was sufficient. Due to the loss of Delta1'-desaturase in RAW.12, HG supplementation resulted in the accumulation of plasmenylethanolamine's immediate biosynthetic precursor, plasmanylethanolamine. Even though this latter phospholipid contained only the ether functionality (lacking the vinyl ether double bond) it was sufficient to restore wild type-like fatty acid composition and DHA labeling of the ethanolamine phospholipids, identifying the ether bond as a structural determinant for this specificity. In summary, we have used these mutants to establish that the plasmalogen status of a cell can influence the levels of certain polyunsaturated fatty acids. These results support the notion that certain polyunsaturated fatty acids, such as DHA, can be selectively targeted to plasmalogens and that this targeting occurs during de novo biosynthesis, or shortly thereafter, through modification of nascent plasmalogen pools.