Multi-omics phenotyping characterizes molecular divergence underlying different clinical scenarios of inflammatory bowel disease

ABSTRACT Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This study set out to explore the serum molecular profiles (I) of IBD subtypes; in association with (II) elevated fecal calprotectin and (III) disease activity states; (IV) upon treatment escalation; and (V) in patients who needed treatment escalation. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures. (I) Chronic inflammation, and phosphatidylcholine and bile acid homeostasis disturbances underlined the differences between Crohn’s disease (CD) and ulcerative colitis. (II) Elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to patient remission, active disease state (III) was characterized by decreased SMs and increased inflammatory proteins and TGs. (IV) Treatment escalation was associated with augmented levels of inflammatory response-related proteins and reduced levels of amino acids. Most TG species increased in the post-treatment escalation. Moreover, needed-treatment-escalation patients had significantly lower levels of TGs (V). They also showed increased SMs and decreased signaling receptor binding proteins. Multi-omics analysis revealed biosignatures that captured the differences between groups of each scenario. Eight analytes, including NFASC, ANGPTL4, and chenodeoxycholate, were found in at least three biosignatures. Collectively, disturbances in immune response, bile acid homeostasis, amino acids, and lipids alteration potentially underlie the clinically heterogeneous spectrum of IBD.