Serum Metabolomics Identifies Altered Bioenergetics, Signaling Cascades in Parallel with Exposome Markers in Crohn’s Disease

Abstract

Inflammatory bowel disease (IBD) has stimulated much interest due to its surging incidences and health impacts in the U.S. and worldwide. However, the exact cause of IBD remains incompletely understood, and biomarker is lacking towards early diagnostics and effective therapy assessment. To tackle these, the emerging high-resolution mass spectrometry (HRMS)-based metabolomics shows promise. Here, we conducted a pilot untargeted LC/MS metabolomic profiling in Crohn’s disease, for which serum samples of both active and inactive cases were collected, extracted, and profiled by a state-of-the-art compound identification workflow. Results show a distinct metabolic profile of Crohn’s from control, with most metabolites downregulated. The identified compounds are structurally diverse, pointing to important pathway perturbations ranging from energy metabolism (e.g., β-oxidation of fatty acids) to signaling cascades of lipids (e.g., DHA) and amino acid (e.g., L-tryptophan). Importantly, an integral role of gut microbiota in the pathogenesis of Crohn’s disease is highlighted. Xenobiotics and their biotransformants were widely detected, calling for massive exposomic profiling for future cohort studies as such. This study endorses the analytical capacity of untargeted metabolomics for biomarker development, cohort stratification, and mechanistic interpretation; the findings might be valuable for advancing biomarker research and etiologic inquiry in IBD.

Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

“…In general, it has been possible to stratify patients with IBD from healthy individuals as controls 47,49,51 , although differences between the metabolomes of patients with Crohn's disease and those with ulcerative colitis are less clear. Increased catabolism of fatty acids, changes (mostly reductions) in amino acid metabolites, notably serotonergic and indole derivatives of tryptophan, as well as reductions in levels of phenylalanine and the histidine metabolite ergothioneine and some alterations in xenobiotic metabolism were observed using liquid chromatography-mass spectrometry on serum samples in patients with Crohn's disease compared with controls 55 .…”

The biology of ergothioneine, an antioxidant nutraceutical

“…Similar effects were observed in Caenorhabditis elegans (411) . Polymorphisms in SLC22A4, of which there can be many (177,(412)(413)(414)(415) , under selection (416) , have also been associated with ischaemic stroke (417) , erythroid differentiation (418) , hearing loss (412) , rheumatoid arthritis (126,180,(419)(420)(421)(422)(423)(424)(425)(426)(427) , lupus (428) , Crohn's disease (401,(429)(430)(431)(432)(433)(434)(435)(436) , hearing loss (412) , type 1 diabetes (437) and diabetic embryopathy (438) . The expression of SLC22A4 can itself be modulated by other factors, including by PPAR-α activity (439) .…”

Mucosal Metabolomic Profiling and Pathway Analysis Reveal the Metabolic Signature of Ulcerative Colitis

“…Previous published metabolomic data from IBD patients have given first hints on metabolic changes during the course of the disease. However, these data are either generated from serum [9][10][11][12][13][14], stool [12], or urine [15] samples. Moreover, these studies were restricted to pediatric patients [12,14], or treated patients [9,11,13,15].…”