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. 2019 Jan 27;24(3):449.
doi: 10.3390/molecules24030449.

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

Yunjia Lai  1 , Jingchuan Xue  2 , Chih-Wei Liu  3 , Bei Gao  4 , Liang Chi  5 , Pengcheng Tu  6 , Kun Lu  7 , Hongyu Ru  8
Affiliations

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

Yunjia Lai et al. Molecules. .

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.

Keywords: Crohn’s Disease; Docosahexaenoic acid; Ergothioneine; Exposome; Gut Microbiota; Inflammatory Bowel Disease; Serum Metabolomics; Tryptophan Metabolism.

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Conflict of interest statement

The authors declare no conflict of financial interest.

Figures

Figure 1
Figure 1
Distinct metabolic profiles of Crohn’s disease compared with control, as revealed by total ion chromatogram (TIC)-based metabolomic cloudplots defined by Welch’s t-test (p < 0.05) (Panel A, C) and principal component analysis (PCA) plots with 95% confidence area highlighted (Panel B, D), which passed permutation tests as part of the validation procedures.
Figure 2
Figure 2
Perturbed pathways identified in MetaboAnalyst 3.0 using hypergeometric test for over-representation analysis and relative-betweenness centrality for pathway topology analysis. Here, the x-axis marks the pathway impact and the y-axis represents the pathway enrichment. Each node marks a pathway, with larger sizes and darker colors representing higher pathway enrichment and higher pathway impact values.
Figure 3
Figure 3
Enhanced β-oxidation of fatty acids and altered lipid signaling cascades is observed in Crohn’s patients, as evidenced by decreasing long-chain fatty acids (A–C) and medium-chain fatty acids (D), as well as increasing acylcarnitine (E–H) in blood circulation. The y-axis measures the peak height of the profiled metabolites, and the x-axis marks the three IBD groups for comparison, namely control (green), inactive (orange), and active (red), outliers, represented as dots, were excluded from comparison. *** p < 0.001, ** p < 0.01, * p < 0.05.
Figure 4
Figure 4
Altered metabolism of amino acids were extensively observed for Crohn’s patients. This includes diminishing 5-HTP, the immediate precursor of 5-HT (A), microbe-mediated tryptophan metabolism (B–D), phenylalanine metabolism (E), and histidine metabolism (F). The y-axis measures the peak height of the profiled metabolites, and the x-axis marks the three IBD groups for comparison, namely control (green), inactive (orange) and active (red), outliers, represented as dots, were excluded from comparison. *** p < 0.001, ** p < 0.01, * p < 0.05.
Figure 5
Figure 5
Other than canonical pathways, xenobiotics and novel metabolites were detected in our study at stratified levels among active Crohn’s, inactive Crohn’s, and the Control. Examples include xenobiotic marker AAMU (Panel A) and Pterosin E (Panel B), as well as novel metabolite 2′-O-methyl-5-methyluridine (Panel C). The y-axis measures the peak height of the profiled metabolites, whereas the x-axis marks the three IBD groups for comparison, namely control (green), inactive (orange), and active (red), outliers, represented as dots in the boxplot, were excluded from comparison. ** p < 0.01, * p < 0.05.
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