Novel, Objective, Multivariate Biomarkers Composed of Plasma Amino Acid Profiles for the Diagnosis and Assessment of Inflammatory Bowel Disease

Abstract

BackgroundInflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram).Methodology and Principal FindingsWe measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898–0.983) and 0.894 (95%CI: 0.853–0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853–0.935) and 0.849 (95%CI: 0.770–0.928), and correlated with clinical disease activity indexes for CD (rs = 0.592, 95%CI: 0.385–0.742, p<0.001) or UC (rs = 0.598, 95%CI: 0.452–0.713, p<0.001), respectively.Conclusions and SignificanceIn this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.

Metabolomics in the Clinical Diagnosis of Inflammatory Bowel Disease

“…Also Hisamatsu et al [52] distinguished between patients (UC and CD) with active disease and those in remission using plasma aminograms. Other studies failed to distinguish between active and inactive IBD [44,50] .…”

Systems biology in inflammatory bowel diseases

“…The analytical techniques used to study the metabolome, include gas chromatography (GC), liquid chromatography (LC) and high/ultra-performance liquid chromatography (H/UPLC) followed by mass spectrometry (MS), and nuclear magnetic resonance spectroscopy (NMR) 54 . Different metabolomic approaches have been applied in human biomaterials, including fecal water extracts, blood serum and urine samples, aiming to discriminate IBD patients from control subjects [55][56][57][58][59][60][61][62] . Furthermore, 1 H NMR spectroscopy and LC-MS have revealed distinct metabolic profiles between different intestinal compartments 63 .…”

Immunological Abnormalities in the Pathogenesis of Inflammatory Bowel Disease

“…32 Interestingly, amino acid profiling revealed decreased levels of plasma histidine concentration in the patients with active Crohn' s disease. 33 We have demonstrated that several molecules can affect the differentiation of monocytes to DCs. Am80, a synthetic retinoic acid receptor (RAR) agonist, promotes the differentiation of monocytes to an IL-12p70 hypo-producing DC phenotype with a reduced Th1 polarizing ability.…”