TGR 5 signalling inhibits the production of pro‐inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97471/1/imm12045.pd

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

BACKGROUND: Inflammatory 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 FINDINGS: We 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 (r(s) = 0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s) = 0.598, 95%CI: 0.452-0.713, p<0.001), respectively. CONCLUSIONS AND SIGNIFICANCE: In 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

Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission.

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41-4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease

P-values and regression coefficient of Cox regression analysis with/without gender- and age-adjustment, and data normalization for each amino acid and CRP.

<p>a-ABA, α-aminobutyric acid.</p><p>P-values and regression coefficient of Cox regression analysis with/without gender- and age-adjustment, and data normalization for each amino acid and CRP.</p

Flowchart of the patients in the study.

<p>Flowchart of the patients in the study.</p

Relapse ratio for each quartile by normalized plasma histidine level at each observational term.

<p>Relapse ratio for each quartile by normalized plasma histidine level at each observational term.</p

Kaplan—Meier analysis of whole patients who have successfully followed up.

<p>Kaplan—Meier analysis of whole patients who have successfully followed up.</p