Abstract
Phenotypic diversity in urinary metabolomes of different geographical populations has been recognized recently. In this study, urinary metabolic signatures from Western (United Kingdom) and South-East Asian (Thai) cholangiocarcinoma patients were characterized to understand spectral variability due to host carcinogenic processes and/or exogenous differences (nutritional, environmental and pharmaceutical). Urinary liquid chromatography mass spectroscopy (LC–MS) spectral profiles from Thai (healthy = 20 and cholangiocarcinoma = 14) and UK cohorts (healthy = 22 and cholangiocarcinoma = 10) were obtained and modelled using chemometric data analysis. Healthy metabolome disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Metabolites excreted due to drug treatment were dominant in urine specimens from cholangiocarcinoma patients, particularly in Western individuals. Urine from participants with sporadic (UK) cholangiocarcinoma contained greater levels of a nucleotide metabolite (uridine/pseudouridine). Higher relative concentrations of 7-methylguanine were observed in urine specimens from Thai cholangiocarcinoma patients. The urinary excretion of hippurate and methyladenine (gut microbial-host co-metabolites) showed a similar pattern of lower levels in patients with malignant biliary tumours from both countries. Intrinsic (body weight and body composition) and extrinsic (xenobiotic metabolism) factors were the main causes of disparities between the two populations. Regardless of the underlying aetiology, biological perturbations associated with cholangiocarcinoma urine metabolome signatures appeared to be influenced by gut microbial community metabolism. Dysregulation in nucleotide metabolism was associated with sporadic cholangiocarcinoma, possibly indicating differences in mitochondrial energy production pathways between cholangiocarcinoma tumour subtypes. Mapping population-specific metabolic disparities may aid in interpretation of disease processes and identification of candidate biomarkers.
Highlights
Collisioninduced dissociation (CID) Collision-induced dissociation computed tomography (CT) Computed tomography CV‐ANOVA ANOVA of cross‐validated residuals DDA Data-dependent acquisition electrospray ionisation (ESI) Electrospray ionization ESI − Electrospray ionisation negative mode ESI + Electro spray ionisation positive mode liquid chromatography mass spectroscopy (LC–MS) Liquid chromatography mass spectroscopy magnetic resonance imaging (MRI) Magnetic resonance imaging nuclear magnetic resonance (NMR) Nuclear magnetic resonance orthogonal projections to latent structures discriminant analysis (OPLS-DA) Orthogonal projections to latent structures discriminant analysis quality control (QC) Quality control RP Reverse phase TOF Time of flight UPLC Ultra performance liquid chromatography
The unique characteristics of Isaan people from North-East Thailand, where eating raw, or partially cooked and/or fermented cyprinid fish from river systems which flow into the Mekong River leads to the frequent development of Opisthorchis viverrini liver fluke-associated cholangiocarcinoma (CCA), may lead to population-specific metabolic patterns in the urinary profile of both heathy and diseased individuals[2]
Malignant strictures were diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI) and further confirmed by histology at surgical operation
Summary
CID Collision-induced dissociation CT Computed tomography CV‐ANOVA ANOVA of cross‐validated residuals DDA Data-dependent acquisition ESI Electrospray ionization ESI − Electrospray ionisation negative mode ESI + Electro spray ionisation positive mode LC–MS Liquid chromatography mass spectroscopy MRI Magnetic resonance imaging NMR Nuclear magnetic resonance OPLS-DA Orthogonal projections to latent structures discriminant analysis QC Quality control RP Reverse phase TOF Time of flight UPLC Ultra performance liquid chromatography. In a study applying nuclear magnetic resonance (NMR)-based metabolomics to a large-scale dataset (n = 4630, from China, Japan, UK and USA), geographic differences were found to contribute greatly to metabolic phenotype variation in urine, and were of greater magnitude than gender-related metabolic differences[3]. The main focus of our study was to compare the global urinary metabotype from a Thai population with Opisthorchis-associated CCA, to a Western patient population where CCA is sporadic. Another aim was to characterize the baseline healthy metabolome of the two distinct populations
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