Genome scale metabolic network modelling for metabolic profile predictions

Metabolic profiling (metabolomics) aims at measuring small molecules (metabolites) in complex samples like blood or urine for human health studies. While biomarker-based assessment often relies on a single molecule, metabolic profiling combines several metabolites to create a more complex and more specific fingerprint of the disease. However, in contrast to genomics, there is no unique metabolomics setup able to measure the entire metabolome. This challenge leads to tedious and resource consuming preliminary studies to be able to design the right metabolomics experiment. In that context, computer assisted metabolic profiling can be of strong added value to design more quickly and efficiently metabolomics studies. We propose a constraint-based modelling approach which predicts in silico profiles of metabolites that are more likely to be differentially abundant under a given metabolic perturbation (e.g. due to a genetic disease), using flux simulation. In genome-scale metabolic networks, the fluxes of exchange reactions, also known as the flow of metabolites through their external transport reactions, can be simulated and compared between control and disease conditions in order to calculate changes in metabolite import and export. These import/export flux differences would be expected to induce changes in circulating biofluid levels of those metabolites, which can then be interpreted as potential biomarkers or metabolites of interest. In this study, we present SAMBA (SAMpling Biomarker Analysis), an approach which simulates fluxes in exchange reactions following a metabolic perturbation using random sampling, compares the simulated flux distributions between the baseline and modulated conditions, and ranks predicted differentially exchanged metabolites as potential biomarkers for the perturbation. We show that there is a good fit between simulated metabolic exchange profiles and experimental differential metabolites detected in plasma, such as patient data from the disease database OMIM, and metabolic trait-SNP associations found in mGWAS studies. These biomarker recommendations can provide insight into the underlying mechanism or metabolic pathway perturbation lying behind observed metabolite differential abundances, and suggest new metabolites as potential avenues for further experimental analyses. Author summary Associating diseases and other metabolic disruptions with physiological markers is key for diagnostic and personalised medicine. These markers can be metabolites - small molecules involved in every living being’s metabolism, and can be measured in biofluids such as blood or urine using metabolic profiling (metabolomics). Nevertheless, this experimental metabolomics design needs to be tailor made for each disease to ensure that most relevant metabolites will be detected. The selection of metabolites to analyse for future experiments can be time-consuming and expensive. In this paper, we build upon an existing computational method for simulating metabolite changes in a human model. This provides a prediction of the change in biofluid abundance of every known metabolite involved in human metabolism in a potentially large number of metabolic situations. The newly introduced method produces a change score and a rank for each metabolite in each condition. We show the strong potential of the approach by comparing predictions with experimental results.