Journal Article

Personalized whole‐body models integrate metabolism, physiology, and the gut microbiome

Sahoo, Swagatika, Heinken, Almut, Hertel, Johannes, Thiele, Ines, Heirendt, Laurent, Fleming, Ronan MT, Aurich, Maike K

2020

Overview

Comprehensive molecular‐level models of human metabolism have been generated on a cellular level. However, models of whole‐body metabolism have not been established as they require new methodological approaches to integrate molecular and physiological data. We developed a new metabolic network reconstruction approach that used organ‐specific information from literature and omics data to generate two sex‐specific whole‐body metabolic (WBM) reconstructions. These reconstructions capture the metabolism of 26 organs and six blood cell types. Each WBM reconstruction represents whole‐body organ‐resolved metabolism with over 80,000 biochemical reactions in an anatomically and physiologically consistent manner. We parameterized the WBM reconstructions with physiological, dietary, and metabolomic data. The resulting WBM models could recapitulate known inter‐organ metabolic cycles and energy use. We also illustrate that the WBM models can predict known biomarkers of inherited metabolic diseases in different biofluids. Predictions of basal metabolic rates, by WBM models personalized with physiological data, outperformed current phenomenological models. Finally, integrating microbiome data allowed the exploration of host–microbiome co‐metabolism. Overall, the WBM reconstructions, and their derived computational models, represent an important step toward virtual physiological humans. Synopsis Sex‐specific, whole‐body human metabolic models were developed and constrained with physiological, dietary, and metabolomic data. They recapitulate known whole‐body metabolic functions and enable mechanistic exploration of host‐microbiome co‐metabolism. Sex‐specific whole‐body metabolic reconstructions represent the integrated function of 26 organs and six blood cell types. Stoichiometric reconstructions of metabolism can be constrained with whole‐body physiological and metabolomic data to generate personalized models. Whole‐body metabolic models recapitulate known inter‐organ metabolic cycles and energy use, successfully predict known biomarkers of inherited metabolic diseases, and explore potential host‐microbiome co‐metabolism. Graphical Abstract Sex‐specific, whole‐body human metabolic models were developed and constrained with physiological, dietary, and metabolomic data. They recapitulate known whole‐body metabolic functions and enable mechanistic exploration of host‐microbiome co‐metabolism.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Algorithms / Biomarkers / Biomarkers - metabolism / Blood / Blood cells / Cervix / Computer applications / Computer Simulation / Customization / Digestive system / EMBO10 / EMBO21 / Energy consumption / Energy Metabolism - genetics / Energy Metabolism - physiology / Female / flux balance analysis / Gastrointestinal Microbiome - genetics / Gene Expression Regulation - genetics / Gene Expression Regulation - physiology / Genomes / Gut microbiota / Human body / human metabolism / Humans / Intestinal microflora / Male / Mathematical models / Metabolic disorders / metabolic modeling / Metabolic networks / Metabolic Networks and Pathways - genetics / Metabolic rate / Metabolism / Metabolites / Metabolome - genetics / Metabolomics / Metabolomics - methods / microbiome / Microbiomes / Microbiota / Molecular modelling / Organ Specificity / Organs / Ovaries / Physiology / Prostate / Proteomics / Reconstruction / Small intestine / Systems Biology - methods / Uterus