"Defining the Human Metabotype" [Human metabolic status defined through genetic, diet,environmental exposure and exercise perturbations]

PROJECT SUMMARY/ABSTRACT Molecular Transducers of Physical Activity (MoTrPAC), Nutrition for Precision Health (NPH), and the Human Health Exposure Analysis Resource (HHEAR) are NIH-funded national projects (three originating from NIH Common Fund initiatives) that measure thousands of metabolites in large cohorts of human subjects under exercise, diet, environmental exposure conditions respectively. The Common Fund initiated Metabolomics Workbench, which serves as the data repository, the metabolomics harmonization center and the data analytics workbench for deep analyses of human metabolomics and provides the infrastructure to develop the concept of human metabotype. We characterize the metabolomic state of groups of individuals with common homeostatic points for a collection of metabolites as “human metabotypes”. More precisely, the metabotype defines a collection of metabolites or metabolite classes that is unique (in the metabolomic hyperspace) to a class of individuals – defined in this project through metabolomics measurements from humans subject to exercise and diet perturbations and humans subject to distinct environmental exposures. Human subjects can be classified as belonging to one of several distinct groups (e.g., clusters in a UMAP) defining the metabotype for a chosen set of metabolites in a class. At the quantitative level, the distinct groups are defined by distinct profiles of metabolites or metabolite classes. The major goal of this project is to use the three national projects to develop the “metabotype” concept into a concrete set of points in the metabolomics hyperspace that define the human physiological state. Towards this, we harmonize the metabolomics data across the national projects, identify the clusters of metabolites/metabolite classes that define a group of human subjects, and provide the biological context to the metabotype. The tools we will develop will enable an end user to analyze and decipher the physiological function that further defines the metabotype and explore perturbations such as exercise, diet, or changing environment to see how the homeostatic endotype points change into another possible homeostatic state. Most importantly, given that the definition of the endotypes in the MoTrPAC, NPH and HHEAR projects largely refer to healthy human subjects, we will develop the ability for any individual with their metabolomic measurements to map their data on the metabotype space. Using such a “Metabotype Calculator”, the most valuable product of this project, a human subject will be able to assess their “state of health” and assess how perturbations such as exercise or diet will alter their homeostatic metabotype states. We anticipate that the “Metabotype Calculator” will serve as a dynamic living counterpart to the genotype in defining the human subject’s state of physiology. All the resources developed in this project will be available on the Common Fund Data Ecosystem Data Repository Center (CFDE DRC). The Principal Investigator (PI) of this U24, also the CFDE DRC PI, will facilitate making this resource available to the user community.