Translational Metabolomics in Critical Care

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Linked publications & trials

Abstract

Sepsis and other critical illnesses remain significant hazards to human health. Sepsis and the Acute Respiratory Distress Syndrome (ARDS) are particularly challenging because they are associated with great heterogeneity that has kept the identification of diagnostic and predictive biomarkers and effective pharmacotherapy elusive. To tackle the problem of critical illness heterogeneity, my research program employs Translational Metabolomics which bridges the translational gap between analytical and experimental techniques and the clinical application of the science of metabolomics. To achieve my goals, I have innovative swine models of sepsis and ARDS that faithfully recapitulate the human situations, ready access to human sepsis cohorts for clinical validation, novel point-of-care (POC) technology and can assay clinical and experimental biospecimens using a range of analyt- ical platforms including liquid chromatography (LC)-mass spectroscopy (MS) and quantitative nuclear magnetic resonance (NMR). Over the last four years of MIRA funding, I have advanced understanding about the meta- bolic mechanisms that underlie sepsis morbidity and mortality, identified a metabolic signature that is predictive of these outcomes, and uncovered a relationship between angiopoietin (ANG) 2 blood levels and phenotypes of sepsis and ARDS. Under this MIRA renewal application, I will advance these initiatives to achieve the over- arching and long-term goal of my program which is to move metabolomics from knowledge discovery to imple- mentation that will transform the care of patients with critical illnesses. To achieve this, I will address four key questions: 1) How do gut pH and gut microbial metabolites contribute to the heterogeneity of sepsis? 2) Does inhibition of ANG 2 intensify sepsis-induced disruption in energy homeostasis or improve end-organ function? 3) What is the predictive value of blood acetylcarnitine concentration for sepsis induced organ dysfunction, per- sistent critical illness, and mortality? and 4) Does supplemental L-carnitine remedy the loss of cardiac meta- bolic homeostasis during sepsis? By addressing these critical questions, we will gain novel insights into the role of gut pH in sepsis heterogeneity, learn about the metabolic contribution of ANG 2 in ARDS, further cre- dential acetylcarnitine as a candidate biomarker of sepsis outcome, and advance understanding of organ-level changes in energy homeostasis during sepsis. Collectively, these findings will contribute to fundamental knowledge of metabolic mechanisms that drive critical illness heterogeneity. These new insights will provide a precision medicine directive for the effective treatment of sepsis and ARDS, fuel the advancement of well-in- formed adaptive clinical trial design, and improve human health.