The Emerging Field of Quantitative Blood Metabolomics for Biomarker Discovery in Critical Illnesses

Abstract

Metabolomics, a science of systems biology, is the global assessment of endogenous metabolites within a biologic system and represents a "snapshot" reading of gene function, enzyme activity, and the physiological landscape. Metabolite detection, either individual or grouped as a metabolomic profile, is usually performed in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry followed by sophisticated multivariate data analysis. Because loss of metabolic homeostasis is common in critical illness, the metabolome could have many applications, including biomarker and drug target identification. Metabolomics could also significantly advance our understanding of the complex pathophysiology of acute illnesses, such as sepsis and acute lung injury/acute respiratory distress syndrome. Despite this potential, the clinical community is largely unfamiliar with the field of metabolomics, including the methodologies involved, technical challenges, and, most importantly, clinical uses. Although there is evidence of successful preclinical applications, the clinical usefulness and application of metabolomics in critical illness is just beginning to emerge, the advancement of which hinges on linking metabolite data to known and validated clinically relevant indices. In addition, other important aspects, such as patient selection, sample collection, and processing, as well as the needed multivariate data analysis, have to be taken into consideration before this innovative approach to biomarker discovery can become a reliable tool in the intensive care unit. The purpose of this review is to begin to familiarize clinicians with the field of metabolomics and its application for biomarker discovery in critical illnesses such as sepsis.

Early hemorrhage triggers metabolic responses that build up during prolonged shock

“…However, most of the evidence accumulated during the past decades has been based upon targeted biochemical assays, and no panoramic overview has been hitherto produced about the dynamic changes to the plasma metabolome induced by trauma/hemorrhagic shock. The advent of NMR-based metabolomics has allowed us to analyze tens of metabolites in a single analysis, thereby paving the way for a deeper understanding of the main metabolic changes secondary to traumatic injury (8,32,32,42). Recent advances in the field of MS-based metabolomics have brought about a new era in the field of trauma metabolomics, even though reports available so far mainly focus on the "ischemia/reperfusion" stage (6).…”

“…Other overlapping stages have been described over the years, such as the "ischemia-reperfusion," "leukocytic," and "angiogenic" (2), although the boundaries between these phases are rather labile (4, 24). The incomplete understanding of the metabolic stages seen during trauma and hemorrhage has hampered the capacity to significantly improve resuscitative strategies.Advances in fields such as proteomics (10) and metabolomics (6,8,32,42) offer big strides toward the understanding of the complex biochemistry underpinning metabolic responses to trauma/hemorrhagic shock. Mass spectrometry-based metabolomics has emerged as a more sensitive analytical approach in early "ischemia-reperfusion injury phase" responses (6), allowing detection of thousands of molecular features corresponding to hundreds of small molecules (Ͻ1.5 kDa) representative of key metabolic pathways (e.g., glycolysis, Krebs cycle, and ATP/purine catabolism).…”

“…Advances in fields such as proteomics (10) and metabolomics (6,8,32,42) offer big strides toward the understanding of the complex biochemistry underpinning metabolic responses to trauma/hemorrhagic shock. Mass spectrometry-based metabolomics has emerged as a more sensitive analytical approach in early "ischemia-reperfusion injury phase" responses (6), allowing detection of thousands of molecular features corresponding to hundreds of small molecules (Ͻ1.5 kDa) representative of key metabolic pathways (e.g., glycolysis, Krebs cycle, and ATP/purine catabolism).…”

Exhaled breath metabolomics as a noninvasive diagnostic tool for acute respiratory distress syndrome

“…Metabolomics can provide an integrated view of upstream physiological, genomic, transcriptomic and proteomic data by assessment of the composition of metabolite mixtures in biological material [10][11][12]. Exhaled breath contains metabolites that are volatile [13].…”

Clinical Implementation of Metabolomics

“…Recently, several applications of metabolome analysis based on computer-aided detection and diagnosis (CAD) has been demonstrated (Duda, 2001;Gu et al, 2011;Kell, 2002;Kim et al, 2010;Montoliu et al, 2009;Righi et al, 2009;Serkova et al, 2011;Taylor et al, 2010). The importance of objective indices for diagnosis based on empirical and statistical knowledge are increasing due to the trend called "Evidence Based Medicine (EBM)".…”