Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

Abstract

Objective The objective of this review is to explain the science of metabolomics—a science of systems biology that measures and studies endogenous small molecules (metabolites) that are present in a single biological sample—and its application to the diagnosis and treatment of sepsis. In addition, we discuss how discovery through metabolomics can contribute to the development of precision medicine targets for this complex disease state and the potential avenues for those new discoveries to be applied in the clinical environment. Methods A nonsystematic literature review was performed focusing on metabolomics, pharmacometabolomics, and sepsis. Human (adult and pediatric) and animal studies were included. Main Results Metabolomics has been investigated in the diagnosis, prognosis, and risk stratification of sepsis, as well as for the identification of drug target opportunities. Metabolomics elucidates a new level of detail, when compared with other systems biology sciences, with regard to the metabolites that are most relevant in the pathophysiology of sepsis, as well as highlighting specific biochemical pathways at work in sepsis. Metabolomics also highlights biochemical differences between sepsis survivors and nonsurvivors at a level of detail greater than that demonstrated by genomics, transcriptomics, or proteomics, potentially leading to actionable targets for new therapies. The application of pharmacometabolomics and its integration with other systems pharmacology to sepsis therapeutics could be particularly helpful in differentiating drug responders and nonresponders and furthering knowledge of mechanisms of drug action and response. Conclusion The accumulated literature on metabolomics suggest that it is a viable tool for continued discovery around the pathophysiology, diagnosis and prognosis, and treatment of sepsis in both adults and children, and provides a greater level of biochemical detail and insight than other systems biology approaches. However, the clinical application of metabolomics in sepsis has not yet been fully realized. For this to be achieved, prospective validation studies are needed to translate metabolites from the discovery phase into the clinical utility phase.

Metabolomics in Sepsis and Its Impact on Public Health

“…On the other hand, metabolomics has been characterized as a driver for personalized medicine in sepsis [99]. Taken together with the fact that sepsis, as mentioned above, is a global health concern, this underlines the significance of metabolomics for public health.…”

A Multivariate Metabolomics Method for Estimating Platelet Mitochondrial Oxygen Consumption Rates in Patients with Sepsis

“…Rather, we reviewed the literature surrounding the biological relevance of the metabolites in the context of sepsis. A literature review by Eckerle et al, reported statistically significant metabolites that were found to be related to three pathways, namely, energy metabolism, mitochondrial dysfunction, and platelet activation and/or aggregation (Table 4) [17].…”

“…Critically, platelet mitochondrial respiration, or mitochondrial oxygen consumption rates (mOCR), has been found to be associated with sepsis clinical parameters, such as severity of illness, organ failure, and mortality [11,12]. Metabolomics, the measurement of small molecules (<1500 Daltons), or metabolites, in a single biological sample, is an another effective approach for the study of the impact of sepsis on mitochondrial function [17]. Recently, Chacko et al, showed that the platelet metabolome in healthy subjects is functionally integrated with platelet mOCR [18].…”

Disposable Paper-on-CMOS Platform for Real-Time Simultaneous Detection of Metabolites

“…SIRS can be too sensitive and not specific and qSOFA has been found to be specific but poorly sensitive [34,35]. Metabolite biomarkers such as lactate and creatinine have been proven to have the potential to assist the diagnosis of sepsis, and ongoing work seeks panels of metabolites whose abundance changes provide increased sensitivity in diagnosis [36][37][38]. Therefore, methods to detect multiple metabolite biomarkers simultaneously in a short time will be necessary for the rapid diagnosis of sepsis, reducing the risk of death.…”

“…To illustrate the capability of the sensor platform, glucose and lactate were chosen as the analytes since they have been shown to have relevance as indicators in early diagnosis of sepsis. [37,[39][40][41][42] Three microfluidic channels were fabricated on a single paper strip and each channel subsequently printed with enzymes for detecting glucose and lactate. The third channel was used as a control in this study.…”