Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks

Abstract

A disruption of several metabolic pathways in critically ill patients with sepsis indicates that metabolomics might be used as a more precise tool for sepsis and septic shock when compared with the conventional biomarkers. This article provides information regarding metabolomics studies in sepsis and septic shock patients. It has been shown that a variety of metabolomic pathways are altered in sepsis and septic shock, including amino acid metabolism, fatty acid oxidation, phospholipid metabolism, glycolysis, and tricarboxylic acid cycle. Based upon this comprehensive review, here, we demonstrate that metabolomics is about to change the world of sepsis biomarkers, not only for its utilization in sepsis diagnosis, but also for prognosticating and monitoring the therapeutic response. Additionally, the future direction regarding the establishment of studies integrating metabolomics with other molecular modalities and studies identifying the relationships between metabolomic profiles and clinical characteristics to address clinical application are discussed in this article. All of the information from this review indicates the important impact of metabolomics as a tool for diagnosis, monitoring therapeutic response, and prognostic assessment of sepsis and septic shock. These findings also encourage further clinical investigations to warrant its use in routine clinical settings.

Keywords: critically ill patients; diagnosis; metabolism; metabolomics; prognosis; sepsis; septic shock; treatment monitoring.

Figure 1

Alterations of amino acids and amines for sepsis diagnosis (Table 1), septic shock diagnosis (Table 2), prognostication of sepsis (Table 3), prognostication of septic shock (Table 4), and monitoring the treatment response (Table 5). A down-sided triangle (▼) represents a decreased level, whereas an up-sided triangle (▲) represents vice versa. (A) Aromatic amino acids (AAAs) and its down-stream amino acid are illustrated. Phenylalanine is converted to tyrosine before metabolizing to dihydroxyphenylalanine (DOPA) and catecholamines, respectively. Tryptophan is another AAA that can change to either kynurenine or serotonin and melatonin. (B) Branched-chain amino acids (BCAAs) including leucine, isoleucine, and valine are catabolized to S-(3-methylbutanoyl)-dihydrolipoamide-E and amino acid-derived acylcarnitines (C3-5), respectively. (C) A substrate of glutathione synthesis begins with methionine that converts into homocysteine, cystathionine, and cysteine, respectively. Moreover, serine is involved in the cystathionine production with an exchange of α-ketoglutarate. Cysteine can also turn into taurine, which has an anti-oxidant effect. (D) Glutamate is an intermediate substrate between glutathione production and urea cycle-related metabolites. Glutamate can be converted into glutamine and pyrroline-5-carboxylate (P5C). The latter metabolite is a precursor for proline synthesis. Moreover, glutamate can interchange with the urea cycle pathway metabolites. (E) The urea cycle pathway metabolites included citrulline, arginine, and ornithine. Arginine is a key amino acid for nitric oxide (NO) synthesis and NO inhibitors, including symmetric dimethylarginine (SMDA), asymmetric dimethylarginine (ADMA), total dimethylarginine (total DMA), and dimethylamine. (F) Polyamines are converted from ornithine. The polyamine metabolites include putrescine, spermidine, and spermine.

Figure 2

The alterations of fatty acids and fatty acid-related metabolites for sepsis diagnosis (Table 1), septic shock diagnosis (Table 2), prognostication of sepsis (Table 3), prognostication of septic shock (Table 4), and monitoring the treatment response (Table 5). A down-sided triangle (▼) represents a decreased level, whereas an up-sided triangle (▲) represents vice versa. Monounsaturated fatty acids (MUFAs) are found increased in sepsis diagnosis, whereas polyunsaturated fatty acids (PUFAs) are found contractedly. Most of ceramides are increased, together with an increase in arachidonic acids. Long-chain fatty acids enter mitochondrial for fatty acid oxidation (β-oxidation) under the carnitine shuttle process. The final product of β-oxidation is acetyl-CoA that can enter TCA cycle for an energy production. However, mitochondrial dysfunction in sepsis can alter β-oxidation process, leading to an accumulation of medium-chain acylcarnitines in the cytoplasm and in the circulation, which indicates incomplete β-oxidation.

Figure 3

(Previous page) The alterations of cell membrane phospholipids for sepsis diagnosis (Table 1), septic shock diagnosis (Table 2), prognostication of sepsis (Table 3), prognostication of septic shock (Table 4), and monitoring the treatment response (Table 5). A down-sided triangle (▼) represents a decreased level, whereas an up-sided triangle (▲) represents vice versa. Several kinds of the cell membrane phospholipids are involved in this setting. An alteration of phosphatidylcholines (PCs), phosphatidylserine (PS), phosphatidylglycerols (PGs), lysophosphatidylcholines (LysoPCs), lysophosphatidylethanolamines (LysoPEs), cardiolipins, and sphingomyelines (SMs) are demonstrated.

Figure 4

The alterations of glycolysis-related metabolites and tricarboxylic acid (TCA) cycle metabolites for sepsis diagnosis (Table 1), septic shock diagnosis (Table 2), prognostication of sepsis (Table 3), prognostication of septic shock (Table 4), and monitoring the treatment response (Table 5). A down-sided triangle (▼) represents a decreased level, whereas an up-sided triangle (▲) represents the opposite. The alterations of several sugars are found, including glucose, sucrose, mannose, and myo-inositol. Glucose, a main energy source for human cells, converts to pyruvate and acetyl-CoA, respectively, before entering the TCA cycle. In addition, acetylcarnitine (C2 carnitine) can feed via acetyl-CoA as well. Another anaerobic metabolite, lactate, are found to be increased in sepsis patients with poor prognosis. Citrate is the initial metabolite of the TCA cycle, which turns into isocitrate, α-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, and oxaloacetate, respectively. The increases in TCA cycle-related metabolites represent an augmentation of aerobic metabolism during sepsis, which can promote oxidative phosphorylation and reactive oxygen species (ROS) production. An increase in the ROS level may be one of the potential mechanisms mediating sepsis-induced mitochondrial dysfunction.