Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes

Abstract

Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.Objectives: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. Measurements and Main Results:The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).Conclusions: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

“…A similar systems biology analysis of sepsis was performed in a non-human primate (NHP) model and confirmed that carnitine esters were increased in septic animals [37]. RNAseq analysis was performed on the whole lungs taken from these animals.…”

“…Recent advances in systems biology can minimize some weaknesses of the single omics methods by utilizing holistic approaches that compare multiple data streams for correlative molecular pathways in the host response. The integrative approach assumes that a comprehensive, hypothesis-agnostic description of the molecular changes can identify unbiased signatures that maybe lost in one-dimensional analyses [35, 37]. Moreover, the correlation of molecular networks and pathways in complementary datasets can potentially identify and prioritize likely causal molecular mechanisms.…”

“…Most of these biochemical changes were validated in an independent cohort of sepsis patients enrolled in the ICU. Using predictive modeling approaches, the metabolites could predict sepsis patient outcomes in the ED and ICU better than lactate, SOFA and APACHEII [76, 36, 37]. Many of these metabolites have been independently identified in a number of recent clinical ICU studies pointing to a common mechanism of metabolic dysfunction [77, 40, 78, 79].…”

“…The most notable altered biochemical pathway was increased concentrations of small-chain, medium-chain fatty acids and branched-chain amino acids (BCAA) bound to carnitine which from hereon will be referred to as carnitine esters [40, 37, 35, 36]. The increases are similar to plasma changes found in patients with acyl-CoA dehydrogenase deficiencies which is characterized by the accumulation of fatty acids bound to carnitine [80].…”

Metabonomics and Intensive Care

“…Several animal models have been used, testing different biofluids including blood [16][17][18][19][20], broncheoalveolar (BAL) fluid [16] and lymph [18] as well as tissue, such as lung [16,17], liver [17,21], kidney [22] and spleen [17,22]. Infections as diffuse as cerebral malaria [22], influenza [23], tuberculosis [17], peritonitis [16,18,24] and Escherichia coli sepsis [20] have been investigated.…”