Plasma Metabolomics Reveals Distinct Biological and Diagnostic Signatures for Melioidosis

Abstract

Rationale The global burden of sepsis is greatest in low-resource settings. Melioidosis, infection with the gram-negative bacterium Burkholderia pseudomallei , is a frequent cause of fatal sepsis in endemic tropical regions such as Southeast Asia. Objectives To investigate whether plasma metabolomics would identify biological pathways specific to melioidosis and yield clinically meaningful biomarkers. Methods Using a comprehensive approach, differential enrichment of plasma metabolites and pathways was systematically evaluated in individuals selected from a prospective cohort of patients hospitalized in rural Thailand with infection. Statistical and bioinformatics methods were used to distinguish metabolomic features and processes specific to patients with melioidosis and between fatal and nonfatal cases. Measurements and Main Results Metabolomic profiling and pathway enrichment analysis of plasma samples from patients with melioidosis ( n = 175) and nonmelioidosis infections ( n = 75) revealed a distinct immuno-metabolic state among patients with melioidosis, as suggested by excessive tryptophan catabolism in the kynurenine pathway and significantly increased levels of sphingomyelins and ceramide species. We derived a 12-metabolite classifier to distinguish melioidosis from other infections, yielding an area under the receiver operating characteristic curve of 0.87 in a second validation set of patients. Melioidosis nonsurvivors ( n = 94) had a significantly disturbed metabolome compared with survivors ( n = 81), with increased leucine, isoleucine, and valine metabolism, and elevated circulating free fatty acids and acylcarnitines. A limited eight-metabolite panel showed promise as an early prognosticator of mortality in melioidosis. Conclusions Melioidosis induces a distinct metabolomic state that can be examined to distinguish underlying pathophysiological mechanisms associated with death. A 12-metabolite signature accurately differentiates melioidosis from other infections and may have diagnostic applications.

Shared genetic correlations between kidney diseases and sepsis

“…DOCK7 is associated with serum lipid level ( 39 ), which are known to play a role in both sepsis and kidney health ( 40 ). Finally, HIBADH , previously connected to kidney stones ( 41 ), has been documented to be involved in valine metabolism disorders ( 42 ),a pathway recently implicated in sepsis ( 43 ). The established roles of these genes in inflammation, lipid metabolism, and metabolic disorders, alongside our findings in sepsis and kidney diseases, suggest a potential interplay in the pathogenesis of these conditions.…”

Precision Medicine for Sepsis Management in Low- and Middle-Income Countries—Melioidosis as a Model?

“…In the study by Xia and colleagues (pp. 288–298 ) in this issue of the Journal , the metabolomic profile of patients enrolled from a single health care center in northeast Thailand who were microbiologically confirmed to have melioidosis was compared with a variety of other bacterial pathogens ( 9 ). The demonstration of several significant differences between the groups suggests that in subjects with other etiologies of sepsis in the region, mainly Gram-negative pathogens, melioidosis represents a subphenotype.…”