Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis

Abstract

Background Sepsis is defined as a systemic inflammatory response to microbial infections with multiple organ dysfunction. This study analysed untargeted metabolomics combined with proteomics of serum from patients with sepsis to reveal the underlying pathological mechanisms involved in sepsis. Methods A total of 63 patients with sepsis and 43 normal controls were enrolled from a prospective multicentre cohort. The biological functions of the metabolome were assessed by coexpression network analysis. A molecular network based on metabolomics and proteomics data was constructed to investigate the key molecules. Results Untargeted metabolomics analysis revealed widespread dysregulation of amino acid metabolism, which regulates inflammation and immunity, in patients with sepsis. Seventy-three differentially expressed metabolites (|log2 fold change| > 1.5, adjusted P value < 0.05 and variable importance in the projection (VIP) > 1.5) that could predict sepsis were identified. External validation of the hub metabolites was consistent with the derivation results (area under the receiver operating characteristic curve (AUROC): 0.81–0.96/0.62–1.00). The pentose phosphate pathway was found to be related to sepsis-associated encephalopathy. Phenylalanine metabolism was associated with sepsis-associated acute kidney injury. The key molecular alterations of the multiomics network in sepsis compared to normal controls implicate acute inflammatory response, platelet degranulation, myeloid cell activation involved in immune response and phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis. Conclusions Integrated analysis of untargeted metabolomics and proteomics revealed characteristic metabolite and protein alterations in sepsis, which were mainly involved in inflammation-related pathways and amino acid metabolism. This study depicted the pathological characteristics and pathways involved in sepsis and potential therapeutic targets.

Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis

“…The drop in intestinal bacterial diversity might have been partly responsible for the apparent scarcity of gut metabolites that we observed in sepsis patients. Consistent with previous findings based on serum specimens [ 5 ], metabolites involved in aromatic amino acid metabolism were the most interrupted. Our sepsis cohort exhibited reductions in a variety of aromatic amino acid metabolites, which are also closely linked with the gut microbiome and the outcome of sepsis, especially those involved in tryptophan and tyrosine metabolism.…”

“…Although previous studies have focused on the microbial features of patients with sepsis, the role of bacteria found to be altered in sepsis remains unclear. Metabolic signatures of sepsis have been determined in serum, but metabolic changes in the gut during sepsis are poorly understood [ 5 ]. The microbiota is known to generate metabolites that affect physiological processes of the host [ 6 , 7 ].…”

Metabolomics meets systems immunology

“…Untargeted metabolomics can reveal important biological associations in immunology research and identify novel metabolites/biomarkers specific to a disease (Ding et al , 2021b ; Alboniga et al , 2022 ; Aximujiang et al , 2022 ; Chen et al , 2022 ; Tian et al , 2022 ). For example, Zhu et al ( 2022 ) used high‐resolution untargeted metabolomics analysis to study influenza A virus subtype H1N1 (H1N1) infected patients and found an association between abnormal arginine metabolism produced by the virus and the immunity of the respiratory mucosa.…”

Host Response Biomarkers for Sepsis in the Emergency Room

“…A novel technique, Raman spectroscopy, uses light scattering to non-destructively provide a structural fingerprint by which particles can be identified and has been used for identifying pathogens and metabolites, such as IL-6 [ 41 , 42 ]. In a cohort of 63 critically ill patients with sepsis and 43 controls, Chen et al used a combined proteomics and metabolomics approach to identify specific profiles in amino acid metabolism that could differentiate between patients with sepsis and healthy controls, with AUC values ranging from 0.81 to 0.96 [ 43 ]. In a validation group, the AUC value ranged from 0.62 to 1.00.…”