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Integration of untargeted metabolomics with transcriptomics reveals active metabolic pathways.

ABSTRACT: While recent advances in metabolomic measurement technologies have been dramatic, extracting biological insight from complex metabolite profiles remains a challenge. We present an analytical strategy that uses data obtained from high resolution liquid chromatography-mass spectrometry and a bioinformatics toolset for detecting actively changing metabolic pathways upon external perturbation. We begin with untargeted metabolite profiling to nominate altered metabolites and identify pathway candidates, followed by validation of those pathways with transcriptomics. Using the model organisms Rhodospirillum rubrum and Bacillus subtilis, our results reveal metabolic pathways that are interconnected with methionine salvage. The rubrum-type methionine salvage pathway is interconnected with the active methyl cycle in which re-methylation, a key reaction for recycling methionine from homocysteine, is unexpectedly suppressed; instead, homocysteine is catabolized by the transsulfuration pathway. Notably, the non-mevalonate pathway is repressed, whereas the rubrum-type methionine salvage pathway contributes to isoprenoid biosynthesis upon 5'-methylthioadenosine feeding. In this process, glutathione functions as a coenzyme in vivo when 1-methylthio-d-xylulose 5-phosphate (MTXu 5-P) methylsulfurylase catalyzes dethiomethylation of MTXu 5-P. These results clearly show that our analytical approach enables unexpected metabolic pathways to be uncovered.

SUBMITTER: Cho K

PROVIDER: S-EPMC4334135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary tuberculosis (PTB) and diabetes mellitus (DM) are common chronic diseases that threaten human health. Patients with DM are susceptible to PTB, an important factor that aggravates the complications of diabetes. However, the molecular regulatory mechanism underlying the susceptibility of patients with DM to PTB infection remains unknown. In this study, healthy subjects, patients with primary PTB, and patients with primary PTB complicated by DM were recruited according to inclusion and exclusion criteria. Peripheral whole blood was collected, and alteration profiles and potential molecular mechanisms were further analyzed using integrated bioinformatics analysis of metabolomics and transcriptomics. Transcriptional data revealed that lipocalin 2 (LCN2), defensin alpha 1 (DEFA1), peptidoglycan recognition protein 1 (PGLYRP1), and integrin subunit alpha 2b (ITGA2B) were significantly upregulated, while chloride intracellular channel 3 (CLIC3) was significantly downregulated in the group with PTB and DM (PTB_DM) in contrast to the healthy control (HC) group. Additionally, the interleukin 17 (IL-17), phosphatidylinositol 3-kinase (PI3K)-AKT, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are important for PTB infection and regulation of PTB-complicated diabetes. Metabolomic data showed that glycerophospholipid metabolism, carbon metabolism, and fat digestion and absorption processes were enriched in the differential metabolic analysis. Finally, integrated analysis of both metabolomic and transcriptomic data indicated that the NOTCH1/JAK/STAT signaling pathway is important in PTB complicated by DM. In conclusion, PTB infection altered the transcriptional and metabolic profiles of patients with DM. Metabolomic and transcriptomic changes were highly correlated in PTB patients with DM. Peripheral metabolite levels may be used as biomarkers for PTB management in patients with DM. IMPORTANCE The comorbidity of diabetes mellitus (DM) significantly increases the risk of tuberculosis infection and adverse tuberculosis treatment outcomes. Most previous studies have focused on the relationship between the effect of blood glucose control and the outcome of antituberculosis treatment in pulmonary tuberculosis (PTB) with DM (PTB_DM); however, early prediction and the underlying molecular mechanism of susceptibility to PTB infection in patients with DM remain unclear. In this study, transcriptome sequencing and untargeted metabolomics were performed to elucidate the key molecules and signaling pathways involved in PTB infection and the susceptibility of patients with diabetes to PTB. Our findings contribute to the development of vital diagnostic biomarkers for PTB or PTB_DM and provide a comprehensive understanding of molecular regulation during disease progression.

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Integration of untargeted metabolomics with transcriptomics reveals active metabolic pathways.

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