l-Histidine, arachidonic acid, biliverdin, and l-cysteine-glutathione disulfide as potential biomarkers for cured pulmonary tuberculosis

Wang, Yi; Han, Yu-Shuai; Wei, Li-Liang; Shi, Lei; Huang, Huai; Jiang, Tingting; Li, Zhibin; Chen, Jing; Yong, Hu; Tu, Hui‐Hui; Li, Jicheng

doi:10.1016/j.biopha.2019.108980

Cited by 25 publications

(20 citation statements)

References 21 publications

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“…Our data also found that the combination of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified an initial treatment response with an AUC of 0.86, which-if confirmed in other studies including patients who fail treatment-represents improvement over smear and culture conversion to predict durable cure, which have only 24% and 40% sensitivity, respectively 49 . Previous studies have identified metabolomic signatures of treatment response, including one study identifying a 4 metabolite signature with 86.2% sensitivity, 85.2% specificity and an AUC of 0.91 27 , and another study finding changes of 5 metabolites during treatment 50 . These specific metabolites were not significantly different between pre-and post-treatment samples in our study, demonstrating the need to replicate diagnostic accuracy studies in special populations, such as children, before they are broadly employed.…”

Section: Discussionmentioning

confidence: 99%

“…Despite these diagnostic challenges, TB induces profound changes in whole-body energy and protein metabolism that can be identified in blood 11 – 21 . Such testing could also potentially identify extrapulmonary TB without invasive sampling of pleural or cerebrospinal fluid 22 – 24 and improve assessments of treatment response 25 – 27 . Limited data are available, however, on the metabolic changes affecting children with TB 12 , 13 , and it is unknown whether the same differences described in other populations and body compartments will be relevant for blood-based diagnosis of pediatric TB or that the same metabolites will characterize treatment response among children.…”

Section: Introductionmentioning

confidence: 99%

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Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

Dutta

Tornheim

Fukutani

et al. 2020

Sci Rep

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Pediatric tuberculosis (TB) remains a major global health problem. Improved pediatric diagnostics using readily available biosources are urgently needed. We used liquid chromatography-mass spectrometry to analyze plasma metabolite profiles of Indian children with active TB (n = 16) and age- and sex-matched, Mycobacterium tuberculosis-exposed but uninfected household contacts (n = 32). Metabolomic data were integrated with whole blood transcriptomic data for each participant at diagnosis and throughout treatment for drug-susceptible TB. A decision tree algorithm identified 3 metabolites that correctly identified TB status at distinct times during treatment. N-acetylneuraminate achieved an area under the receiver operating characteristic curve (AUC) of 0.66 at diagnosis. Quinolinate achieved an AUC of 0.77 after 1 month of treatment, and pyridoxate achieved an AUC of 0.87 after successful treatment completion. A set of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified treatment response with an AUC of 0.86. Pathway enrichment analyses of these metabolites and corresponding transcriptional data correlated N-acetylneuraminate with immunoregulatory interactions between lymphoid and non-lymphoid cells, and correlated pyridoxate with p53-regulated metabolic genes and mitochondrial translation. Our findings shed new light on metabolic dysregulation in children with TB and pave the way for new diagnostic and treatment response markers in pediatric TB.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

Dutta

Tornheim

Fukutani

et al. 2020

Sci Rep

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“…In this study it was shown that changes in various metabolites were predictive for the onset of clinical TB as early as 12 months prior to TB diagnosis in a trans-African population 11 . Using MS, Yi et al demonstrated that histidine, arachidonic acid and biliverdin were decreased in Chinese TB patients compared to the group of healthy individuals, but could be restored to normal levels following TB cure 12 . In an MS study that compared the effects of curing patients from Gambia of an infection of Mtb or M. africanum on metabolism, it was shown that in both cases the levels of many amino acids such as histidine, ornithine, tryptophan and leucine were increasing strongly after 6 months of antibiotic treatment 7 .…”

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confidence: 99%

Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae

Ding

Raterink

Marín-Juez

et al. 2020

Sci Rep

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tuberculosis is a highly infectious and potentially fatal disease accompanied by wasting symptoms, which cause severe metabolic changes in infected people. in this study we have compared the effect of mycobacteria infection on the level of metabolites in blood of humans and mice and whole zebrafish larvae using one highly standardized mass spectrometry pipeline, ensuring technical comparability of the results. Quantification of a range of circulating small amines showed that the levels of the majority of these compounds were significantly decreased in all three groups of infected organisms. Ten of these metabolites were common between the three different organisms comprising: methionine, asparagine, cysteine, threonine, serine, tryptophan, leucine, citrulline, ethanolamine and phenylalanine. The metabolomic changes of zebrafish larvae after infection were confirmed by nuclear magnetic resonance spectroscopy. Our study identified common biomarkers for tuberculosis disease in humans, mice and zebrafish, showing across species conservation of metabolic reprogramming processes as a result of disease. Apparently, the mechanisms underlying these processes are independent of environmental, developmental and vertebrate evolutionary factors. The zebrafish larval model is highly suited to further investigate the mechanism of metabolic reprogramming and the connection with wasting syndrome due to infection by mycobacteria. Infection with Mycobacterium tuberculosis (Mtb) can result in tuberculosis (TB) that currently is newly affecting over 10 million people per year and leading to 1.6 million deaths annually 1. However, the majority of people that have been infected with Mtb, estimated to be in the order of 2 billion, do not experience any symptoms in the presence of positive immunological (blood or skin) test results. In patients diagnosed with TB, the disease is uniformly characterized by a metabolic wasting syndrome that leads to heavy weight loss that concurs with a strong reduction of muscle mass. TB has therefore historically earned the name of "consumption". Novel tools for control of TB should include not only better treatments, including attention to the deleterious effects of wasting syndrome, but also needs to include cost-effective assays for robust and sensitive diagnosis of TB 2. Recent metabolomics studies have identified valuable diagnostic metabolic blood markers that can discriminate TB patients from healthy individuals 3-13. This appeared to be applicable to very different population groups, ranging from trans-Africa, China, Georgia, and Indonesia, and therefore highlighting that blood metabolites are robust and validating biomarkers for TB progression. These studies used mostly mass spectrometry (MS) and

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“…The detail of methods for sample preparation referred to previous study [11]. Briefly, 100 μL of sample was transferred to an Eppendorf (EP) tube and vortexed for 30 s with the addition of 300 μL of methanol (containing 1 μg/mL internal standard).…”

Section: Sample Preparationmentioning

confidence: 99%

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

Pan

et al. 2020

Respir Res

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Background: There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model.Methods: Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder. Results: The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. Conclusion: Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.

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l-Histidine, arachidonic acid, biliverdin, and l-cysteine-glutathione disulfide as potential biomarkers for cured pulmonary tuberculosis

Cited by 25 publications

References 21 publications

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

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