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

Yi Ding,Susan Van Den Eeden,Tom H M Ottenhoff,Amy C Harms,Herman P Spaink,Koen Egbers,Rubén Marín-Juez,Thomas Hankemeier,Wouter J Veneman,A Alia,Mariëlle C Haks,Robert-Jan Raterink,Simone A Joosten

doi:10.1038/s41598-020-68443-y

Abstract

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.

Highlights

Tuberculosis is a highly infectious and potentially fatal disease accompanied by wasting symptoms, which cause severe metabolic changes in infected people
Metabolite profiles of TB patients measured by mass spectrometry
To measure metabolite profiles in TB patients compared to healthy people, 20 blood samples from each group were analysed by mass spectrometry (MS)

Summary

Introduction

Tuberculosis is a highly infectious and potentially fatal disease accompanied by wasting symptoms, which cause severe metabolic changes in infected people. Recent metabolomics studies have identified valuable diagnostic metabolic blood markers that can discriminate TB patients from healthy individuals[3,4,5,6,7,8,9,10,11,12,13] This appeared to be applicable to very different population groups, ranging from trans-Africa, China, Georgia, and Indonesia, and highlighting that blood metabolites are robust and validating biomarkers for TB progression. A majority of these metabolites including tyrosine, glutamine, leucine, isoleucine were increased in lung, liver, spleen and serum[20] These NMR studies identified metabolic markers for TB, there was little correlation with the markers identified in human studies using MS

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Results

Conclusion