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

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.

Leptin mutation and mycobacterial infection lead non-synergistically to a similar metabolic syndrome

“…We have shown that even in entire zebrafish larvae, infection with Mycobacterium marinum (M. marinum), a natural fish pathogen and a close relative of Mtb, leads to a very similar metabolic syndrome as observed in mice and patients after infection with Mtb (Ding et al, 2020). Ten metabolites were identified as common biomarkers of mycobacterial infection in TB patients, mice and zebrafish larvae (Ding et al, 2020).…”

“…TB is often associated with severe wasting syndrome accompanied by loss of whole body mass and increased risk of death (Paton & Ng, 2006). The metabolic abnormalities underlying the wasting syndrome in TB have been studied in humans and TB animal models (Ding et al, 2020;Weiner et al, 2018). TB causes metabolic reprogramming characterized by decrease of many metabolites in the blood of patients from Africa (Weiner et al, 2018), China (Deng et al, 2021), Indonesia (Vrieling et al, 2019) and the Netherlands (Ding et al, 2020).…”

“…The metabolic abnormalities underlying the wasting syndrome in TB have been studied in humans and TB animal models (Ding et al, 2020;Weiner et al, 2018). TB causes metabolic reprogramming characterized by decrease of many metabolites in the blood of patients from Africa (Weiner et al, 2018), China (Deng et al, 2021), Indonesia (Vrieling et al, 2019) and the Netherlands (Ding et al, 2020). The metabolic responses towards mycobacterial infection in the blood of mice were highly similar to that in TB patients (Ding et al, 2020).…”

“…TB causes metabolic reprogramming characterized by decrease of many metabolites in the blood of patients from Africa (Weiner et al, 2018), China (Deng et al, 2021), Indonesia (Vrieling et al, 2019) and the Netherlands (Ding et al, 2020). The metabolic responses towards mycobacterial infection in the blood of mice were highly similar to that in TB patients (Ding et al, 2020). We have shown that even in entire zebrafish larvae, infection with Mycobacterium marinum (M. marinum), a natural fish pathogen and a close relative of Mtb, leads to a very similar metabolic syndrome as observed in mice and patients after infection with Mtb (Ding et al, 2020).…”

Host-directed therapies for tuberculosis: quantitative systems pharmacology approaches

“…Consolidating immune-relevant differences between preclinical models and humans [56] may be challenging and resource intensive, as there may be varying strains of models used across different experiments depending on the objectives of the experiments. The shown evolutionary conservation of the metabolic responses to mycobacterial infection in human patients, mice, and zebrafish shows that basic disease symptoms such as wasting syndrome are not dependent on species or varying strains [57]. Gene expression analysis data across species may be used to inform parameters of expressions of genes responsible for certain immune functions [58].…”