Tryptophan catabolism reflects disease activity in human tuberculosis

Collins, Jeffrey M.; Siddiqa, Amnah; Jones, Dean P.; Liu, Ken; Kempker, Russell R.; Nizam, Azhar; Shah, N Sarita; Ismail, Nazir; Ouma, Samuel Gurrion; Tukvadze, Nestani; Li, Shuzhao; Day, Cheryl L.; Rengarajan, Jyothi; Brust, James C.M.; Gandhi, Neel R.; Ernst, Joel D.; Blumberg, Henry M.; Ziegler, Thomas R.

doi:10.1172/jci.insight.137131

Cited by 49 publications

(50 citation statements)

References 62 publications

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“…Sphingolipids are fundamental building blocks for cell membranes, are important to immune signaling, and are major constituents of the mucus secreted by lung alveolar epithelial cells [13]. Metabolic signature identification in pulmonary active TB, employing high-resolution plasma metabolomics (HRM), revealed that tryptophan metabolism is highly regulated during TB infection and disease and is characterized by increased catabolism to kynurenine, which occurs in both latent and active TB patients [63]. Increased tryptophan catabolism may enable the survival of Mtb at the site of infection by modulating CD4 + T cell responses, inducing immune tolerance and bacterial persistence, and could also protect the host from excessive inflammation.…”

Section: Impact Of Infection On Host Metabolic Signaturesmentioning

confidence: 99%

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

et al. 2020

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Approaches to the identification of metabolites have progressed from early biochemical pathway evaluation to modern high-dimensional metabolomics, a powerful tool to identify and characterize biomarkers of health and disease. In addition to its relevance to classic metabolic diseases, metabolomics has been key to the emergence of immunometabolism, an important area of study, as leukocytes generate and are impacted by key metabolites important to innate and adaptive immunity. Herein, we discuss the metabolomic signatures and pathways perturbed by the activation of the human immune system during infection and vaccination. For example, infection induces changes in lipid (e.g., free fatty acids, sphingolipids, and lysophosphatidylcholines) and amino acid pathways (e.g., tryptophan, serine, and threonine), while vaccination can trigger changes in carbohydrate and bile acid pathways. Amino acid, carbohydrate, lipid, and nucleotide metabolism is relevant to immunity and is perturbed by both infections and vaccinations. Metabolomics holds substantial promise to provide fresh insight into the molecular mechanisms underlying the host immune response. Its integration with other systems biology platforms will enhance studies of human health and disease.

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Section: Impact Of Infection On Host Metabolic Signaturesmentioning

confidence: 99%

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

et al. 2020

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“…In macaques with TB disease, plasma concentrations of IL-1β are highly correlated with levels of pulmonary inflammation and IL-1 receptor blockade limits tissue damage ( 8 ). Thus, accumulating TCA cycle intermediates and decreased itaconate during later stages of TB disease may be another example of Mtb exploiting a host metabolic adaption aimed at controlling Mtb replication during the initial stages of infection ( 30 31 ). While TCA cycle remodeling and increased IL-1β initially promotes control of bacterial replication ( 25 ), our findings suggest that as humans progress to TB disease it increases AA metabolism and conversion to proinflammatory eicosanoids, potentially worsening tissue damage and increasing disease severity.…”

Section: Discussionmentioning

confidence: 99%

“…For untargeted metabolomics and lipidomics analyses, metabolite intensity values were log 2 transformed and compared between groups using linear regression, controlling for age, sex and HIV status ( 47 ). Metabolic pathway enrichment analysis was performed using mummichog , a Python-based informatics tool that leverages the organization of metabolic networks to predict functional changes in metabolic pathway activity ( 15, 30, 48 ). Following quantification of selected metabolites and lipids, cross-sectional comparison of plasma concentrations between groups was made using the Wilcoxon Rank Sum test.…”

Section: Methodsmentioning

confidence: 99%

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

Jones

Sharma

et al. 2021

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The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of TCA cycle intermediates such as succinate and decreases in itaconate. This inflammatory metabolic network was particularly active in persons with multidrug-resistant (MDR)-TB after receiving 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were closely associated with increases in proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates are important drivers of IL-1β-mediated proinflammatory eicosanoid signaling in humans with pulmonary TB disease. Host-directed therapies that mitigate such metabolic reprograming may have potential to limit excessive pulmonary inflammation and tissue damage.

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“…In a randomized control trial, the antiinflammatory drug prednisone reduced the incidence of tuberculosis-associated IRIS (Meintjes et al, 2018). In a recent multi-cohort study, increased catabolism of tryptophan to kynurenine was associated with active TB compared to healthy subjects, and gradually reverted to baseline during the course of successful treatment (Collins et al, 2020). Increased kynurenine/tryptophan was associated with significant increases in IDO transcripts, suggesting that tryptophan catabolism is mediated by induction of IDO.…”

Section: Ipa For Tb-immune Reconstitution Inflammatory Syndrome?mentioning

confidence: 99%

“…Increased kynurenine/tryptophan was associated with significant increases in IDO transcripts, suggesting that tryptophan catabolism is mediated by induction of IDO. The authors suggested IDO mediated tryptophan catabolism as a biomarker of TB disease progression as well as host-directed therapy (Collins et al, 2020). Accordingly, the early treatment with corticosteroids was effective in reducing the incidence of TB-IRIS and symptom severity (Sereti, 2020), partly due to increased IDO expression (Maneechotesuwan et al, 2008).…”

Section: Ipa For Tb-immune Reconstitution Inflammatory Syndrome?mentioning

confidence: 99%

Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties

et al. 2020

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Most antibiotics are produced by soil microbes and typically interfere with macromolecular synthesis processes as their antibacterial mechanism of action. These natural products are often large and suffer from poor chemical tractability. Here, we discuss discovery, mechanism of action, and the therapeutic potentials of an unusual antibiotic, indole propionic acid (IPA). IPA is produced by the human gut microbiota. The molecule is small, chemically tractable, and targets amino acid biosynthesis. IPA is active against a broad spectrum of mycobacteria, including drug resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Interestingly, the microbiota-produced metabolite is detectable in the serum of healthy individuals, tuberculosis (TB) patients, and several animal models. Thus, the microbiota in our gut may influence susceptibility to mycobacterial diseases. If a gut-lung microbiome axis can be demonstrated, IPA may have potential as a biomarker of disease progression, and development of microbiota-based therapies could be explored. In addition to its antimycobacterial activity, the molecule displays antiinflammatory and antioxidant properties. This raises the possibility that IPA has therapeutic potential as both antibiotic and add-on host-directed drug for the treatment of TB in patient populations where disease morbidity and mortality is driven by excessive inflammation and tissue damage, such as TB-associated immune reconstitution inflammatory syndrome, TB-meningitis, and TB-diabetes.

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Tryptophan catabolism reflects disease activity in human tuberculosis

Cited by 49 publications

References 62 publications

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties

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