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Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway...

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Autores principales: Millischer, Vincent, Heinzl, Matthias, Faka, Anthi, Resl, Michael, Trepci, Ada, Klammer, Carmen, Egger, Margot, Dieplinger, Benjamin, Clodi, Martin, Schwieler, Lilly
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286561/
https://www.ncbi.nlm.nih.gov/pubmed/34273987
http://dx.doi.org/10.1186/s12974-021-02196-x
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author Millischer, Vincent
Heinzl, Matthias
Faka, Anthi
Resl, Michael
Trepci, Ada
Klammer, Carmen
Egger, Margot
Dieplinger, Benjamin
Clodi, Martin
Schwieler, Lilly
author_facet Millischer, Vincent
Heinzl, Matthias
Faka, Anthi
Resl, Michael
Trepci, Ada
Klammer, Carmen
Egger, Margot
Dieplinger, Benjamin
Clodi, Martin
Schwieler, Lilly
author_sort Millischer, Vincent
collection PubMed
description BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02196-x.
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spelling pubmed-82865612021-07-19 Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial Millischer, Vincent Heinzl, Matthias Faka, Anthi Resl, Michael Trepci, Ada Klammer, Carmen Egger, Margot Dieplinger, Benjamin Clodi, Martin Schwieler, Lilly J Neuroinflammation Research BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02196-x. BioMed Central 2021-07-17 /pmc/articles/PMC8286561/ /pubmed/34273987 http://dx.doi.org/10.1186/s12974-021-02196-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Millischer, Vincent
Heinzl, Matthias
Faka, Anthi
Resl, Michael
Trepci, Ada
Klammer, Carmen
Egger, Margot
Dieplinger, Benjamin
Clodi, Martin
Schwieler, Lilly
Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title_full Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title_fullStr Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title_full_unstemmed Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title_short Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
title_sort intravenous administration of lps activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286561/
https://www.ncbi.nlm.nih.gov/pubmed/34273987
http://dx.doi.org/10.1186/s12974-021-02196-x
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