Gut

, volume 72 , issue 7 , pages gutjnl-2022-327337

Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases

Chloé Michaudel ^{1, 2}

Camille Danne ^{1, 2, 3}

Allison Agus ^{1, 2}

Aurélie Magniez ^{1, 2}

Anne Aucouturier ^{1, 2}

Madeleine Spatz ^{1, 2}

Antoine Lefevre ⁴

Julien Kirchgesner ^{2, 5}

Nathalie Rolhion ^{2, 3}

Yazhou Wang ^{1, 2}

Aonghus Lavelle ^{2, 3}

Chloé Galbert ^{2, 3}

Gregory Da Costa ^{1, 2}

Maxime Poirier ^{1, 2}

Alexia Lapière ^{1, 2}

Julien Planchais ^{1, 2}

Petr Nádvorník ⁶

Peter Illes ⁶

Cyriane Oeuvray ^{2, 3}

Laura Creusot ^{2, 3}

Marie-Laure Michel ^{1, 2}

Nicolas Benech ^{2, 3, 5}

Anne Bourrier ^{2, 5}

Isabelle Nion-Larmurier ^{2, 5}

Cecilia Landman ^{2, 5}

Mathias L. Richard ^{1, 2}

Patrick Emond ^{4, 7}

Philippe Seksik ^{2, 3, 5}

Laurent Beaugerie ^{2, 5}

Rafael Rose Arguello ⁸

David Moulin ⁹

Sridhar Mani ¹⁰

Zdenek Dvorák ⁶

Luis G. Bermúdez-Humarán ^{1, 2}

Philippe Langella ^{1, 2}

Harry Sokol ^{1, 2, 3, 5}

Hide authors affiliations Show authors affiliations: 10 affiliations

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute

Paris Center for Microbiome Medicine (PaCeMM) FHU

Sorbonne Université, INSERM UMRS-, Centre de Recherche Saint-Antoine, CRSA, AP-HP

Sorbonne University

French Institute of Health and Medical Research

⁴

UMR , iBrain, University of Tours, Inserm

French Institute of Health and Medical Research

University of Tours

⁵

Gastroenterology department, Saint Antoine Hospital, APHP

⁶

Department of Cell Biology and Genetics, Faculty of Science, Palacky University |

⁷

CHRU Tours, Medical Biology Center |

⁸

Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy

Aix-Marseille University

French Institute of Health and Medical Research

⁹

CNRS, IMoPA, Université de Lorraine |

¹⁰

Molecular Pharmacology, Genetics and Medicine, Albert Einstein College of Medicine |

Publication type: Journal Article

Publication date: 2022-10-21

BMJ

Gut

scimago Q1

wos Q1

SJR: 8.874

CiteScore: 46.7

Impact factor: 25.8

ISSN: 00175749, 14683288

DOI: 10.1136/gutjnl-2022-327337

Copy DOI

PubMed ID: 36270778

Gastroenterology

Abstract

Objective

The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway.

Design

Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition.

Results

In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models.

Conclusion

Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4⁺T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.

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GOST |

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GOST Copy

Michaudel C. et al. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases // Gut. 2022. Vol. 72. No. 7. p. gutjnl-2022-327337.

GOST all authors (up to 50) Copy

Michaudel C. et al. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases // Gut. 2022. Vol. 72. No. 7. p. gutjnl-2022-327337.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1136/gutjnl-2022-327337

UR - https://doi.org/10.1136/gutjnl-2022-327337

TI - Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases

T2 - Gut

AU - Michaudel, Chloé

AU - Danne, Camille

AU - Agus, Allison

AU - Magniez, Aurélie

AU - Aucouturier, Anne

AU - Spatz, Madeleine

AU - Lefevre, Antoine

AU - Kirchgesner, Julien

AU - Rolhion, Nathalie

AU - Wang, Yazhou

AU - Lavelle, Aonghus

AU - Galbert, Chloé

AU - Da Costa, Gregory

AU - Poirier, Maxime

AU - Lapière, Alexia

AU - Planchais, Julien

AU - Nádvorník, Petr

AU - Illes, Peter

AU - Oeuvray, Cyriane

AU - Creusot, Laura

AU - Michel, Marie-Laure

AU - Benech, Nicolas

AU - Bourrier, Anne

AU - Nion-Larmurier, Isabelle

AU - Landman, Cecilia

AU - Richard, Mathias L.

AU - Emond, Patrick

AU - Seksik, Philippe

AU - Beaugerie, Laurent

AU - Arguello, Rafael Rose

AU - Moulin, David

AU - Mani, Sridhar

AU - Dvorák, Zdenek

AU - Bermúdez-Humarán, Luis G.

AU - Langella, Philippe

AU - Sokol, Harry

PY - 2022

DA - 2022/10/21

PB - BMJ

SP - gutjnl-2022-327337

IS - 7

VL - 72

PMID - 36270778

SN - 0017-5749

SN - 1468-3288

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2022_Michaudel,

author = {Chloé Michaudel and Camille Danne and Allison Agus and Aurélie Magniez and Anne Aucouturier and Madeleine Spatz and Antoine Lefevre and Julien Kirchgesner and Nathalie Rolhion and Yazhou Wang and Aonghus Lavelle and Chloé Galbert and Gregory Da Costa and Maxime Poirier and Alexia Lapière and Julien Planchais and Petr Nádvorník and Peter Illes and Cyriane Oeuvray and Laura Creusot and Marie-Laure Michel and Nicolas Benech and Anne Bourrier and Isabelle Nion-Larmurier and Cecilia Landman and Mathias L. Richard and Patrick Emond and Philippe Seksik and Laurent Beaugerie and Rafael Rose Arguello and David Moulin and Sridhar Mani and Zdenek Dvorák and Luis G. Bermúdez-Humarán and Philippe Langella and Harry Sokol and others},

title = {Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases},

journal = {Gut},

year = {2022},

volume = {72},

publisher = {BMJ},

month = {oct},

url = {https://doi.org/10.1136/gutjnl-2022-327337},

number = {7},

pages = {gutjnl--2022--327337},

doi = {10.1136/gutjnl-2022-327337}

}

MLA

Cite this

MLA Copy

Michaudel, Chloé, et al. “Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases.” Gut, vol. 72, no. 7, Oct. 2022, pp. gutjnl-2022-327337. https://doi.org/10.1136/gutjnl-2022-327337.

Publisher

BMJ

Journal

Gut

scimago Q1

wos Q1

SJR

8.874

CiteScore

46.7

Impact factor

25.8

ISSN

00175749 (Print)

14683288 (Electronic)

Profiles

Harry Sokol