Titre :

Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis

Auteur(s) :

Millet, Virginie [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Gensollen, Thomas [Auteur]
Brigham & Women’s Hospital [Boston] [BWH]
Harvard Medical School [Boston] [HMS]
Maltese, Michael [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Serrero, Melanie [Auteur]
Lesavre, Nathalie [Auteur]
Hôpital Nord [CHU - APHM]
Bourges, Christophe [Auteur]
The Francis Crick Institute [London]
Pitaval, Christophe [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Cadra, Sophie [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Chasson, Lionel [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Vu Man, Thien [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Masse, Marion [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Martinez-Garcia, Juan [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Tranchida, Fabrice [Auteur]
Institut des Sciences Moléculaires de Marseille [ISM2]
Shintu, Laetitia [Auteur]
Institut des Sciences Moléculaires de Marseille [ISM2]
Mostert, Konrad [Auteur]
Stellenbosch University
Strauss, Erick [Auteur]
Stellenbosch University
Lepage, Patricia [Auteur]
MICrobiologie de l'ALImentation au Service de la Santé [MICALIS]
Peyrin‐biroulet, Laurent [Auteur]
Nutrition-Génétique et Exposition aux Risques Environnementaux [NGERE]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Broggi, Achille [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Grimaud, Jean-Charles [Auteur]
Hôpital Nord [CHU - APHM]
Naquet, Philippe [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]
Galland, Franck [Auteur]
Centre d'Immunologie de Marseille - Luminy [CIML]

Titre de la revue :

BMJ - British Medical Journal

Éditeur :

BMJ

Date de publication :

2022-09-29

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Objective In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. ...
Lire la suite >Objective In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B 5 , a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. Design We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. Results VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. Conclusion The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B 5-driven metabolism should improve mucosal healing and might increase the efficacy of antiinflammatory therapy.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL