Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue BMJ - British Medical Journal Année : 2022

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

Résumé

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.
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Dates et versions

hal-03975895 , version 1 (06-02-2023)

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Virginie Millet, Thomas Gensollen, Michael Maltese, Melanie Serrero, Nathalie Lesavre, et al.. Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis. BMJ - British Medical Journal, 2022, ⟨10.1136/gutjnl-2021-325792⟩. ⟨hal-03975895⟩
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