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

Autor: Millet V; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Gensollen T; Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Maltese M; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Serrero M; Gastroenterology, AP-HM Hôpital Nord, Aix Marseille Université, Marseille, France., Lesavre N; Centre d'investigation Clinique (CIC), AP-HM Hôpital Nord, Aix-Marseille Université, Marseille, France., Bourges C; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK., Pitaval C; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Cadra S; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Chasson L; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Vu Man TP; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Masse M; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Martinez-Garcia JJ; Inserm U1019 Team 7, Inserm, Lille, France., Tranchida F; ISM2, Aix Marseille Université, Centre National de la Recherche Scientifique, Centrale Marseille, Marseille, France., Shintu L; ISM2, Aix Marseille Université, Centre National de la Recherche Scientifique, Centrale Marseille, Marseille, France., Mostert K; Stellenbosch University, Stellenbosch, Western Cape, South Africa., Strauss E; Stellenbosch University, Stellenbosch, Western Cape, South Africa., Lepage P; MICALIS-UMR1319, INRA, Jouy-en-Josas, France., Chamaillard M; Inserm U1019 Team 7, Inserm, Lille, France., Broggi A; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Peyrin-Biroulet L; Department of Gastroenterology, Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France., Grimaud JC; Gastroenterology, AP-HM Hôpital Nord, Aix Marseille Université, Marseille, France., Naquet P; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France., Galland F; Centre d'Immunologie de Marseille Luminy, Aix Marseille Université, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Marseille, France galland@ciml.univ-mrs.fr.
Jazyk: angličtina
Zdroj: Gut [Gut] 2023 Jun; Vol. 72 (6), pp. 1115-1128. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1136/gutjnl-2021-325792
Abstrakt: 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 anti-inflammatory therapy.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze: MEDLINE
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