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Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis
  1. Virginie Millet1,
  2. Thomas Gensollen2,
  3. Michael Maltese1,
  4. Melanie Serrero3,
  5. Nathalie Lesavre4,
  6. Christophe Bourges5,
  7. Christophe Pitaval1,
  8. Sophie Cadra1,
  9. Lionel Chasson1,
  10. Thien Phong Vu Man1,
  11. Marion Masse1,
  12. Juan Jose Martinez-Garcia6,
  13. Fabrice Tranchida7,
  14. Laetitia Shintu7,
  15. Konrad Mostert8,
  16. Erick Strauss8,
  17. Patricia Lepage9,
  18. Mathias Chamaillard6,
  19. Achille Broggi1,
  20. Laurent Peyrin-Biroulet10,
  21. Jean-Charles Grimaud3,
  22. Philippe Naquet1,
  23. Franck Galland1
  1. 1Centre 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
  2. 2Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Gastroenterology, AP-HM Hôpital Nord, Aix Marseille Université, Marseille, France
  4. 4Centre d’investigation Clinique (CIC), AP-HM Hôpital Nord, Aix-Marseille Université, Marseille, France
  5. 5Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK
  6. 6Inserm U1019 Team 7, Inserm, Lille, France
  7. 7ISM2, Aix Marseille Université, Centre National de la Recherche Scientifique, Centrale Marseille, Marseille, France
  8. 8Stellenbosch University, Stellenbosch, Western Cape, South Africa
  9. 9MICALIS—UMR1319, INRA, Jouy-en-Josas, France
  10. 10Department of Gastroenterology, Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
  1. Correspondence to Professor Franck Galland, CIML, Marseille, France; galland{at}ciml.univ-mrs.fr

Abstract

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 B5, 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 B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.

  • inflammation
  • inflammatory bowel disease
  • colonic mucosal metabolism
  • vitamins

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Twitter @achillebro

  • VM, TG and MMal contributed equally.

  • Contributors Data curation, formal analysis, investigation and methodology: VM, TG, MMal. Formal analysis and methodology: CB, CP, SC, LC, TPVM, JJM-G. Investigation and methodology: MS, NL, J-CG, ES, PL, MC, MMas, LS, KM, LP-B. Conceptualisation, formal analysis, supervision, funding acquisition, validation, investigation, methodology, project administration, writing original draft, review and editing: PN, FG. Guarantor: FG.

  • Funding TG and MMal were recipients of a doctoral contract from Aix-Marseille University. KM was supported by a doctoral bursary from the South African National Research Foundation. JJM-G was a recipient of a postdoctoral fellowship from the Fondation Pour la Recherche Médicale (FRM). Financial resources originated from institutional funding from CNRS, INSERM, AMU and APHM. This project benefited from a FRM grant (Equipe FRM DEQ20140329532) and Inserm-Transfer COPOC (n°: R19020AS), and was supported by SANOFI in the I2HD collaborative scientific programme between CIML and SANOFI (Aviesan n° 10756A10). This work was also supported by European Union under the European Regional Development Fund (MP0009273—EIRC Synchrohne) that was granted to MC.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.