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.
- inflammatory bowel disease
- colonic mucosal metabolism
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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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.
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