TY - JOUR
T1 - Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis
AU - Millet, Virginie
AU - Gensollen, Thomas
AU - Maltese, Michael
AU - Serrero, Melanie
AU - Lesavre, Nathalie
AU - Bourges, Christophe
AU - Pitaval, Christophe
AU - Cadra, Sophie
AU - Chasson, Lionel
AU - Vu Man, Thien Phong
AU - Masse, Marion
AU - Martinez-Garcia, Juan Jose
AU - Tranchida, Fabrice
AU - Shintu, Laetitia
AU - Mostert, Konrad
AU - Strauss, Erick
AU - Lepage, Patricia
AU - Chamaillard, Mathias
AU - Broggi, Achille
AU - Peyrin-Biroulet, Laurent
AU - Grimaud, Jean Charles
AU - Naquet, Philippe
AU - Galland, Franck
N1 - Publisher Copyright:
© 2023 Journal. All rights reserved.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - colonic mucosal metabolism
KW - inflammation
KW - inflammatory bowel disease
KW - vitamins
UR - http://www.scopus.com/inward/record.url?scp=85140998962&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2021-325792
DO - 10.1136/gutjnl-2021-325792
M3 - Article
C2 - 36175116
AN - SCOPUS:85140998962
SN - 0017-5749
VL - 72
SP - 1115
EP - 1128
JO - Gut
JF - Gut
IS - 6
ER -