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Article

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

1
Department of Biopharmacy, Medical University of Lublin, 20-093 Lublin, Poland
2
Department of Medical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland
3
Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, 20-090 Lublin, Poland
*
Author to whom correspondence should be addressed.
Academic Editors: Astrid Parenti and Eid Ali Hussein
Int. J. Mol. Sci. 2021, 22(24), 13497; https://doi.org/10.3390/ijms222413497
Received: 5 November 2021 / Revised: 3 December 2021 / Accepted: 14 December 2021 / Published: 16 December 2021
(This article belongs to the Special Issue Kynurenine Pathway: A Bridge between Health and Disease)
A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies. View Full-Text
Keywords: metabolic network reconstruction; G protein-coupled receptor 109B; immune-mediated inflammatory disease; gut inflammation; anti-cytokine monoclonal antibodies; nicotinamide phosphoribosyltransferase metabolic network reconstruction; G protein-coupled receptor 109B; immune-mediated inflammatory disease; gut inflammation; anti-cytokine monoclonal antibodies; nicotinamide phosphoribosyltransferase
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MDPI and ACS Style

Wnorowski, A.; Wnorowska, S.; Kurzepa, J.; Parada-Turska, J. Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets. Int. J. Mol. Sci. 2021, 22, 13497. https://doi.org/10.3390/ijms222413497

AMA Style

Wnorowski A, Wnorowska S, Kurzepa J, Parada-Turska J. Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets. International Journal of Molecular Sciences. 2021; 22(24):13497. https://doi.org/10.3390/ijms222413497

Chicago/Turabian Style

Wnorowski, Artur, Sylwia Wnorowska, Jacek Kurzepa, and Jolanta Parada-Turska. 2021. "Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets" International Journal of Molecular Sciences 22, no. 24: 13497. https://doi.org/10.3390/ijms222413497

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