Abstract
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.
Highlights
IDO1, KYNU and hydroxycarboxylic acid receptor 3 (HCAR3) Are Upregulated in inflammatory bowel disease (IBD) and Suppressed upon Effective
Datasets were searched for genes that were markedly deregulated in Crohn’s disease (CD) and ulcerative colitis (UC) patients and that were returning to baseline only in response to the successful treatment with infliximab
We searched for genes that were either: (a) down-regulated in IBD patients compared to normal controls and up-regulated in IBD patients successfully treated with infliximab, compared to baseline and non-responders, or (b) up-regulated in IBD patients compared to normal controls and down-regulated in IBD patients successfully treated with infliximab, compared to baseline and non-responders
Summary
Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by disturbed gut homeostasis, leading to chronic inflammation. The prevalence of IBD continuously rises in industrialized societies, especially across individuals with genetic susceptibility who are exposed to certain dietary and environmental factors [1]. The exact etiology and pathophysiology of IBD remains unknown. The treatment options for IBD were glucocorticoids, immunomodulators (e.g., methotrexate), 5-aminosalicylic acid, cyclosporine, and antibiotics. The introduction of anticytokine therapies revolutionized the management of chronic inflammatory diseases, including IBD. Current CD and UC treatment recommendations, formulated by medical societies and other representative bodies, include the use of anticytokines [3,4]. Infliximab, an anti-TNFα agent, was approved for IBD in 1998 and is still commonly used [5,6]. Other human monoclonal antibodies interacting with this cytokine were introduced, i.e., adalimumab, certolizumab, and golimumab [7]
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