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

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.

Tryptophan Metabolism ‘Hub’ Gene Expression Associates with Increased Inflammation and Severe Disease Outcomes in COVID-19 Infection and Inflammatory Bowel Disease

“…In further studies, pathways affected during IBD progression and post treatment recovery included genes involved in tryptophan degradation, receptors of tryptophan metabolites and NAD + turnover (i.e., IDO, KYNU, HCAR3, CD38 and NNMT) being synchronously co-regulated [ 61 ]. Treatment with Infliximab (TNFα inhibitor) removes excess of inhibitory NAM and helps maintain high levels of NAD + -dependent pro-inflammatory signaling [ 62 , 63 ]. While KYNU relevance to inflammation has been demonstrated in psoriasis in which epithelial cells only expressed KYNU after stimulation with IFNγ or TNFα; and combining the cytokines significantly enhanced IDO and KYNU in various cell types as much as 100 fold [ 64 ].…”

Microarray-Based Prediction of Polycythemia after Exposure to High Altitudes

“…HCAR3 and LRRC18 were also sensitive to exposure to high altitudes and might be able to predict whether a person would develop HAPC. HCAR3 activates Gi signaling in immune cells and is also a therapeutic target for breast cancer and inflammatory bowel diseases [ 40 , 41 , 42 ], and these diseases cause hypoxia response. HCAR3 activates ERK1/2, which in turn activates NFκB-mediated hypoxia responses.…”

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

“…A total of 957 DEGs were screened: 478 up regulated genes and 479 down regulated genes. Lee et al [41], Gijsbers et al [42], Hashash et al [43], Wnorowski et al [44] and Kyodo et al [45] found that FCGR3A, CXCL8, MUC1, HCAR3 and DUOX2 might play an important role in the pathophysiology of CD. Nourse et al [46] and Nakashima et al [47] found that FCGR3A and MUC1 was altered expressed in coagulation and fibrinolysis.…”