NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies
Abstract
:1. Introduction
2. Immunometabolism and Inflammatory Bowel Disease
3. NAD+ Metabolism
4. The Role of NAD+ in Regulating IBD
4.1. NAD+ and IBD
4.2. NAD+ Metabolic Enzyme
4.2.1. Sirtuins
4.2.2. CD38
4.2.3. PARP
4.2.4. NAMPT and NAPRT
4.2.5. NNMT
4.3. IBD and NAD+ Regulation
4.3.1. NAD+ and Mitochondrial Dysfunction
4.3.2. Intestinal Epithelial Barrier
4.3.3. Intestinal Stem Cells
5. IBD NAD+ Regulation: Clinical Possibility
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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NAD+ Metabolic Enzyme | Intracellular or Extracellular | Regulation of NAD+ | Cellular Processes and Pathways | Illnesses | IBD-Related Studies | Mechanisms Associated with IBD |
---|---|---|---|---|---|---|
Sirtuins | Intracellular | Sirtuins are NAD+ substrates and cofactors in deacetylated ADP-ribosylation reactions. In chronic inflammatory diseases, NAD+ and SIRT are downregulated in specific tissues [66]. | Energy shifts [67], cell differentiation [68], apoptosis [69], autophagy [70], development [71], and metabolism [72]; regulates circadian clock proteins CLOCK/Per [73,74,75,76,77], NF-κB/p65 [78], PPAR-γ/pgc1α [79], NLRP3 inflammation [80], TLR4 [81]. | Fat deposits in obesity and inflammation, atherosclerosis [82], Alzheimer’s [83], and sepsis [84]. | Some sirtuins (SIRT2, 3, 5, 6) protect against IBD [85,86,87,88,89,90] and some sirtuins (SIRT1) might be pathogenic [91]. | Activate macrophages [85,92] and remodel the gut microbiota [90,93,94]. |
CD38 | Intracellular and extracellular | Type II glycosylated membrane protein CD38 converts NAD+ to ADPr and cADPr and hydrolyzes cADPr to ADPr [95,96]. Low-level CD38 inhibition increases cellular NAD+ levels [97,98]. | Regulates cell adhesion, differentiation, and proliferation [99]; mobilizes intracellular Ca2+ [100,101]; improves glucose metabolism and maintains lipid homeostasis [97,102]; repels neutrophils [99]. | Aging [103]. | Potential pathogenicity in IBD [58,104,105,106] | Activation and proliferation of T cells [105]. |
NAMPT | Intracellular and extracellular | NAMPT upregulation increases NAD+, and the precursor NMN that converts NAM to NAD+ is essential for cellular NAD+ supply and rate-limiting steps in the NAD+ remediation pathway [40]. | Regulates energy metabolism, circadian rhythm, and immunity production [107]; proliferation, anti-apoptotic, pro-inflammatory, pro-angiogenic, and metastatic properties [108]. | Sepsis, rheumatoid arthritis, diabetes [109,110,111]. | NAMPT inhibition prevents experimental colitis in humans and mice [18,62] and colon tumor pathogenesis in mice [18,112]. | Reduces NF-κB activation and inflammatory cell infiltration [18]; decreases cell ATP levels; inhibits IL-1β, IL-6, and TNF-α secretion in vitro [113]. |
PARP | Intracellular | NAD+ decomposing enzyme, cleavage of the nicotinamide-glycosidic bond of NAD+ to generate ADPr polymer [114]; enhances PARP activity and has significant harmful effects on NAD+ pools [115,116]. | Pro-inflammatory, pro-proliferative, oxidative stress [117,118]; NF-κB pathway [119]. | Peritonitis, septic shock, ovarian cancer [120], and alcoholic fatty liver [117,118]. | PARP1 and PARP2 promote colitis in mice [121,122]. | Downregulates SIRT1 and causes mucosal atrophy [123]. |
NNMT | Intracellular | NAD+-dependent pro-inflammatory signals are maintained by methylation and excretion of NAM, which reduces precursors for NAD+ synthesis [41,124]. | Modulates tumor resistance and chemotherapy sensitivity [125,126,127,128], glucose metabolism [129]; NF-κB pathway [130]. | Colorectal cancer, breast cancer, esophageal squamous cell carcinoma, colorectal cancer, melanoma [125,126,127,128], type 2 diabetes [47], obesity [131], COPD [132,133], liver injury [134,135]. | Infliximab-treated IBD patients show normalized NNMT expression [124]. | No studies were found. |
Drugs | Effects on NAD+ Metabolic Pathways | Research Models | Mechanism | References |
---|---|---|---|---|
NMN | NAD+ precursor, activate the NAMPT-dependent NAD+ biosynthetic pathway, increase NAD+ content | DSS-induced colitis mice | Improves inflammatory intestine morphology, colon length, intestinal epithelial barrier, blood serum pro-inflammatory factors, and gut microbiota composition. | [261,269] |
Resveratrol | Increases SIRT1 expression | TNBS-induced colitis mice | Inhibits NF-κB signaling and activates NRF2 antioxidant program. | [262] |
Cay10591 | Activates SIRT1 | TNBS or oxazolidinone-induced colitis in mice | Block NF-κB signaling and cytokine production. | [89] |
Catalpol | Activates SIRT1 | TNBS-induced colitis mice | Improves endoplasmic reticulum stress | [263] |
EX-527 | Inhibits SIRT1 | DSS-induced colitis mice | Promotes the formation of Treg | [264] |
Norisoboldine | Reduce NAD+ levels and inhibit SIRT1 | DSS-induced colitis mice | Enhances the differentiation of Treg, regulates the AhR/glycolysis axis | [65] |
PJ34 | Inhibits PARP1 | DSS-induced colitis mice | [265] | |
1,5-Dihydroxyisoquinoline | Inhibits PARP1 | TNBS-induced colitis rats | Inhibits NF-κB pathway and AP-1 | [266,267] |
FK866 | NAMPT inhibitors | Isolated lamina propria mononuclear cells (LPMCs) from IBD patients and DSS-induced colitis mice | Inhibits intestinal mucosa immunity and cytokines. | [18] |
Cyclosporine A | Inhibits SIRT6 | Neutrophils in peripheral blood from patients with acute UC | Inhibits peripheral blood neutrophil function and migration in acute UC | [268] |
NNMT | Restores NAD+ | Intestinal mucosa from IBD patients | Tryptophan metabolism | [124] |
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Chen, C.; Yan, W.; Tao, M.; Fu, Y. NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies. Antioxidants 2023, 12, 1230. https://doi.org/10.3390/antiox12061230
Chen C, Yan W, Tao M, Fu Y. NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies. Antioxidants. 2023; 12(6):1230. https://doi.org/10.3390/antiox12061230
Chicago/Turabian StyleChen, Chaoyue, Wei Yan, Meihui Tao, and Yu Fu. 2023. "NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies" Antioxidants 12, no. 6: 1230. https://doi.org/10.3390/antiox12061230