NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota

Abstract

The oxidized form of nicotinamide adenine dinucleotide (NAD+) is a critical metabolite for living cells. NAD+ may act either as a cofactor for many cellular reactions as well as a coenzyme for different NAD+-consuming enzymes involved in the physiological homeostasis of different organs and systems. In mammals, NAD+ is synthesized from either tryptophan or other vitamin B3 intermediates that act as NAD+ precursors. Recent research suggests that NAD+ precursors play a crucial role in maintaining the integrity of the gut barrier. Indeed, its deficiency has been associated with enhanced gut inflammation and leakage, and dysbiosis. Conversely, NAD+-increasing therapies may confer protection against intestinal inflammation in experimental conditions and human patients, with accumulating evidence indicating that such favorable effects could be, at least in part, mediated by concomitant changes in the composition of intestinal microbiota. However, the mechanisms by which NAD+-based treatments affect the microbiota are still poorly understood. In this context, we have focused specifically on the impact of NAD+ deficiency on intestinal inflammation and dysbiosis in animal and human models. We have further explored the relationship between NAD+ and improved host intestinal metabolism and immunity and the composition of microbiota in vivo. Overall, this comprehensive review aims to provide a new perspective on the effect of NAD+-increasing strategies on host intestinal physiology.

Nutrition in chronic inflammatory conditions: Bypassing the mucosal block for micronutrients

“…Deficiencies here results in pellagra characterized by dementia, dermatitis, and diarrhea 227 . NAD+ precursors play a crucial role in maintaining the integrity of the gut barrier and deficiencies are associated with enhanced gut inflammation and leakage, and dysbiosis, 228 whereas niacin supplementation effects intestinal cell proliferation and health in piglets and improved intestinal epithelial integrity and inflammation markers of chronic alcohol fed rats 229 . As essential co‐factor, nicotinic acid also boosts macrophage activity and NK function 230 and acts as an antioxidants able to scavenge radicals and suppress inflammatory mediators 231,232 …”

Epithelial NAD+ depletion drives mitochondrial dysfunction and contributes to intestinal inflammation

“…Indeed, NAD + supplementation has been shown to rejuvenate adult stem cells from aged mice in vitro ( 96 ), as well as improve the structure and function of the intestine in aging mice ( 117 , 120 ). Although NAD + supplementation has shown beneficial effects against murine colitis (present study ( 99 , 100 ); and healthy intestinal aging ( 119 ), knowledge regarding the outcomes of administering NAD + precursors for the prevention or treatment of IBD in the context of aging is limited ( 121 ). There are physiologic and phenotypic differences in geriatric-onset IBD, as compared to pediatric- and adult-onset IBD, that impact the therapeutic management of IBD in the elderly ( 122 ).…”

Explainable AI-prioritized plasma and fecal metabolites in inflammatory bowel disease and their dietary associations

“…Nonetheless, higher levels of fecal NMPC and 1-MNA being associated with IBD prediction could be due to increased levels of NAM, 81 , 82 a degradation product of nicotinamide adenine dinucleotide (NAD). 83 , 84 NA and NAM metabolism, which involves NAD turnover that is increased in IBD, 85 is currently a therapeutic target of manipulation for IBD patients, 86 as multiple studies show the involvement of these metabolic processes and pathways with IBD. 81 , 87 , 88 , 89 …”