Previous studies have demonstrated that oral intake of NMN and NR cannot directly raise human blood NAD+ levels. Their effects largely rely on transformation carried out by gut microbiota. These microbes convert NMN and NR into nicotinic acid, which serves as the major circulating precursor for NAD+. Once absorbed into cells, nicotinic acid generates NAD+ efficiently through the Preiss-Handler pathway without restrictions from rate-limiting enzymes. Gut microbiota are far more than simple conversion tools. They build a mutually beneficial symbiotic relationship with the human host. While breaking down NMN and NR into nicotinic acid, microbes boost the production of short-chain fatty acids and lower intestinal pH, creating favorable conditions for their own reproduction. NR tends to specifically promote the growth of Enterocloster aldensis, whereas NMN exerts broader regulatory effects on overall gut flora composition. Earlier mouse studies further confirmed the tight cooperation between host and gut microbiota in NAD+ metabolism. Even intravenously injected NMN and NR fail to elevate hepatic NAD+ concentrations without the participation of intestinal microbes. The underlying mechanism follows the enterohepatic circulation. Injected NMN and NR degrade rapidly into nicotinamide in the bloodstream. The substance is then secreted into the gut via bile. Gut microbes perform deamidation to convert nicotinamide into nicotinic acid, which is later reabsorbed and utilized by the liver. The liver predominantly synthesizes NAD+ via the Preiss-Handler pathway using nicotinic acid. A natural recycling system of NAD+ metabolites operates continuously inside the body even without external supplementation. Endogenous NAD+ gets consumed by sirtuins, CD38 and PARPs, producing nicotinamide as a byproduct. This metabolic waste flows into the gut, transforms into nicotinic acid under microbial action, and re-enters systemic circulation to sustain basic bodily NAD+ reserves. (Source:Science Advances, 2025) Gut microorganisms also depend on NAD+ to sustain normal growth and metabolism. They synthesize required NAD+ from nicotinamide released by host metabolism and dietary fiber intake. Some nicotinamide is directly absorbed by intestinal epithelial cells to generate local NAD+, supporting intestinal energy metabolism and physiological stability. Not all nicotinamide requires microbial conversion to function properly. Some nicotinamide travels through blood circulation to skeletal muscle and nerve tissues, where it participates in NAD+ synthesis through the salvage pathway. This pathway is strictly controlled by the rate-limiting enzyme NAMPT. For this reason, oral and injected NAD+ precursors show limited effectiveness in boosting NAD+ content within skeletal muscle. These findings offer novel guidance for anti-aging practice. To improve muscular fitness via NAD+ related mechanisms, people need to optimize precursor selection and daily health regimens. Special precursors such as trigonelline and NADH are viable choices. Moderate physical exercise combined with supplementation can enhance NAD+ synthesis efficiency and generate synergistic health benefits. Deep research reveals that gut microbiota act as indispensable symbiotic partners for the human host. Intestinal health will undoubtedly become a core part of systematic anti-aging strategies in the future. Reference Yaku K, Palikhe S, Iqbal T, et al. Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation[J]. Science Advances, 2025, 11(12): eadr1538. Chellappa K, McReynolds M R, Lu W, et al. NAD precursors cycle between host tissues and the gut microbiome[J]. Cell metabolism, 2022, 34(12): 1947-1959. e5. Disclaimer These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
