Host-derived nicotinamide in circulation feed gut microbiome

Nicotinamide adenine nucleotide (NAD), a redox cofactor and a co-substrate for signaling enzymes, is essential in mammals and microbes. In this study we used heavy isotope labeled tracers to identify the precursors used by gut microbiome for NAD synthesis. We found that precursors available in the diet, amino acids and vitamin B3 (nicotinamide and nicotinic acid), are absorbed in the proximal parts of the digestive tract. Dietary fiber that reaches the colon feed into de novo NAD synthesis, but a large portion of NAD synthesis in gut microbiome remained unaccounted. We made a surprising discovery that the host-derived nicotinamide in circulation enter gut lumen and support NAD synthesis, almost in entirety in small intestinal microbiota and more than 50% to large intestinal microbiota. We show that nicotinic acid produced by microbial deamidation of nicotinamide provide alternate precursor to by-pass salvage synthesis in host tissues. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to boost host NAD is via conversion into nicotinic acid by the gut microbiome. Together, we establish that vitamin B3 cycles between host and gut microbiome to increase mammalian robustness.