The (amide-)N-methylnicotinamide is a microbe-derived NAD + precursor that drives gut stem cell renewal

Nicotinamide Adenine Dinucleotide (NAD) is a critical cellular coenzyme whose decline associates with various chronic and inflammatory diseases. Improved NAD restoration may reduce disease risks and extend healthy lifespan. We report here that certain commensal bacteria including specific probiotic species produce (amide-)N-methylnicotinamide (N-MNA), which is a structural isomer of methylnicotinamide, a nicotinamide degradative metabolite. Patients with gut dysbiosis and inflammation show reduced stool N-MNA. Stable isotope tracing revealed that N-MNA can be rapidly taken up and incorporated into NAD redox reactions by intestinal epithelial cells (IECs) and non-IECs of fruit fly, mouse, and human. Genetic and pharmacological analyses suggest that N-MNA is converted to NAD + via the Preiss-Handler pathway, independent of the salvage pathway. Cell-type-specific ablation or overexpression of SIRT1, an NAD-consuming enzyme, in Drosophila , along with intestinal stem cell (ISC) lineage tracing in mice revealed that systemic N-MNA supplementation promotes ISC regeneration and gut epithelial repair. Compared to known NAD precursors, N-MNA brings a methyl group into host cells, representing a class of microbe-derived NAD precursor that stimulates the tissue regenerative power.