NIH Research Festival
Nicotinamide adenine dinucleotide (NAD+), a cofactor for hundreds of metabolic reactions in all cell types, is essential for life. Dysregulation of NAD+ homeostasis has been associated with several human diseases, such as metabolic diseases, cancer, immune dysfunction, and aging. Cellular NAD+ biosynthesis pathways, including salvage from nicotinamide (amidated synthesis), synthesis from nicotinic acid (deamidated synthesis), and de novo synthesis from tryptophan, have been extensively studied in various model organisms. However, the tissue-specific importance of different NAD+ biosynthesis pathways remain largely unknown. We have recently discovered that gut microbiota interacts with dietary NAD+ precursors to mediate the deamidated NAD+ biosynthesis. To directly investigate the functional importance of the microbiota-enabled deamidated NAD+ biosynthesis, we generated a mouse model in which the first enzyme of this pathway, nicotinic acid phosphoribosyl transferase (NAPRT), is deleted. Isotopic tracing experiments demonstrated that deletion of NAPRT leads to a massive accumulation of its substrate nicotinic acid and abolishes the dramatic rise in the deamidated intermediates, thereby blunting the increase in newly synthesized and total NAD+ in a variety of mouse tissues. Functionally, deletion of NAPRT in mice increases the sensitivity to chemically induced colonic tissue damage and inflammation (colitis) and enhances the development and growth of colorectal cancer. In conclusion, our animal model enables the investigation of the functional role of the deamidated NAD+ biosynthesis in vivo and our findings reveal a crucial role of bacteria-enabled deamidated pathway in host NAD+ metabolism and physiology.
Scientific Focus Area: ACI/IRS
This page was last updated on Monday, September 25, 2023