PncA from bacteria improves diet-induced NAFLD by enabling the transition from NAM to NA in mice

Abstract Nicotinamide adenine dinucleotide (NAD + ) is crucial for energy metabolism, oxidative stress, DNA damage repair, longevity regulation, and several signaling processes. To date, three NAD + synthesis pathways have been found in microbiota and hosts, but the potential relationship between gut microbiota and their hosts in regulating NAD + homeostasis remains unknown. Here, we show that an analog of the first-line tuberculosis drug pyrazinamide (a bacterial NAD + synthesis inhibitor) affected NAD + levels in the intestines and liver of mice and disrupted the intestinal microecological balance. Furthermore, using microbiota expressing the pyrazinamidase/nicotinamidase ( PncA ) gene, which is a target of pyrazinamide, hepatic NAD + levels were greatly increased and significantly increased compared with other NAD + precursors, and diet-induced non-alcoholic fatty liver disease (NAFLD) in mice was improved. Overall, the PncA gene in microbiota plays an important role in regulating NAD + synthesis in the host, thereby providing a potential target for modulating the host’s NAD + level. Highlights PncA inhibitors disrupt gut microbiome homeostasis and reduce host NAD + levels but do not affect NAD + levels in cultured cells PncA gene in microbiota affects host liver NAD metabolism PncA affects lipid metabolism-related genes and metabolites in mice with NAFLD Diet-induced NAFLD is improved by PncA overexpression in the liver of mice Graphical abstract