Bacterial PncA improves diet-induced NAFLD in mice by enabling the transition from nicotinamide to nicotinic acid

Abstract

Nicotinamide adenine dinucleotide (NAD+) is crucial for energy metabolism, oxidative stress, DNA damage repair, longevity regulation, and several signaling processes. To date, several NAD+ synthesis pathways have been found in microbiota and mammals, but the potential relationship between gut microbiota and their hosts in regulating NAD+ homeostasis remains largely unknown. Here, we showed that an analog of the first-line tuberculosis drug pyrazinamide, which is converted by nicotinamidase/pyrazinamidase (PncA) to its active form, affected NAD+ level in the intestines and liver of mice and disrupted the homeostasis of gut microbiota. Furthermore, by overexpressing modified PncA of Escherichia coli, NAD+ levels in mouse liver were significantly increased, and diet-induced non-alcoholic fatty liver disease (NAFLD) was ameliorated in mice. Overall, the PncA gene in microbiota plays an important role in regulating NAD+ synthesis in the host, thereby providing a potential target for modulating host NAD+ level.