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.

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