RT Journal Article SR Electronic T1 PncA from bacteria improves diet-induced NAFLD by enabling the transition from NAM to NA in mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.04.471202 DO 10.1101/2021.12.04.471202 A1 Shengyu Feng A1 Liuling Guo A1 Hailiang Liu YR 2021 UL http://biorxiv.org/content/early/2021/12/04/2021.12.04.471202.abstract AB 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.HighlightsPncA inhibitors disrupt gut microbiome homeostasis and reduce host NAD+ levels but do not affect NAD+ levels in cultured cellsPncA gene in microbiota affects host liver NAD metabolismPncA affects lipid metabolism-related genes and metabolites in mice with NAFLDDiet-induced NAFLD is improved by PncA overexpression in the liver of miceCompeting Interest StatementThe authors have declared no competing interest.