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

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 hosts NAD+ level. HighlightsO_LIPncA inhibitors disrupt gut microbiome homeostasis and reduce host NAD+ levels but do not affect NAD+ levels in cultured cells C_LIO_LIPncA gene in microbiota affects host liver NAD metabolism C_LIO_LIPncA affects lipid metabolism-related genes and metabolites in mice with NAFLD C_LIO_LIDiet-induced NAFLD is improved by PncA overexpression in the liver of mice C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/471202v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@7279aeorg.highwire.dtl.DTLVardef@192a133org.highwire.dtl.DTLVardef@195482forg.highwire.dtl.DTLVardef@1b634a2_HPS_FORMAT_FIGEXP M_FIG C_FIG