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

Shengyu Feng, Liuling Guo, Hailiang Liu
doi: https://doi.org/10.1101/2021.12.04.471202
Shengyu Feng
1Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
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Liuling Guo
1Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
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Hailiang Liu
1Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
2Key Laboratory of Xinjiang Phytomedicine Resource and Utilization of Ministry of Education, College of Life Sciences, Shihezi University, Shihezi, 832003, China
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  • For correspondence: hailiang_1111@tongji.edu.cn
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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

  1. PncA inhibitors disrupt gut microbiome homeostasis and reduce host NAD+ levels but do not affect NAD+ levels in cultured cells

  2. PncA gene in microbiota affects host liver NAD metabolism

  3. PncA affects lipid metabolism-related genes and metabolites in mice with NAFLD

  4. Diet-induced NAFLD is improved by PncA overexpression in the liver of mice

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 04, 2021.
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PncA from bacteria improves diet-induced NAFLD by enabling the transition from NAM to NA in mice
Shengyu Feng, Liuling Guo, Hailiang Liu
bioRxiv 2021.12.04.471202; doi: https://doi.org/10.1101/2021.12.04.471202
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PncA from bacteria improves diet-induced NAFLD by enabling the transition from NAM to NA in mice
Shengyu Feng, Liuling Guo, Hailiang Liu
bioRxiv 2021.12.04.471202; doi: https://doi.org/10.1101/2021.12.04.471202

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