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Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway
Open accessPublished version of a preprint
Abstract
Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.
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“Shats et al. (2020) also reported that NAD+ enhancement by NAM and NR was mostly through microbiota-dependent deamidated pathway [44].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [44]
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“While microorganisms that inhabit the gut play a role in the metabolism of NAD+ and its metabolites [43, 44]”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [44]
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“For example, the gut microbiota deamidates orally administered NAM to NA, which is then used for NAD+ synthesis via the Preiss-Handler pathway in the liver (23).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD + synthesis via enterohepatic circulation (2025) · cites this paper as [23]
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“Recent studies indicated that the gut microbiota is essentially involved in the host NAD+ metabolism network (22–24).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD + synthesis via enterohepatic circulation (2025) · cites this paper as [23]
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“However, subsequent studies and our current study demonstrated that orally administered NR was degraded into NAM and then converted to NA by gut microbiota before absorption (22–24).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD + synthesis via enterohepatic circulation (2025) · cites this paper as [23]
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NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,147
Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651
Evolving concepts in NAD+ metabolism
Chini, C. C. S., Zeidler, J. D., Kashyap, S., Warner, G. M., & Chini, E. N. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.04.003 · Cited by 301
NAD + Metabolism in Cardiac Health, Aging, and Disease
Abdellatif, M., Sedej, S., & Kroemer, G. (2021) · Circulation · doi:10.1161/circulationaha.121.056589 · Cited by 267
NAD precursors cycle between host tissues and the gut microbiome
Chellappa, K., McReynolds, M. R., Lu, W., Zeng, X., Makarov, M., Hayat, F., Mukherjee, S., Bhat, Y. R., Lingala, S. R., Shima, R. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.004 · Cited by 146
Self-citation
Metadata
- Authors
- Shats, I., Williams, J. G., Liu, J., Makarov, M. V., Wu, X., Lih, F. B., Deterding, L. J., Lim, C., Xu, X., Randall, T. A., Lee, E., Li, W., Fan, W., Li, J.-L., Sokolsky, M., Kabanov, A. V., Li, L., Migaud, M. E., Locasale, J. W., & Li, X.
- Affiliations
- National Institutes of Health (US)
- Duke University (US)
- University of South Alabama (US)
- National Institute of Environmental Health Sciences (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Shats, Igor
- Li, Xiaoling
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 31
- Issue
- 3
- Pages
- 564-579.e7
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7194078
- OpenAlex
- W3010636379
- Cited by
- 242
- References
- 73
- Citations by year
- 2026: 31 · 2025: 52 · 2024: 37 · 2023: 37 · 2022: 42 · 2021: 28 · 2020: 14
- FWCI
- 15.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Environmental Health Sciences
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- NAD+ metabolism, NAD biosynthesis, NAMPT inhibitors, nicotinamide, nicotinamide riboside, gut microbiota, host-microbe interactions, cancer cells, tumor xenografts
- MeSH terms
- Gastrointestinal Microbiome, Administration, Oral, Amides, Animals, Energy Metabolism, Female, Humans, Male, Mammals, Mice, Inbred C57BL, Mycoplasma, NAD, Nicotinamidase, Niacinamide, Nicotinamide Mononucleotide, Pyridinium Compounds, Cytokines, Cell Line, Tumor, Biosynthetic Pathways, Nicotinamide Phosphoribosyltransferase, Metabolome
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