Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway
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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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NAD+ enhancement by NAM and NR occurs mostly through a microbiota-dependent deamidated pathway.
“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]
The Discussion reports that microbiota-enabled deamidated flux accounts for 66–77% of the increase in the hepatic NAD pool after oral NAM or NR. The claim omits that liver and oral-supplementation scope; the Results also note that microbiota processing of NR activates both deamidated and amidated pathways. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGut microorganisms participate in the metabolism of NAD+ and its metabolites.
“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]
The gut microbiota deamidates orally administered NAM to NA, which is then used for NAD+ synthesis via the Preiss-Handler pathway in the liver.
“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 <sup>+</sup> synthesis via enterohepatic circulation (2025) · cites this paper as [23]
The gut microbiota is essentially involved in the host NAD+ metabolism network.
“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 <sup>+</sup> synthesis via enterohepatic circulation (2025) · cites this paper as [23]
Orally administered NR was degraded into NAM and then converted to NA by gut microbiota before absorption.
“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 <sup>+</sup> synthesis via enterohepatic circulation (2025) · cites this paper as [23]
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Self-citation
- 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 · 2019: 1
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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