Biology of nitrogen oxides in the gastrointestinal tract
Abstract
Throughout the human gastrointestinal tract a variety of reactive nitrogen oxides are continuously formed as a result of a complex interplay between the host, commensal bacteria and dietary factors. These compounds include nitric oxide, nitrite, nitrate, peroxynitrite, S-nitrosothiols, nitrated fatty acids and N-nitrosamines, all of which are bioactive with the potential to affect physiological and pathological processes locally in the gut as well as systemically after absorption. Historically, the literature has been dominated by studies on the formation of potentially carcinogenic nitrosamines, but the focus was shifted in the 1980s with the seminal discovery of the L-arginine-nitric oxide pathway and its profound impact on normal physiological functions. More recently, a nitrate-nitrite-nitric oxide pathway has been discovered, with implications for local host defence and gut mucosal integrity and, intriguingly, also for systemic regulation of cardiovascular and metabolic function. This review discusses recent advances in the understanding of the formation, biochemistry, physiology and pathophysiology of reactive nitrogen oxides in the gastrointestinal tract. In addition, opportunities for nitric oxide-based pharmacological or dietary interventions are highlighted.
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These reactions lead to generation of electrophilic nitro-fatty acid signaling mediators, including NO2-CLA and S-nitrosothiol derivatives, detected at increased concentrations in systemic circulation following oral consumption of nitrate.
“These reactions also lead to the generation of electrophilic nitro-fatty acid (NO2-FA) signaling mediators, including NO2-conjugated linoleic acid (NO2-CLA) and S-nitrosothiol derivatives, all of which can be detected at increased concentrations in the systemic circulation following oral consumption of nitrate[72,92–96].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [96]
The acidic milieu of the gastric compartment and the presence of nitrite (NO2−) in food promotes a nitrative environment due to HNO2 formation that can mediate biomolecule nitration.
“The acidic milieu of the gastric compartment and the presence of NO2 − in food promotes a nitrative environment due to HNO2 formation (NO2 − pKa, 3.4) that in turn can mediate biomolecule nitration [41], [42].”
From Olives and olive oil are sources of electrophilic fatty acid nitroalkenes (2014) · cites this paper as [42]
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Self-citationTherapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases
Omar, S. A., Webb, A. J., Lundberg, J. O., & Weitzberg, E. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12441 · Cited by 175 · see citing works
Self-citationSignaling and stress: The redox landscape in NOS2 biology
Thomas, D. D., Heinecke, J. L., Ridnour, L. A., Cheng, R. Y., Kesarwala, A. H., Switzer, C. H., McVicar, D. W., Roberts, D. D., Glynn, S., Fukuto, J. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.002 · Cited by 150 · see citing works
Oleskin, A. V., & Shenderov, B. A. (2016) · Microbial Ecology in Health & Disease · doi:10.3402/mehd.v27.30971 · Cited by 145 · see citing works
Olives and olive oil are sources of electrophilic fatty acid nitroalkenes
Fazzari, M., Trostchansky, A., Schopfer, F. J., Salvatore, S. R., Sánchez-Calvo, B., Vitturi, D., Valderrama, R., Barroso, J. B., Radi, R., Freeman, B. A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084884 · Cited by 114 · see citing works
Charles, R. L., Rudyk, O., Prysyazhna, O., Kamynina, A., Yang, J., Morisseau, C., Hammock, B. D., Freeman, B. A., & Eaton, P. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402965111 · Cited by 100 · see citing works
The redox interplay between nitrite and nitric oxide: From the gut to the brain
Pereira, C., Ferreira, N. R., Rocha, B. S., Barbosa, R. M., & Laranjinha, J. (2013) · Redox Biology · doi:10.1016/j.redox.2013.04.004 · Cited by 92 · see citing works
Dietary nitrate reduces resting metabolic rate: A randomized, crossover study in humans
Larsen, F. J., Schiffer, T. A., Ekblom, B., Mattsson, M. P., Checa, A., Wheelock, C. E., Nyström, T., Lundberg, J. O., & Weitzberg, E. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.079491 · Cited by 92 · see citing works
Self-citationJädert, C., Phillipson, M., Holm, L., Lundberg, J. O., & Borniquel, S. (2014) · Redox Biology · doi:10.1016/j.redox.2013.12.012 · Cited by 73 · see citing works
Self-citationInorganic nitrite supplementation for healthy arterial aging
Sindler, A. L., DeVan, A. E., Fleenor, B. S., & Seals, D. R. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01100.2013 · Cited by 68 · see citing works
Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride
Vitturi, D. A., Minarrieta, L., Salvatore, S. R., Postlethwait, E. M., Fazzari, M., Ferrer-Sueta, G., Lancaster, J. R., Freeman, B. A., & Schopfer, F. J. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1814 · Cited by 65 · see citing works
On the mechanism by which dietary nitrate improves human skeletal muscle function
Affourtit, C., Bailey, S. J., Jones, A. M., Smallwood, M. J., & Winyard, P. G. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00211 · Cited by 58 · see citing works
Role of Oral and Gut Microbiota in Dietary Nitrate Metabolism and Its Impact on Sports Performance
González-Soltero, R., Bailén, M., de Lucas, B., Ramírez-Goercke, M. I., Pareja-Galeano, H., & Larrosa, M. (2020) · Nutrients · doi:10.3390/nu12123611 · Cited by 54 · see citing works
Rocha, B. S. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.778467 · Cited by 30 · see citing works
“Also, the major source of nitrate are green leafy vegetables and roots such as lettuce, spinach, rucola and beetroot (Weitzberg and Lundberg, 2013).”
BackgroundBescos, R., Gallardo-Alfaro, L., Ashor, A., Rizzolo-Brime, L., Siervo, M., & Casas-Agustench, P. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.11.010 · Cited by 13 · see citing works
Nowak, A., Szymańska, A., Kwaśniewska, M., Kochan, E., & Lipert, A. (2025) · Nutrients · doi:10.3390/nu17243954 · Cited by 5 · see citing works
- Authors
- Lundberg, J. O., & Weitzberg, E.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Lundberg, Jon O
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2012-01-20
- Volume
- 62
- Issue
- 4
- Pages
- 616-629
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W1983361198
- Semantic Scholar
- dc9d2405843db7d57211c493bbd4161dd06851f0
- Cited by
- 200
- References
- 186
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 11 · 2023: 6 · 2022: 14 · 2021: 19 · 2020: 16 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 17 · 2013: 13 · 2012: 3
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- reactive nitrogen oxides, nitric oxide, nitrite, nitrate, peroxynitrite, S-nitrosothiols, nitrated fatty acids, nitrosamines, L-arginine-nitric oxide pathway, nitrate-nitrite-nitric oxide pathway, gut microbiota, commensal bacteria, dietary factors, host defense, cardiovascular regulation, metabolic regulation, dietary intervention
- MeSH terms
- Diet, Free Radicals, Humans, Nitrogen Oxides, Stomach Neoplasms, Gastrointestinal Tract
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