Gastrointestinal nitric oxide generation in germ-free and conventional rats
Abstract
Nitric oxide (NO) is a central mediator of various physiological events in the gastrointestinal tract. The influence of the intestinal microflora for NO production in the gut is unknown. Bacteria could contribute to this production either by stimulating the mucosa to produce NO, or they could generate NO themselves. Using germ-free and conventional rats, we measured gaseous NO directly in the gastrointestinal tract and from the luminal contents using a chemiluminescence technique. Mucosal NO production was studied by using an NO synthase (NOS) inhibitor, and to evaluate microbial contribution to the NO generation, nitrate was given to the animals. In conventional rats, luminal NO differed profoundly along the gastrointestinal tract with the greatest concentrations in the stomach [>4,000 parts per billion (ppb)] and cecum (approximately 200 ppb) and lower concentrations in the small intestine and colon (< or =20 ppb). Cecal NO correlated with the levels in incubated luminal contents. NOS inhibition lowered NO levels in the colon, without affecting NO in the stomach and in the cecum. Gastric NO increased greatly after a nitrate load, proving it to be a substrate for NO generation. In germ-free rats, NO was low (< or =30 ppb) throughout the gastrointestinal tract and absent in the incubated luminal contents. NO also remained low after a nitrate load. Our results demonstrate a pivotal role of the intestinal microflora in gastrointestinal NO generation. Distinctly compartmentalized qualitative and quantitative NO levels in conventional and germ-free rats reflect complex host microbial cross talks, possibly making NO a regulator of the intestinal eco system.
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Human nitrate reduction is highly dependent on oral commensal bacteria because human cells do not convert nitrate to nitrite to a high degree.
“Human nitrate reduction is highly dependent on the oral commensal bacteria because our cells do not convert nitrate to nitrite to a high degree.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [56]
Rats treated with dietary nitrate for up to 5 days still have decreased blood pressure compared with controls.
“Rats treated with dietary nitrate for up to 5 days still have decreased blood pressure compared with controls.56”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [56]
Effects on blood pressure by nitrate and nitrite do not show any signs of tolerance.
“In contrast, effects on blood pressure by nitrate and nitrite do not show any signs of tolerance.Rats treated with dietary nitrate for up to 5 days still have decreased blood pressure compared with controls.56”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [56]
Many bacteria are capable of reducing nitrate to nitrite to NO via the denitrification pathway.
“Many bacteria are capable of reducing nitrate to nitrite to NO via the denitrification pathway.”
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 [278]
Commensal gut bacteria are able to directly produce NO and also modify NO production.
“commensal gut bacteria are able to directly produce NO and also modify NO production, potentially influencing regional blood flow, mucosal integrity, microbial diversity, and effective nitrate and nitrite uptake.”
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 [278]
Lactobacilli and Bifidobacteria generate NO from nitrite in culture.
“both Lactobacilli and Bifidobacteria have been shown to generate NO from nitrite in culture”
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 [278]
Lactobacilli, Escherichia coli and Salmonella typhimurium increase cecal NO production when supplied with nitrate.
“while Lactobacilli, Escherichia coli and Salmonella typhimurium all increase cecal NO production when supplied with nitrate[217,233,271,278].”
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 [278]
L. rhamnosus produces NO in the gut in response to oral nitrate administration.
“producing NO in the gut in response to oral nitrate administration[74,217,278]”
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 [278]
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- Authors
- Sobko, T., Reinders, C., Norin, E., Midtvedt, T., Gustafsson, L. E., & Lundberg, J. O.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2004-11
- Volume
- 287
- Issue
- 5
- Pages
- G993-G997
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2140332763
- Cited by
- 75
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 4 · 2017: 6 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 6
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- nitric oxide, gastrointestinal tract, germ-free rats, gut microbiota, nitric oxide synthase, nitrate, luminal contents, cecum, stomach, host-microbe interactions, chemiluminescence
- MeSH terms
- Animals, Enzyme Inhibitors, Female, Gastrointestinal Contents, Germ-Free Life, Male, Nitrates, Nitric Oxide, Osmolar Concentration, Rats, Inbred Strains, NG-Nitroarginine Methyl Ester, Gastrointestinal Tract, Rats
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