Nitrate, a preservative in hot dogs and other meats as well as a natural ingredient in greens such as lettuce and spinach, was once considered a dietary scourge for its potential link to stomach cancer. But biologists are now starting to think that dietary nitrate is actually part of the body's inherent defense against infection and have begun testing treatments based on the idea.
Nitrate (NO3¿) became suspect in the 1950s, when researchers found that a class of its derivatives, called N-nitrosamines, damages DNA and causes cancer in laboratory rats and farm animals. A score of subsequent epidemiological studies generally found no consistent association between nitrate intake and human stomach cancer, however.
The story of nitrate's positive side began in 1994, when Jon Lundberg of the Karolinska Institute in Stockholm and Nigel Benjamin of Peninsula Medical School in Exeter, England, independently observed that the human stomach harbors large amounts of the gas nitric oxide (NO). Lundberg and Benjamin immediately suspected that the gas might be killing germs in the stomach, because nitric oxide, when presented to microbes by white blood cells, weakens them.
The question was where the gas was coming from. Nitric oxide performs several vital functions in the body, including dilating blood vessels, and for these activities, a cellular enzyme called nitric oxide synthase extracts the gas molecule from arginine, an amino acid. Chemists have long known another mechanism: at low pH, nitrite (NO2¿) forms a stew of nitrogen-oxygen compounds, including nitric oxide. Bacteria in the mouth convert nitrate to nitrite, which gets swallowed, so the stomach can naturally produce nitric oxide. If nitric oxide were truly beneficial to the stomach, harmless bacteria feeding on nitrate-rich saliva might have a symbiotic relationship with humans.
Benjamin's group confirmed the antimicrobial effect right away by exposing bacteria responsible for stomach infections to stomach acid both alone and mixed with nitrite. Although acid is often thought to be the stomach's main line of defense against invading bugs, the researchers found that E. coli, Salmonella and other bacteria could survive for hours in it, whereas high normal concentrations of nitrite plus acid killed the bacteria in less than an hour. Next, Lundberg and his co-workers placed saliva from people who had ingested nitrate tablets onto the inside surface of the stomachs of rats. The mucous membranes lining their stomachs thickened and received more blood, both of which are important barriers to infection and ulcers. Rats that received nitrate-poor saliva showed no change. Benjamin has also observed that cavity-causing bacteria self-destruct in a high- nitrite environment, suggesting an experiment to see if a high-nitrate diet prevents cavities.
"We've gone from considering all of these things to be toxic and carcinogenic to realizing that [nitrates are] playing a fundamental homeostatic role," says microbiologist Ferric Fang of the University of Washington.
Both groups are working on antimicrobial therapies based on nitrate chemistry. Benjamin has prepared a nitric oxide cream to treat bacterial skin infections common in developing countries, and Lundberg is conducting a study at Karolinska to see if giving saliva to dry-mouthed intubated patients can prevent ulcers. Researchers are still far from understanding how to treat systemic infections with nitric oxide, Fang says: "It has so many biological activities, how do you really deliver nitric oxide only to that bug without dropping your blood pressure? We don't know how to do that."