Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite

Formation of nitrite and propagation of its downstream NO-signaling effects depends on the oral bacterial reduction of inorganic nitrate by bacterial nitrate reductase enzymes (NaRs) that are largely absent from the human genome.

“Formation of nitrite and propagation of its downstream NO-signaling effects depends on the oral bacterial reduction of inorganic nitrate by a set of bacterial nitrate reductase enzymes (NaRs) that are largely absent from the human genome[73–78].”

Nitrite is swallowed and can undergo downstream reactions, including formation of NO and NO-donating species following protonation to HNO2 and secondary nitrosating and nitrating species in the low pH of the stomach, or further reduction by enteric bacterial nitrite reductases.

“Nitrite is then swallowed where it can undergo a diversity of downstream reactions, including formation of NO and NO-donating species following a) protonation to HNO2 and an array of secondary nitrosating and nitrating species in reactions facilitated by the low pH of the stomach[80,83,89–91], or b) further reduction by enteric bacterial nitrite reductases (NiRs)[74].”

Bacteria in the distal GI tract have the capacity to reduce nitrate.

“despite the capacity of bacteria in the distal GI tract to reduce nitrate[74]”

Human and animal studies have established the ability to successfully populate the oral cavity or gastrointestinal tract with specific strains, combinations of bacteria, or bacteria genetically modified to produce enzymes or metabolites.

“While human and animal studies have established the ability to successfully populate the oral cavity or gastrointestinal tract with specific strains, combinations of bacteria, or bacteria genetically modified to produce enzymes or metabolites[74,404–407]”

Lactobacilli are common and robust bacteria in the mouth and gut, able to tolerate low pH and to generate NO in culture.

“At the genus level, Lactobacilli are common and robust bacteria in the mouth and gut, able to tolerate low pH and to generate NO in culture[74,412].”

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]”

The normal bacterial flora generates NO and gut luminal NO levels have been measured in vivo in rats.

“More recently, the normal bacterial flora has been shown to generate NO and gut luminal NO levels have been measured in vivo in rats [15,16].”

Several following studies have proposed different mechanisms of bacterial NO formation independent of respiratory denitrification, such as arginine-dependent bacterial NOS activity, DNRA, and non-enzymatic processes.

“However, several following studies on bacterial NO formation have proposed different mechanisms independent of respiratory denitrification such as arginine dependent bacterial NOS enzymatic activity, DNRA and non-enzymatic processes [15,32–34].”

Our data are consistent with the report that E. coli generated insignificant NO levels during 24 h incubation with 0.1 mM nitrate.

“Importantly, our data are consistent with the report by Sobko and colleagues that E. coli generated insignificant NO levels during 24 h incubation with 0.1 mM nitrate [15].”

In contrast to conventional rats, NO levels in the intestine of germ-free rats are extremely low, and inoculation with normal bacteria flora increased observed NO production 10-fold.

“Sobko et al. [15] showed that in contrast to conventional rats, NO levels in the intestine of germ-free rats are extremely low and when inoculated with normal bacteria flora the observed NO production increased 10 fold.”