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Review
. 2017 Apr;105:48-67.
doi: 10.1016/j.freeradbiomed.2016.12.015. Epub 2016 Dec 16.

Enterosalivary Nitrate Metabolism and the Microbiome: Intersection of Microbial Metabolism, Nitric Oxide and Diet in Cardiac and Pulmonary Vascular Health

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Free PMC article
Review

Enterosalivary Nitrate Metabolism and the Microbiome: Intersection of Microbial Metabolism, Nitric Oxide and Diet in Cardiac and Pulmonary Vascular Health

Carl D Koch et al. Free Radic Biol Med. .
Free PMC article

Abstract

Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors.

Keywords: Cardiovascular disease; Inflammation; Microbiome; Nitrate; Nitrated fatty acids; Nitric oxide; Nitrite; Pulmonary hypertension.

Figures

Figure 1
Figure 1
Schematic of the enterosalivary nitrate (NO3), nitrite (NO2), nitric oxide (NO), and nitro-fatty acid (NO2-FA) pathways and interactions with the oral and gut microbiome.
Figure 2
Figure 2
The ‘core’ oral microbiome. Charts represent a general summary of the relative abundances of major bacterial phyla (>1% total microbial abundance) constituting the normal microbiome of the human oral cavity. Individual charts represent regional microbial diversity within the entire oral cavity, saliva and oral wash, dorsum of the tongue, buccal mucosa, subgingiva, and the hard palate. Values presented are summary estimates only, extrapolated and pooled from multiple published analyses[–175,177,194].
Figure 3
Figure 3
Schematic representation of major bacterial nitrate reduction pathways. Abbreviations: DNRA, dissimilatory nitrate reduction to ammonia; ATP, adenosine triphosphate; NO3, nitrate; NO2,nitrite; NO, nitric oxide; N2O, nitrous oxide; N2, dinitrogen; NH3, ammonia; NH4, ammonium; glu, glutamine; nar, nap, and nas, nitrate reductases; nir, nrf, nitrite reductases; nor, nitric oxide reductase; nos, nitrous oxide reductase; nif, nitrogenase; e, electrons. Adapted from Sparacino-Watkins et al.[77] with permission of The Royal Society of Chemistry. http://dx.doi.org/10.1039/c3cs60249d.
Figure 4
Figure 4
Diagram of estimated oxygen concentration at various locations in the oral cavity and gastrointestinal tract. Left figure identifies locations in the oral cavity, stomach, and large and small bowel. Right figure is representative of a segment of bowel in cross-section. pO2, partial pressure of oxygen (mmHg). pO2 estimates from Espey 2013[267] and Hill & Marsh 1989[266].

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