The tongue microbiome and nitric oxide bioavailability across the human lifespan

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Context: The human digestive system contains trillions of microbes collectively called the gut microbiota. Important discoveries have been made through better understanding the role the gut microbiota has in maintaining physical and mental health. Imbalances in the oral microbial community, and poor dental health, have been associated with impaired cardiovascular health, but the role of the oral microbiota as a potential modulator of human health is not well understood. One mechanism that may link the oral microbiota to good health is the nitrate-nitrite-nitric oxide (NO) reduction pathway. This, for its first step, crucially relies on the reduction of nitrate, which has been ingested through the diet, to nitrite by bacteria residing in the mouth. Among many other physiological roles, NO regulates vascular endothelial function, and therefore blood pressure (BP). In the UK, at least 25% of adults and more than 50% of people over 60 years old have elevated BP and this is considered a significant cause of premature morbidity and mortality. Epidemiological studies indicate that a greater consumption of high nitrate foodstuffs (specifically, green leafy vegetables and some fruits, such as in the 'Mediterranean' or '5 a day' diets) may protect against adverse cardiovascular events, and it is known that dietary nitrate supplementation significantly reduces BP in both young and older adults. Differences between individuals in the ability to reduce nitrate to nitrite and in the effects on BP indicate that the benefits derived from a high nitrate diet may be contingent on individuals having the 'right' oral microbiota.The ability to produce NO in the body through the classical pathway involving nitric oxide synthase (NOS) enzymes is impaired in older age, leading to a gradual increase in BP. We propose that the nitrate-nitrite-NO pathway has significant potential to compensate for dysfunctional NOS in older age. Little is known, however, about how the symbiotic relationship between the human host and the oral microbiota might change with ageing and how the microbiota could be harnessed to maintain cardiovascular health during ageing. Aims and Objectives: We aim to investigate whether the prevalence of specific nitrate-reducing bacteria residing on the surface of the tongue influences the cardiovascular benefits that may be derived from the consumption of a high nitrate diet and whether there are differences between young and older adults. This builds on our preliminary data which indicate differences in the oral microbiome between young and older adults as well as correlations between the prevalence of specific oral bacteria in an individual and their ability to reduce a standardised dietary nitrate bolus to nitrite and the observed reduction in BP. This suggests that augmentation of this nitrate-nitrite-NO pathway through manipulation of diet and/or the oral microbiome might compensate for a reduced ability to generate NO endogenously with older age. Objectives:1) Identify the bacterial species responsible for the reduction of inorganic nitrate to nitrite in the human oral cavity.2) Compare the oral microbiomes and nitrate reduction ability of young and older adults.3) Establish the in vivo effects of dietary nitrate supplementation and antibacterial mouthwash on the oral microbiome, NO bioavailability/bioactivity and indices of cardiovascular health (blood pressure, arterial stiffness, flow-mediated dilation).4) Assess the effects of nitrate, antibacterial mouthwash and the sweetening agent, xylitol, on the quantities and relative abundances of oral bacteria in an in vitro biofilm model.Potential Applications and Benefits: The results of this work, which will be undertaken in collaboration with industrial sponsor DuPont Nutrition & Health, may ultimately lead to the development of prebiotic and/or probiotic interventions that help to maintain NO homeostasis and cardiovascular health across the human lifespan.