Abstract
The microbiota of the human lower intestinal tract helps maintain healthy host physiology, for example through nutrient acquisition and bile acid recycling, but specific positive contributions of the oral microbiota to host health are not well established. Nitric oxide (NO) homeostasis is crucial to mammalian physiology. The recently described entero-salivary nitrate-nitrite-nitric oxide pathway has been shown to provide bioactive NO from dietary nitrate sources. Interestingly, this pathway is dependent upon oral nitrate-reducing bacteria, since humans lack this enzyme activity. This pathway appears to represent a newly recognized symbiosis between oral nitrate-reducing bacteria and their human hosts in which the bacteria provide nitrite and nitric oxide from nitrate reduction. Here we measure the nitrate-reducing capacity of tongue-scraping samples from six healthy human volunteers, and analyze metagenomes of the bacterial communities to identify bacteria contributing to nitrate reduction. We identified 14 candidate species, seven of which were not previously believed to contribute to nitrate reduction. We cultivated isolates of four candidate species in single- and mixed-species biofilms, revealing that they have substantial nitrate- and nitrite-reduction capabilities. Colonization by specific oral bacteria may thus contribute to host NO homeostasis by providing nitrite and nitric oxide. Conversely, the lack of specific nitrate-reducing communities may disrupt the nitrate-nitrite-nitric oxide pathway and lead to a state of NO insufficiency. These findings may also provide mechanistic evidence for the oral systemic link. Our results provide a possible new therapeutic target and paradigm for NO restoration in humans by specific oral bacteria.
Highlights
The human gastrointestinal tract represents a major habitat for bacterial colonization
The majority of operational taxonomic units (OTUs) in the original samples belonged to Streptococcus (20.2%+/29.75%), Veillonella (14.1%+/24.15%), Prevotella (11.8%+/25.88%), Neisseria (10.8%+/29.62%), and Haemophilus (8.64%+/24.93%), there was notable variation observed among the samples (Table 1)
These data reveal that communities of bacteria change in culture and allow us to monitor these changes and correlate changes in communities with changes in nitrate reduction in order to identify which bacteria in complex communities are primarily responsible for nitrate reduction
Summary
The human gastrointestinal tract represents a major habitat for bacterial colonization. In various animal models and in humans, dietary nitrate supplementation has shown numerous beneficial effects, including a reduction in blood pressure, protection against ischemia-reperfusion damage, restoration of NO homeostasis with associated cardioprotection, increased vascular regeneration after chronic ischemia, and a reversal of vascular dysfunction in the elderly [22,23] Some of these benefits were reduced or completely prevented when the oral microbiota were abolished with an antiseptic mouthwash [22,24] it was recently shown that in the absence of any dietary modifications, a seven-day period of antiseptic mouthwash treatment to disrupt the oral microbiota reduced both oral and plasma nitrite levels in healthy human volunteers, and was associated with a sustained increase in both systolic and diastolic blood pressure [25]. These studies firmly establish the role for oral nitrate-reducing bacteria in making a physiologically relevant contribution to host nitrite and NO levels, with measureable physiological effects
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