Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (•NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, •NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of •NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.

Inorganic nitrate prevents the loss of tight junction proteins and modulates inflammatory events induced by broad-spectrum antibiotics: A role for intestinal microbiota?

Upon consumption, dietary nitrate is reduced to nitrite in the oral cavity and to nitric oxide (•NO) in the stomach. Here, •NO increases mucosal blood flow, mucus thickness and prevents microbial infections. However, the impact of nitrate on gut microbiota, a pleiotropic organism essential to maintain gastrointestinal and systemic welfare, remains elusive. This study investigates the impact of nitrate on gut microbiota profile and ensued mucosal effects during dysbiosis. Male Wistar rats were randomly distributed in 4 groups and the drinking water was supplemented for 7 days as follows: 1) antibiotic cocktail (neomycin, bacitracin and imipenem), 2) antibiotic cocktail + sodium nitrate, 3) sodium nitrate and 4) regular drinking water. Animals were weighted daily and feces were collected before and after the treatment. The stomach was isolated and the expression of occludin, claudin-5 as well as myeloperoxidase and iNOS was studied. Bacterial DNA was analyzed in fecal samples by PCR-DGGE genetic fingerprinting. Nitrate prevented antibiotic-induced body weight loss (1.9 ± 1.8% vs 8.9 ±â€¯1.8%, p < 0.05) and cecamegalia (7.1 ±â€¯0.5% vs 5.6 ±â€¯0.4%, p < 0.05). Gastric expression of occludin and claudin-5 tended to decrease during dysbiosis but both protein levels were recovered following nitrate consumption (p < 0.05). Similarly, nitrate inhibited the overexpression of myeloperoxidase and iNOS observed under dysbiosis (p < 0.05). Broad spectrum antibiotics significantly decreased microbiota richness and diversity in comparison to controls (p = 0.0016). After 7 days of treatment, whereas antibiotics reduced microbiota richness by 56%, it was observed that nitrate was able to prevent such microbial loss to only 48%, although without statistical differences (p = 0.068). This data suggests that dietary nitrate may be envisaged as a key component of functional foods with beneficial impact on gastric mucosal integrity during antibiotherapy but further studies are mandatory to better ascertain as to whether it modulates intestinal microbiota in terms of taxonomic and functional levels.

Do oral and gut microbiota communicate through redox pathways? A novel asset of the nitrate-nitrite-NO pathway.

Nitrate may act as a regulator of •NO bioavailability via sequential reduction along the nitrate-nitrite-NO pathway with widespread health benefits, including a eubiotic effect on the oral and gut microbiota. Here, we discuss the molecular mechanisms of microbiota-host communication through redox pathways, via the production of •NO and oxidants by the family of NADPH oxidases, namely hydrogen peroxide (via Duox2), superoxide radical (via Nox1 and Nox2) and peroxynitrite, which leads to downstream activation of stress responses (Nrf2 and NFkB pathways) in the host mucosa. The activation of Nox2 by microbial metabolites is also discussed. Finally, we propose a new perspective in which both oral and gut microbiota communicate through redox pathways, with nitrate as the pivot linking both ecosystems.

Dietary (poly)phenols as modulators of the biophysical properties in endothelial cell membranes: its impact on nitric oxide bioavailability in hypertension.

Hypertension is a major contributor to premature death, owing to the associated increased risk of damage to the heart, brain and kidneys. Although hypertension is manageable by medication and lifestyle changes, the risk increases with age. In an increasingly aged society, the incidence of hypertension is escalating, and is expected to increase the prevalence of (cerebro)vascular events and their associated mortality. Adherence to plant-based diets improves blood pressure and vascular markers in individuals with hypertension. Food flavonoids have an inhibitory effect towards angiotensin-converting enzyme (ACE1) and although this effect is greatly diminished upon metabolization, their microbial metabolites have been found to improve endothelial nitric oxide synthase (eNOS) activity. Considering the transmembrane location of ACE1 and eNOS, the ability of (poly)phenols to interact with membrane lipids modulate the cell membrane's biophysical properties and impact on nitric oxide (· NO) synthesis and bioavailability, remain poorly studied. Herein, we provide an overview of the current knowledge on the lipid remodeling of endothelial membranes with age, its impact on the cell membrane's biophysical properties and · NO permeability across the endothelial barrier. We also discuss the potential of (poly)phenols and other plant-based compounds as key players in hypertension management, and address the caveats and challenges in adopted methodologies.

Randomized controlled trial of an Acceptance and Commitment Therapy and compassion-based group intervention for persons with inflammatory bowel disease: the LIFEwithIBD intervention.

Objectives: This study tested the acceptability and efficacy of an Acceptance and Commitment Therapy and compassion-based intervention (LIFEwithIBD) in people with IBD through a two-arm RCT. Methods: Participants were recruited at the Gastroenterology Department of the Coimbra University Hospital between June and September 2019. Of the 355 patients screened, those who accepted to participate were randomly assigned to one of two conditions: experimental group (LIFEwithIBD; n = 25) or control group (waitlist; n = 29). Participants completed self-report measures at baseline (T0), post-intervention (T1), and 3-month (T2) and 12-month (T3) follow-ups. Intervention acceptability was assessed. Efficacy was examined using intent-to-treat ANCOVA at post-intervention after adjusting for baseline values of depressive, anxiety, and stress symptoms (primary outcomes). Linear mixed models for all longitudinal outcomes were also analysed. Inflammatory and disease biomarkers were determined at T0 and T3. Results: Acceptability results revealed a high level of satisfaction and perceived usefulness regarding the intervention. Both groups experienced a significant decrease in stress symptoms and IBD symptom perception at T1. No significant differences were observed at follow-up for the primary outcomes. The experimental group reported significantly lower Crohn's disease Symptom severity at T2 than the control group. Post-hoc analyses designed to mitigate floor effects revealed substantial treatment effects for the experimental group regarding anxiety symptoms. No significant differences were observed in clinical biomarkers from T0 to T3. Conclusion: The LIFEwithIBD intervention shows promising, although preliminary, benefits for managing disease activity and reducing anxiety symptoms in IBD patients with high severity of psychological distress.Clinical trial registration: https://www.clinicaltrials.gov/ct2/show/NCT03840707, identifier NCT03840707.

Epigenetic Modifications Induced by the Gut Microbiota May Result from What We Eat: Should We Talk about Precision Diet in Health and Disease?

Diet is currently considered one of the most important adjustable determinants of human health. The gut microbiota, the collection of microorganisms that inhabit (mainly) the distal bowel, has recently been shown to ensure critical physiological functions, such as immune, metabolic and neuropsychiatric. Many of these biological effects result from the production of bacterial metabolites that may target host cells, tissues and organs. In line with this rationale, epigenetics has brought new insights to our understanding of how environmental factors influence gene expression and, interestingly, gut microbiota metabolites have recently been proposed as novel and significant inducers of epigenetic modifications. Efforts have been dedicated to unveil how the production of specific metabolites influences the activity of epigenetic writers and erasers in order to establish a mechanistic link between gut microbiota, epigenetic modifications and health. Recent data is now evidencing how specific microbial metabolites shape the epigenetic landscape of eukaryotic cells, paving new avenues for innovative therapeutic strategies relying on diet-driven microbiota: epigenetic interactions. Herein is discussed the impact of diet on gut microbiota and the molecular mechanisms underlying microbiota-host interactions, highlighting the influence of diet on microbiota metabolome and how this may induce epigenetic modifications in host cells. Furthermore, it is hypothesized that epigenetics may be a key process transducing the effects of diet on gut microbiota with consequences for health and disease. Accordingly, innovating strategies of disease prevention based on a "precision diet", a personalized dietary planning according to specific epigenetic targets, are discussed.

(Poly)phenols and nitrolipids: Relevant participants in nitric oxide metabolism.

Nitric oxide (•NO) is an essential molecule able to control and regulate many biological functions. Additionally, •NO bears a potential toxicity or damaging effects under conditions of uncontrolled production, and because of its participation in redox-sensitive pathways and oxidizing reactions. Several plant (poly)phenols present in the diet are able to regulate the enzymes producing •NO (NOSs). In addition, (poly)phenols are implicated in defining •NO bioavailability, especially by regulating NADPH oxidases (NOXs), and the subsequent generation of superoxide and •NO depletion. Nitrolipids are compounds that are present in animal tissues because of dietary consumption, e.g. of olive oil, and/or as result of endogenous production. This endogenous production of nitrolipids is dependent on the nitrate/nitrite presence in the diet. Select nitrolipids, e.g. the nitroalkenes, are able to exert •NO-like signaling actions, and act as •NO reservoirs, becoming relevant for systemic •NO bioavailability. Furthermore, the presence of (poly)phenols in the stomach reduces dietary nitrite to •NO favoring nitrolipids formation. In this review we focus on the capacity of molecules representing these two groups of bioactives, i.e. (poly)phenols and nitrolipids, as relevant participants in •NO metabolism and bioavailability. This participation acquires especial relevance when human homeostasis is lost, for example under inflammatory conditions, in which the protective actions of (poly)phenols and/or nitrolipids have been associated with local and systemic •NO bioavailability.

Corrigendum: The LIFEwithIBD Intervention: Study Protocol for a Randomized Controlled Trial of a Face-to-Face Acceptance and Commitment Therapy and Compassion-Based Intervention Tailored to People With Inflammatory Bowel Disease.

[This corrects the article DOI: 10.3389/fpsyt.2021.699367.].

Corrigendum: The LIFEwithIBD Intervention: Study Protocol for a Randomized Controlled Trial of a Face-to-Face Acceptance and Commitment Therapy and Compassion-Based Intervention Tailored to People With Inflammatory Bowel Disease.

[This corrects the article DOI: 10.3389/fpsyt.2021.699367.].

The Nitrate-Nitrite-Nitric Oxide Pathway on Healthy Ageing: A Review of Pre-clinical and Clinical Data on the Impact of Dietary Nitrate in the Elderly.

We are living longer. Are we living healthier? As we age, cellular and molecular damage reshape our physiological responses towards environmental and endogenous stimuli. The free radical theory of ageing has been proposed long before ageing has been considered a "scientific discipline" and, since then, has been discussed and upgraded as a major contributor to aberrant ageing. Assuming that ageing results merely from the accumulation of oxidative modifications of biomolecules is not only a simplistic and reductive view of such a complex and dynamic process, but also free radicals and related oxidants are now considered pivotal signalling molecules. The fine modulation of critical signalling pathways by redox compounds demands a novel approach to tackle the role of free radicals in ageing. Nitric oxide (⋅NO) is a paradigmatic example given its biological functions in cardiovascular, neurologic and immune systems. In addition to the canonical ⋅NO synthesis by a family of enzymes, nitrate from green leafy vegetables, is reduced to nitrite in the oral cavity which is further reduced to ⋅NO in the stomach. Boosting this nitrate-nitrite-NO pathway has been shown to improve gastrointestinal, cardiovascular, metabolic and cognitive performance both in humans and in animal models of disease. In the elderly, nitrate-derived ⋅NO has been shown improve several physiological functions that typically decline during ageing. In this paper, the role of nitrate and derived nitrogen oxides will be discussed while reviewing pre-clinical and clinical data on the cardiovascular, neuronal, musculoskeletal and metabolic effects of nitrate during healthy ageing.

The LIFEwithIBD Intervention: Study Protocol for a Randomized Controlled Trial of a Face-to-Face Acceptance and Commitment Therapy and Compassion-Based Intervention Tailored to People With Inflammatory Bowel Disease.

Background: There is ample evidence of the high mental health burden caused by Inflammatory Bowel Disease (IBD). Several constructs such as experiential avoidance, cognitive fusion, shame, and self-criticism have recently emerged as potential intervention targets to improve mental health in IBD. Psychotherapeutic models such as Acceptance and Commitment Therapy and compassion-based interventions are known to target these constructs. In this protocol, we aim to describe a two-arm Randomized Controlled Trial (RCT) testing the efficacy of an ACT and compassion-focused intervention named Living with Intention, Fullness, and Engagement with Inflammatory Bowel Disease (LIFEwithIBD) intervention + Treatment As Usual (TAU) vs. TAU in improving psychological distress, quality of life, work and social functioning, IBD symptom perception, illness-related shame, psychological flexibility, self-compassion, disease activity, inflammation biomarkers, and gut microbiota diversity. Methods: This trial is registered at ClinicalTrials.gov (Identifier: NCT03840707, date assigned 13/02/2019). The LIFEwithIBD intervention is an adaptation to the IBD population of the Mind programme for people with cancer, an acceptance, mindfulness, and compassion-based intervention designed to be delivered in a group format. The LIFEwithIBD intervention's structure and topics are presented in this protocol. Participants were recruited at the Gastroenterology Service of the Coimbra University Hospital between June and September 2019. Of the 355 patients screened, 61 participants were selected, randomly assigned to one of two conditions [experimental group (LIFEwithIBD + TAU) or control group (TAU)] and completed the baseline assessment. Outcome measurement took place at baseline, post-intervention, 3- and 12-month follow-ups. Discussion: Results from this RCT will support future studies testing the LIFEwithIBD intervention or other acceptance and/or compassion-based interventions for IBD.

Diffusion of nitric oxide through the gastric wall upon reduction of nitrite by red wine: physiological impact.

In this work we showed that nitric oxide produced via red wine- and ascorbate-dependent reduction of nitrite diffuses through the rat stomach, inducing smooth muscle relaxation. The studies encompassed ex vivo and in vivo models of diffusion. Regarding the former, luminal *NO generated from a mixture of physiologic nitrite and ascorbate or wine diffuses across the stomach wall, being 8-20% of that produced in the mucosal side detected at high microM range (>100 microM) in the serosal side. In order to evaluate whether cellular dysfunction was associated with *NO diffusion at the microM range, the gastric tissue exposed to *NO was evaluated in terms of carbachol-induced muscle contraction in fundal strips and mitochondrial respiration and showed to remain functional and metabolically active. Moreover, pre-contracted gastric strips were shown to relax 86.5+/-5.5% (control) and 75.0+/-4.0% (nitrite/ascorbate-exposed tissue) when challenged with acidified nitrite. The studies in the living animal support the diffusion of luminal *NO to the gastric vasculature as, following addition of nitrite/ascorbate to rat stomach in vivo, *NO was not detected in the serosal environment but concentrations as high as 31 microM of *NO were detected outside the stomach after cardiac arrest. Collectively, the results establish a link between the consumption of nitrite and dietary reductants (e.g., wine polyphenols) and stomach muscle relaxation via the local chemical generation of *NO.

Nitrate from diet might fuel gut microbiota metabolism: Minding the gap between redox signaling and inter-kingdom communication.

The gut microbiota has been recently interpreted in terms of a metabolic organ that influences the host through reciprocal interactions, encompassing metabolic and immune pathways, genetic and epigenetic programming in host mammal tissues in a diet-depended manner, that shape virtually all aspects of host physiology. In this scenario, dietary nitrate, a major component of leafy green vegetables known for their health benefits, might fuel microbiota metabolism with ensued consequences for microbiota-host interaction. Cumulating evidence support that nitrate shapes oral microbiome communities with impact on the kinetics and systemic levels of both nitrate and nitrite. However, the impact of nitrate, which is steadily delivered into the lower gastrointestinal tract after a vegetable-rich meal, in the intestinal microbiome communities and their functional capacity remains largely elusive. Several mechanisms reinforce the notion that nitrate may be a nutrient for the lower microbiome and might participate in local redox interactions with relevance for bacteria-host interactions, among these nitric oxide-dependent mechanisms along the nitrate-nitrite-nitric oxide pathway. Also, by allowing bacteria to thrive, either by increasing microbial biomass or by acting as a respiratory substrate for the existing communities, nitrate ensures the production of bacterial metabolites (e.g., pathogen-associated molecular patterns, PAMP, short chain fatty acids, among other) that are recognised by host receptors (such as toll-like, TLR, and formyl peptide receptors, FPR) thereby activating local signalling pathways. Here, we elaborate on the notion that via modulation of intestinal microbiota metabolism, dietary nitrate impacts on host-microbiota metabolic and redox interactions, thereby contributing as an essential nutrient to optimal health.

The potent vasodilator ethyl nitrite is formed upon reaction of nitrite and ethanol under gastric conditions.

By acting as a bioreactor, affording chemical and mechanical conditions for the reaction between dietary components, the stomach may be a source of new bioactive molecules. Using gas chromatography-mass spectrometry we here demonstrate that, under acidic gastric conditions, ethyl nitrite is formed in microM concentrations from the reaction of red wine or distilled alcoholic drinks with physiological amounts of nitrite. Rat femoral artery rings and gastric fundus strips dose-dependently relaxed upon exposure to nitrite:ethanol mixtures. In contrast, when administered separately in the same dose ranges, nitrite evoked only minor vasorelaxation while ethanol actually caused a slight vasoconstriction. Mechanistically, the relaxation effect was assigned to generation of nitric oxide (*NO) as supported by direct demonstration of *NO release from ethyl nitrite and the absence of relaxation in the presence of the soluble guanylyl cyclase inhibitor, ODQ. In conclusion, these results suggest that ethanol in alcoholic drinks interacts with salivary-derived nitrite in the acidic stomach leading to the production of the potent smooth muscle relaxant ethyl nitrite. These findings reveal an alternative chemical reaction pathway for dietary nitrate and nitrite with possible impact on gastric physiology and pathophysiology.

Tuning constitutive and pathological inflammation in the gut via the interaction of dietary nitrate and polyphenols with host microbiome.

Chronic inflammation is currently recognized as a critical process in modern-era epidemics such as diabetes, obesity and neurodegeneration. However, little attention is paid to the constitutive inflammatory pathways that operate in the gut and that are mandatory for local welfare and the prevention of such multi-organic diseases. Hence, the digestive system, while posing as a barrier between the external environment and the host, is crucial for the balance between constitutive and pathological inflammatory events. Gut microbiome, a recently discovered organ, is now known to govern the interaction between exogenous agents and the host with ensued impact on local and systemic homeostasis. Whereas gut microbiota may be modulated by a myriad of factors, diet constitutes one of its major determinants. Thus, dietary compounds that influence microbial flora may thereby impact on inflammatory pathways. One such example is the redox environment in the gut lumen which is highly dependent on the local generation of nitric oxide along the nitrate-nitrite-nitric oxide pathway and that is further enhanced by simultaneous consumption of polyphenols. In this paper, different pathways encompassing the interaction of dietary nitrate and polyphenols with gut microbiota will be presented and discussed in connection with local and systemic inflammatory events. Furthermore, it will be discussed how these interactive cycles (nitrate-polyphenols-microbiome) may pose as novel strategies to tackle inflammatory diseases.

Role of nitrite, urate and pepsin in the gastroprotective effects of saliva.

Dietary nitrate is now recognized as an alternative substrate for nitric oxide (•NO) production in the gut. This novel pathway implies the sequential reduction of nitrate to nitrite, •NO and other bioactive nitrogen oxides but the physiological relevance of these oxidants has remained elusive. We have previously shown that dietary nitrite fuels an hitherto unrecognized nitrating pathway at acidic gastric pH, through which pepsinogen is nitrated in the gastric mucosa, yielding a less active form of pepsin in vitro. Here, we demonstrate that pepsin is nitrated in vivo and explore the functional impact of protein nitration by means of peptic ulcer development. Upon administration of pentagastrin and human nitrite-rich saliva or sodium nitrite to rats, nitrated pepsin was detected in the animal's stomach by immunoprecipitation. •NO was measured in the gastric headspace before and after nitrite instillation by chemiluminescence. At the end of each procedure, the stomach's lesions, ranging from gastric erosions to haemorrhagic ulcers, were scored. Nitrite increased gastric •NO by 200-fold (p<0.05) and nitrated pepsin was detected both in the gastric juice and the mucosa (p<0.05). Exogenous urate, a scavenger of nitrogen dioxide radical, blunted •NO detection and inhibited pepsin nitration, suggesting an underlining free radical-dependent mechanism for nitration. Functionally, pepsin nitration prevented the development of gastric ulcers, as the lesions were only apparent when pepsin nitration was inhibited by urate. In sum, this work unravels a novel dietary-dependent nitrating pathway in which pepsin is nitrated and inactivated in the stomach, preventing the progression of gastric ulcers.

Dietary nitrite induces occludin nitration in the stomach.

The clinical implications of the nitrate-nitrite-nitric oxide pathway have been extensively studied in recent years. However, the physiological impact of bioactive nitrogen oxides produced from dietary nitrate has remained largely elusive. Here, we report a hitherto unrecognized nitrite-dependent nitrating pathway that targets tight junction proteins in the stomach. Inorganic nitrate, nitrite or saliva obtained after the consumption of lettuce were administered by oral gavage to Wistar rats. The enterosalivary circulation of nitrate was allowed to occur for 4 h after which the animals were euthanized and the stomach collected. Nitrated occludin was detected by immunoprecipitation in the gastric epithelium upon inorganic nitrite administration (p < .05) but was not observed in the case of inorganic nitrate or human saliva administration. This observation, along with differences in •NO production rates from inorganic and salivary nitrite under simulated gastric conditions, suggests that competing reactions at acidic pH determine the production of nitrating agents (•NO2) or other, more stable, oxides. Accordingly, it is shown in vitro that salivary nitrite yields higher steady state concentrations of •NO (0.37 ± 0.01 µM) than sodium nitrite (0.12 ± 0.03 µM). Dietary-dependent reactions involving the production of nitrogen oxides should be further investigated as, in the context of occludin nitration, the consumption of green leafy vegetables (with high nitrate content), if able to modulate gut barrier function, may have important implications in the context of leaky gut disorders.

Ethyl nitrite is produced in the human stomach from dietary nitrate and ethanol, releasing nitric oxide at physiological pH: potential impact on gastric motility.

BACKGROUND: Nitric oxide ((∙)NO), a ubiquitous molecule involved in a plethora of signaling pathways, is produced from dietary nitrate in the gut through the so-called nitrate-nitrite-NO pathway. In the stomach, nitrite derived from dietary nitrate triggers a network of chemical reactions targeting endogenous and exogenous biomolecules, thereby producing new compounds with physiological activity. OBJECTIVE: The aim of this study was to ascertain whether compounds with physiological relevance are produced in the stomach upon consumption of nitrate- and ethanol-rich foods. DESIGN: Human volunteers consumed a serving of lettuce (source of nitrate) and alcoholic beverages (source of ethanol). After 15 min, samples of the gastric headspace were collected and ethyl nitrite was identified by GC-MS. Wistar rats were used to study the impact of ethyl nitrite on gastric smooth muscle relaxation at physiological pH. RESULT: Nitrogen oxides, produced from nitrite in the stomach, induce nitrosation of ethanol from alcoholic beverages in the human stomach yielding ethyl nitrite. Ethyl nitrite, a potent vasodilator, is produced in vivo upon the consumption of lettuce with either red wine or whisky. Moreover, at physiological pH, ethyl nitrite induces gastric smooth muscle relaxation through a cGMP-dependent pathway. Overall, these results suggest that ethyl nitrite is produced in the gastric lumen and releases (∙)NO at physiological pH, which ultimately may have an impact on gastric motility. Systemic effects may also be expected if ethyl nitrite diffuses through the gastric mucosa reaching blood vessels, therefore operating as a (∙)NO carrier throughout the body. CONCLUSION: These data pinpoint posttranslational modifications as an underappreciated mechanism for the production of novel molecules with physiological impact locally in the gut and highlight the notion that diet may fuel compounds with the potential to modulate gastrointestinal welfare.

A shortcut to wide-ranging biological actions of dietary polyphenols: modulation of the nitrate-nitrite-nitric oxide pathway in the gut.

Dietary polyphenols are complex, natural compounds with recognized health benefits. Initially attractive to the biomedical area due to their in vitro antioxidant properties, the biological implications of polyphenols are now known to be far from their acute ability to scavenge free radicals but rather to modulate redox signaling pathways. Actually, it is now recognized that dietary polyphenols are extensively metabolized in vivo and that the chemical, biophysical and biological properties of their metabolites are, in most cases, quite different from the ones of the parent molecules. Hence, the study of the metabolic, absorptive and signaling pathways of both phenolics and derivatives has become a major issue. In this paper we propose a short-cut for the systemic effects of polyphenols in connection with nitric oxide (˙NO) biology. This free radical is a ubiquitous signaling molecule with pivotal functions in vivo. It is produced through an enzymatic pathway and also through the reduction of dietary nitrate and nitrite in the human stomach. At acidic gastric pH, dietary polyphenols, in the form they are conveyed in foods and at high concentration, not only promote nitrite reduction to ˙NO but also embark in a complex network of chemical reactions to produce higher nitrogen oxides with signaling functions, namely by inducing post-translational modifications. Modified endogenous molecules, such as nitrated proteins and lipids, acquire important physiological functions. Thus, local and systemic effects of ˙NO such as modulation of vascular tone, mucus production in the gut and protection against ischemia-reperfusion injury are, in this sense, triggered by dietary polyphenols. Evidence to support the signaling and biological effects of polyphenols by modulation of the nitrate-nitrite-NO pathway will be herein provided and discussed. General actions of polyphenols encompassing absorption and metabolism in the intestine/liver are short-cut via the production of diffusible species in the stomach that have not only a local but also a general impact.

The redox interplay between nitrite and nitric oxide: From the gut to the brain.

The reversible redox conversion of nitrite and nitric oxide ((•)NO) in a physiological setting is now widely accepted. Nitrite has long been identified as a stable intermediate of (•)NO oxidation but several lines of evidence support the reduction of nitrite to nitric oxide in vivo. In the gut, this notion implies that nitrate from dietary sources fuels the longstanding production of nitrite in the oral cavity followed by univalent reduction to (•)NO in the stomach. Once formed, (•)NO boosts a network of reactions, including the production of higher nitrogen oxides that may have a physiological impact via the post-translational modification of proteins and lipids. Dietary compounds, such as polyphenols, and different prandial states (secreting specific gastric mediators) modulate the outcome of these reactions. The gut has unusual characteristics that modulate nitrite and (•)NO redox interplay: (1) wide range of pH (neutral vs acidic) and oxygen tension (c.a. 70 Torr in the stomach and nearly anoxic in the colon), (2) variable lumen content and (3) highly developed enteric nervous system (sensitive to (•)NO and dietary compounds, such as glutamate). The redox interplay of nitrite and (•)NO might also participate in the regulation of brain homeostasis upon neuronal glutamatergic stimulation in a process facilitated by ascorbate and a localized and transient decrease of oxygen tension. In a way reminiscent of that occurring in the stomach, a nitrite/(•)NO/ascorbate redox interplay in the brain at glutamatergic synapses, contributing to local (•)NO increase, may impact on (•)NO-mediated process. We here discuss the implications of the redox conversion of nitrite to (•)NO in the gut, how nitrite-derived (•)NO may signal from the digestive to the central nervous system, influencing brain function, as well as a putative ascorbate-driven nitrite/NO pathway occurring in the brain.