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.
Abstract Nitrite, considered a biological waste and toxic product, is being regarded as an important physiological molecule in nitric oxide ( NO) biochemistry. Because the interaction of dietary ...phenolic compounds and nitrite would be kinetically (due to the high concentrations achieved) and thermodynamically (on basis of the redox potentials) feasible in the stomach, we have studied the potential reduction of nitrite by polyphenols present in several dietary sources. By measuring the time courses of NO production in simulated gastric juice (pH 2), the efficiency of the compounds studied is as follows: Epicatechin-3-O-gallate > quercetin > procyanidin B8 dimer > oleuropein > procyanidin B2 dimer > chlorogenic acid > epicatechin > catechin > procyanidin B5 dimer. The initial rates of NO production fall in a narrow range (ca. 1–5 μM s−1 ) but the distinct kinetics of the decay of NO signals suggest that competition reactions for NO are operative. The proof of concept that, in the presence of nitrite, phenol-containing dietary products induce a strong increase of NO in the stomach was established in an in vivo experiment with healthy volunteers consuming lettuce, onions, apples, wine, tea, berries and cherries. Moreover, selected mixtures of oleuropein and catechin with low nitrite (1 μM) were shown to induce muscle relaxation of stomach strips in a structure-dependent way. Data presented here brings strong support to the concept that polyphenols consumed in a variety of dietary products, under gastric conditions, reduce nitrite to NO that, in turn, may exert a biological impact as a local relaxant.
Inorganic nitrite, derived from the reduction of nitrate in saliva, has recently emerged as a protagonist in nitric oxide (•NO) biology as it can be univalently reduced to •NO, in the healthy human ...stomach. Important physiological implications have been attributed to nitrite-derived •NO in the gastrointestinal tract, namely modulation of host defense, blood flow, mucus formation and motility. At acidic pH, nitrite generates different nitrogen oxides depending on the local microenvironment (redox status, gastric content, pH, inflammatory conditions), including •NO, nitrogen dioxide (•NO₂), dinitrogen trioxide (N₂O₃), and peroxynitrite. Thus, the gastric environment is a significant source of nitrating and nitrosating agents, especially in individuals consuming a nitrate/nitrite-rich diet on a daily basis. Both, the gastric lumen and mucosa contain putative targets for nitration, not only proteins and lipids from ingested aliments but also endogenous proteins secreted by the oxyntic glands. The physiological and functional consequences of nitration of gastric mediators will impact on local processes including food digestion and ulcerogenesis. Additionally, gastric nitration products (such as nitrated lipids) may be absorbed and affect systemic pathways. Thus, dietary ingestion of nitrate will have direct consequences for endogenous protein nitration, as indicated by our preliminary data.
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.
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;
= 25) or control group (waitlist;
= 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.
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.
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.
: https://www.clinicaltrials.gov/ct2/show/NCT03840707, identifier NCT03840707.
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.
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.
Results from this RCT will support future studies testing the LIFEwithIBD intervention or other acceptance and/or compassion-based interventions for IBD.
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.
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.
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•Dietary nitrate may be envisaged as a nutrient for the intestinal microbiome.•Nitrate may mediate bacteria-host interactions by participating in local redox interactions along the NO3-NO2-NO pathway.•Nitrate may increase microbial biomass and act as a respiratory substrate for the existing communities.
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 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 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.
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