Exploring the Molecular Pathways Behind the Effects of Nutrients and Dietary Polyphenols on Gut Microbiota and Intestinal Permeability: A Perspective on the Potential of Metabolomics and Future Clinical Applications.

The gut microbiota is involved in the regulation of the intestinal permeability (IP), whose disruption is a frequent condition in older people and is associated with the development of several diseases. The diet can affect the gut microbiota and IP, although the molecular mechanisms involved are unclear. Metabolomics is one of the suitable approaches to study the effects of diet on gut microbiota and IP, although, up to now, the research has focused only on a few dietary components. The aim here was to review the most recent literature concerning the application of metabolomics to the study of the diet-induced alterations of gut microbiota and the effects on IP, with a particular focus on the molecular pathways involved. An additional aim was to give a perspective on the future research involving dietary polyphenols, because despite their potential use in the management of increased IP, few studies have been reported to date

Role of a Polyphenol-Rich Dietary Pattern in the Modulation of Intestinal Permeability in Older Subjects: The MaPLE Study

The inevitable rise of the proportion of people aged >65 years worldwide is paralleled by an increased burden of chronic diseases often associated with low-grade systemic inflammation. Recent findings suggest a link between inflammation and intestinal permeability (IP), a condition characterized by an impairment of intestinal barrier function which enables the translocation of dietary and bacterial factors into the blood activating the host immune system [1,2]. Dietary components can be significant modulators of inflammation and IP, and can also affect the intestinal microbial ecosystem. In the context of a diet-microbiota-IP axis in older subjects, dietary bioactives such as polyphenols may play a significant protective role due to their widely reported antioxidant and immunomodulatory properties and potential to regulate IP [3-6]

Bacterial DNAemia is associated with serum zonulin levels in older subjects

The increased presence of bacteria in blood is a plausible contributing factor in the development and progression of aging-associated diseases. In this context, we performed the quantification and the taxonomic profiling of the bacterial DNA in blood samples collected from forty-three older subjects enrolled in a nursing home. Quantitative PCR targeting the 16S rRNA gene revealed that all samples contained detectable amounts of bacterial DNA with a concentration that varied considerably between subjects. Correlation analyses revealed that the bacterial DNAemia (expressed as concentration of 16S rRNA gene copies in blood) significantly associated with the serum levels of zonulin, a marker of intestinal permeability. This result was confirmed by the analysis of a second set of blood samples collected from the same subjects. 16S rRNA gene profiling revealed that most of the bacterial DNA detected in blood was ascribable to the phylum Proteobacteria with a predominance of the genus Pseudomonas. Several control samples were also analyzed to assess the influence of contaminant bacterial DNA potentially originating from reagents and materials. The data reported here suggest that para-cellular permeability of epithelial (and, potentially, endothelial) cell layers may play an important role in bacterial migration into the bloodstream. Bacterial DNAemia is likely to impact on several aspects of host physiology and could underpin the development and prognosis of various diseases in older subjects

A Polyphenol-Rich Diet Increases the Gut Microbiota Metabolite Indole 3-Propionic Acid in Older Adults with Preserved Kidney Function

Scope: Dietary polyphenols can alter the gut microbiota (GM) and promote the production of bioactive metabolites. Several indoles result of GM metabolism of dietary tryptophan have been associated with intestinal barrier integrity. Our aim is to study the changes in GM-derived indoles during a polyphenol-rich (PR) diet intervention in older adults. Methods and results: Randomized, controlled, crossover trial in adults ≥ 60 years living in a residential care facility during an 8-week PR versus control diet (n = 51). Seven GM-tryptophan metabolites are measured in serum, and metataxonomic analysis of GM is performed on fecal samples. Exploratory subgroup analyses are performed based on renal function (RF). The PR-diet significantly increases serum indole 3-propionic acid (IPA) in subjects with normal RF, but not in subjects with impaired RF. Other GM-tryptophan metabolites are not affected. Comparison of baseline GM composition shows shifts in Bacteroidales order members as well as higher abundance of Clostridiales in participants with normal RF. During the trial, variations of IPA are associated with changes in C-reactive protein (β = 0.32, p = 0.010) and GM, particularly with the Clostridiales (r = 0.35, p < 0.001) and Enterobacteriales (r = -0.15, p < 0.05) orders. Conclusion: A PR diet increases the serum concentration of IPA in older adults with normal RF. Our findings may be important when defining appropriate dietary interventions for older adults

Intestinal permeability modulation through a polyphenol-rich dietary pattern in older subjects: MaPLE project outcomes and perspectives

In recent years, research has been focusing on strategies to counteract inflammatory processes and age-related diseases(1). During ageing, a low-grade systemic inflammation is often associated to an altered intestinal permeability (IP) a condition that has been shown to promote inflammation possibly through the translocation of dietary and bacterial factors into the blood stream that activates the immune system(2).In this regard, dietary pattern and environmental factors could play a fundamental role because of their potential ability to modulate inflammation, IP and the gut microbial ecosystem (GME). Moreover, it has been hypothesized that bioactive compounds such as polyphenols may affect IP and GME(3).The MaPLE project (Microbiome mAnipulation through Polyphenols for managing gut Leakiness in the Elderly) aimed to investigate the hypothesis that a polyphenol-rich diet can improve IP condition in a target population with beneficial changes at intestine and systemic level. To this aim, a randomised, controlled, crossover dietary intervention study (8-week polyphenol-rich diet versus 8-week control diet, separated by a wash-out period) was carried out in a group of older subjects (> 60 years) living in a well-controlled setting (i.e. nursing home). Markers related with IP, inflammation, oxidative stress, vascular function and intestinal microbial ecosystem were investigated in serum, urine and/or fecal samples. Moreover, blood bacteria DNAemia, and serum/urine metabolomics has been assessed. Moreover, a consistent nutritional evaluation of the standard menu (provided by the nursing home) and of weighed food diaries was performed, providing also data on actual polyphenol intake during the intervention. The results show there were higher levels of IP in the older subjects, and that the polyphenol-enriched diet changed the levels of serum zonulin, a marker of IP. In addition, an association between zonulin and blood bacterial load was demonstrated. Ongoing in vitro and in vivo experiments are exploring the potential effects of different polyphenols on IP and the mechanisms involved. The MaPLE project will generate new data to improve the understanding on the role of polyphenols in the modulation of intestinal microbiome and its interactions with the host

Increased Intestinal Permeability in Older Subjects Impacts the Beneficial Effects of Dietary Polyphenols by Modulating Their Bioavailability

Polyphenols have great potential in regulating intestinal health and ameliorating pathological conditions related to increased intestinal permeability (IP). However, the efficacy of dietary interventions with these phytochemicals may significantly be influenced by interindividual variability factors affecting their bioavailability and consequent biological activity. In the present study, urine samples collected from older subjects undergoing a crossover intervention trial with polyphenol-rich foods were subjected to metabolomics analysis for investigating the impact of increased IP on the bioavailability of polyphenols. Interestingly, urinary levels of phase II and microbiota-derived metabolites were significantly different between subjects with healthier intestinal barrier integrity and those with increased IP disruption. Our results support that this IP-dependent impaired bioavailability of polyphenols could be attributed to disturbances in the gut microbial metabolism and phase II methylation processes. Furthermore, we also observed that microbiota-derived metabolites could be largely responsible for the biological activity elicited by dietary polyphenols against age-related disrupted IP

Association between Food Intake, Clinical and Metabolic Markers and DNA Damage in Older Subjects

Abstract The use of DNA damage as marker of oxidative stress, metabolic dysfunction and age-related diseases is debated. The present study aimed at assessing the level of DNA damage (evaluated as DNA strand-breaks, endogenous and oxidatively-induced DNA damage) in a group of older subjects with intestinal permeability enrolled within the MaPLE (Gut and Blood Microbiomics for Studying the Effect of a Polyphenol-Rich Dietary Pattern on Intestinal Permeability in the Elderly) intervention trial, to evaluate its association with clinical, metabolic and dietary markers. DNA damage in peripheral blood mononuclear cells was assessed by the comet assay in 49 older subjects participating in the study. Clinical and metabolic markers, markers of inflammation, vascular function and intestinal permeability were determined in serum. Food intake was estimated by weighted food diaries. On the whole, a trend towards higher levels of DNA damage was observed in men compared to women (p = 0.071). A positive association between DNA damage and clinical/metabolic markers (e.g., uric acid, lipid profile) and an inverse association with dietary markers (e.g., vitamin C, E, B6, folates) were found and differed based on sex. By considering the importance of DNA stability during aging, the results obtained on sex differences and the potential role of dietary and metabolic factors on DNA damage underline the need for further investigations in a larger group of older adults to confirm the associations found and to promote preventive strategies

22Ne and 23Na ejecta from intermediate-mass stars: The impact of the new LUNA rate for 22Ne(p,gamma)23Na

We investigate the impact of the new LUNA rate for the nuclear reaction $^{22}$Ne$(p,\gamma)^{23}$Na on the chemical ejecta of intermediate-mass stars, with particular focus on the thermally-pulsing asymptotic giant branch (TP-AGB) stars that experience hot-bottom burning. To this aim we use the PARSEC and COLIBRI codes to compute the complete evolution, from the pre-main sequence up to the termination of the TP-AGB phase, of a set of stellar models with initial masses in the range $3.0\,M_{\odot} - 6.0\,M_{\odot}$, and metallicities $Z_{\rm i}=0.0005$, $Z_{\rm i}=0.006$, and $Z_{\rm i} = 0.014$. We find that the new LUNA measures have much reduced the nuclear uncertainties of the $^{22}$Ne and $^{23}$Na AGB ejecta, which drop from factors of $\simeq 10$ to only a factor of few for the lowest metallicity models. Relying on the most recent estimations for the destruction rate of $^{23}$Na, the uncertainties that still affect the $^{22}$Ne and $^{23}$Na AGB ejecta are mainly dominated by evolutionary aspects (efficiency of mass-loss, third dredge-up, convection). Finally, we discuss how the LUNA results impact on the hypothesis that invokes massive AGB stars as the main agents of the observed O-Na anti-correlation in Galactic globular clusters. We derive quantitative indications on the efficiencies of key physical processes (mass loss, third dredge-up, sodium destruction) in order to simultaneously reproduce both the Na-rich, O-poor extreme of the anti-correlation, and the observational constraints on the CNO abundance. Results for the corresponding chemical ejecta are made publicly available

Polyphenols and Intestinal Permeability: Rationale and Future Perspectives

Increasing evidence links intestinal permeability (IP), a feature of the intestinal barrier, to several pathological or dysfunctional conditions. Several host and environmental factors, including dietary factors, can affect the maintenance of normal IP. In this regard, food bioactives, such as polyphenols, have been proposed as potential IP modulators, even if the mechanisms involved are not yet fully elucidated. The aim of the present paper is to provide a short overview of the main evidence from in vitro and in vivo studies supporting the role of polyphenols in modulating IP and briefly discuss future perspectives in this research area

Systematic Review on Polyphenol Intake and Health Outcomes: Is there Sufficient Evidence to Define a Health-Promoting Polyphenol-Rich Dietary Pattern?

Growing evidence support association between polyphenol intake and reduced risk for chronic diseases, even if there is a broad debate about the effective amount of polyphenols able to exert such protective effect. The present systematic review provides an overview of the last 10-year literature on the evaluation of polyphenol intake and its association with specific disease markers and/or endpoints. An estimation of the mean total polyphenol intake has been performed despite the large heterogeneity of data reviewed. In addition, the contribution of dietary sources was considered, suggesting tea, coffee, red wine, fruit and vegetables as the main products providing polyphenols. Total flavonoids and specific subclasses, but not total polyphenols, have been apparently associated with a low risk of diabetes, cardiovascular events and all-cause mortality. However, large variability in terms of methods for the evaluation and quantification of polyphenol intake, markers and endpoints considered, makes it still difficult to establish an evidence-based reference intake for the whole class and subclass of compounds. Nevertheless, the critical mass of data available seem to strongly suggest the protective effect of a polyphenol-rich dietary pattern even if further well targeted and methodologically sound research should be encouraged in order to define specific recommendation