Protection from environmental enteric dysfunction and growth improvement in malnourished newborns by amplification of secretory IgA.

Environmental enteric dysfunction (EED) is a condition associated with malnutrition that can progress to malabsorption and villous atrophy. Severe EED results in linear growth stunting, slowed neurocognitive development, and unresponsiveness to oral vaccines. Prenatal exposure to malnutrition and breast feeding by malnourished mothers replicates EED. Pups are characterized by deprivation of secretory IgA (SIgA) and altered development of the gut immune system and microbiota. Extracellular ATP (eATP) released by microbiota limits T follicular helper (Tfh) cell activity and SIgA generation in Peyer's patches (PPs). Administration of a live biotherapeutic releasing the ATP-degrading enzyme apyrase to malnourished pups restores SIgA levels and ameliorates stunted growth. SIgA is instrumental in improving the growth and intestinal immune competence of mice while they are continuously fed a malnourished diet. The analysis of microbiota composition suggests that amplification of endogenous SIgA may exert a dominant function in correcting malnourishment dysbiosis and its consequences on host organisms, irrespective of the actual microbial ecology

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

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

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

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

Apyrase-mediated amplification of secretory IgA promotes intestinal homeostasis.

Secretory immunoglobulin A (SIgA) interaction with commensal bacteria conditions microbiota composition and function. However, mechanisms regulating reciprocal control of microbiota and SIgA are not defined. Bacteria-derived adenosine triphosphate (ATP) limits T follicular helper (Tfh) cells in the Peyer's patches (PPs) via P2X7 receptor (P2X7R) and thereby SIgA generation. Here we show that hydrolysis of extracellular ATP (eATP) by apyrase results in amplification of the SIgA repertoire. The enhanced breadth of SIgA in mice colonized with apyrase-releasing Escherichia coli influences topographical distribution of bacteria and expression of genes involved in metabolic versus immune functions in the intestinal epithelium. SIgA-mediated conditioning of bacteria and enterocyte function is reflected by differences in nutrient absorption in mice colonized with apyrase-expressing bacteria. Apyrase-induced SIgA improves intestinal homeostasis and attenuates barrier impairment and susceptibility to infection by enteric pathogens in antibiotic-induced dysbiosis. Therefore, amplification of SIgA by apyrase can be leveraged to restore intestinal fitness in dysbiotic conditions

Effect of a polyphenol-rich dietary pattern on intestinal permeability and gut and blood microbiomics in older subjects: study protocol of the MaPLE randomised controlled trial

: During aging, alterations of the intestinal microbial ecosystem can occur contributing to immunosenescence, inflamm-aging and impairment of intestinal barrier function (increased intestinal permeability; IP). In the context of a diet-microbiota-IP axis in older subjects, food bioactives such as polyphenols may play a beneficial modulatory role

Estimated Intakes of Nutrients and Polyphenols in Participants Completing the MaPLE Randomised Controlled Trial and Its Relevance for the Future Development of Dietary Guidelines for the Older Subjects

Abstract: The evaluation of food intake in older subjects is crucial in order to be able to verify adherence to nutritional recommendations. In this context, estimation of the intake of specific dietary bioactives, such as polyphenols, although particularly challenging, is necessary to plan possible intervention strategies to increase their intake. The aims of the present study were to: (i) evaluate the nutritional composition of dietary menus provided in a residential care setting; (ii) estimate the actual intake of nutrients and polyphenols in a group of older subjects participating in the MaPLE study; and (iii) investigate the impact of an eight-week polyphenol-rich dietary pattern, compared to an eight-week control diet, on overall nutrient and polyphenol intake in older participants. The menus served to the participants provided ~770 mg per day of total polyphenols on average with small variations between seasons. The analysis of real consumption, measured using weighed food diaries, demonstrated a lower nutrient (~20%) and polyphenol intake (~15%) compared to that provided by the menus. The feasibility of dietary patterns that enable an increase in polyphenol intake with putative health benefits for age-related conditions is discussed, with a perspective to developing dietary guidelines for this target population. Keywords: nursing home; residential care; aging; menu; flavonoids; phenolic acid