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The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

Background/Objectives: Interindividual variability in polyphenol metabolism may help explain the inconsistent effects of polyphenol intake on health outcomes. This study compared, for the first time, (i) polyphenol-related gut microbiota metabotypes (urolithins: UM0, UMA, UMB; equol: EP, ENP; lunularin: LP, LNP) and their clusters (MCs) in non-medicated premenopausal (Pre-M) and postmenopausal (Post-M) women and (ii) the impact of an 8-week intake of a polyphenol-rich plant extract mixture (PPs) on the quality of life (QoL) of Post-M. Methods: Polyphenol metabotypes were determined in urine via UPLC-QTOF-MS after a 3-day intake of PPs containing resveratrol, pomegranate (ellagitannins and ellagic acid), and red clover (isoflavones) in Pre-M (n = 120) and Post-M (n = 90) women. QoL was assessed with the short-form Cervantes Scale in a randomized, placebo-controlled crossover trial (8-week PPs vs. placebo), completed by 78 Post-M participants. Results: At baseline, Pre-M and Post-M women showed only minor differences in metabotype and MC distributions linked to menopausal status. MC3 (UMA+EP+LP) predominated in Pre-M, while MC7 (UMA+EP+LNP) was most frequent in Post-M. PPs intake in Post-M women led to modest shifts in metabotype and MC distributions toward Pre-M patterns. Quantitative metabolite production was comparable between groups, except for equol, which showed a median 2.8-fold increase after PPs intake in EP Post-M women. Clinically meaningful improvements (score reduction ≥ 6.7 points) in QoL were observed in the Psychic domain in EP women (28%, p = 0.039) and in the Menopause and Health domain, specifically in EP (24.1%, p = 0.004), MC3 (22.5%, p = 0.043), and MC4 (UMB+EP+LP; 41.3%, p = 0.022), were mainly driven by a reduction in hot flashes (p = 0.001). Conclusions: These findings support metabotyping as a tool to guide targeted dietary strategies and enhance QoL through precision health in Post-M women.

Background Aronia melanocarpa is a berry rich in polyphenols known for health benefits. However, the bioavailability of polyphenols has been questioned, and the individual taste acceptance of the fruit with its specific flavor varies. We recently observed substantial differences in the tolerability of aronia juice among healthy females, with half of the individuals tolerating aronia juice without complaints. Given the importance of the gut microbiome in food digestion, we investigated in this secondary analysis of the randomized placebo-controlled parallel intervention study (ClinicalTrials.gov registration: NCT05432362) if aronia juice tolerability was associated with changes in intestinal microbiota and bacterial metabolites, seeking for potential mechanistic insights into the impact on aronia polyphenol tolerance and metabolic outcomes. Results Forty females were enrolled for this 6-week trial, receiving either 100 ml natural aronia juice (verum, V) twice daily or a polyphenol-free placebo (P) with a similar nutritional profile, followed by a 6-week washout. Within V, individuals were categorized into those who tolerated the juice well (Vt) or reported complaints (Vc). The gut microbiome diversity, as analyzed by 16S rRNA gene-based next-generation sequencing, remained unaltered in Vc but changed significantly in Vt. A MICOM-based flux balance analysis revealed pronounced differences in the 40 most predictive metabolites post-intervention. In Vc carbon-dioxide, ammonium and nine O-glycans were predicted due to a shift in microbial composition, while in Vt six bile acids were the most likely microbiota-derived metabolites. NMR metabolomics of plasma confirmed increased lipoprotein subclasses (LDL, VLDL) post-intervention, reverting after wash out. Stool samples maintained a stable metabolic profile. Conclusion In linking aronia polyphenol tolerance to gut microbiota-derived metabolites, our study explores adaptive processes affecting lipoprotein profiles during high polyphenol ingestion in Vt and examines effects on mucosal gut health in response to intolerance to high polyphenol intake in Vc. Our results underpin the importance of individualized hormetic dosing for beneficial polyphenol effects, demonstrate dynamic gut microbiome responses to aronia juice, and emphasize personalized responses in polyphenol interventions. Graphical Abstract DsmAL-oYwbuhyB_vVwEdDj Video Abstract

Background (Poly)phenols are molecules with various structural complexities that are mostly present in fruits, vegetables, and some cereals, and are widely consumed daily. Following ingestion, the phenolic compounds that are not absorbed in the upper gastrointestinal tract—the majority—are metabolized in the colon to form low-molecular-weight phenolic catabolites (LMWP), which potentially make a substantial contribution to the biological activity of (poly)phenol-containing foods. However, the production of LMWP can also occur through the metabolism of the aromatic amino acids phenylalanine and tyrosine as well as via catecholamine pathways. Methods A randomized, controlled, crossover trial in which healthy adults ( n  = 30) follow a very-low-(poly)phenol diet and restrict physical activity for 5 days is proposed. On the morning of the third day, subjects will consume either coffee (known source of (poly)phenols) or hot water (control). Discussion The main objective is the characterization of LMWP in biological samples through metabolomic techniques, attempting to distinguish the possible origin of these metabolites based on the different production of LMWP in the context of a controlled diet with or without a known source of (poly)phenols (primary outcome). Factors leading to interindividual variability and playing a role in phenolic metabolism, such as gut microbiota composition and genetic polymorphisms (secondary outcomes), will also be considered. Emerging evidence suggests that endogenous metabolism also contributes to circulating LMWP, which could lead to an overestimation of their attribution to dietary (poly)phenols. By implementing a long washout and using coffee as the test source, this study aims to capture background phenolic production and better disentangle dietary from endogenous contributions. These insights will support a more accurate understanding of the role of LMWP in nutrition and health. Trial registration This study was approved by the Territorial Ethics Committee (CET) of Area Vasta Emilia Nord (AVEN) (340/2023/SPER/UNIPR). Clinical Trials registration: NCT06028659. Registered on 23 August 2023.

BACKGROUND: Our main objective was to evaluate the ability of cranberry phytochemicals to modify immunity, specifically γδ-T cell proliferation, after daily consumption of a cranberry beverage, and its effect on health outcomes related to cold and influenza symptoms. METHODS: The study was a randomized, double-blind, placebo-controlled, parallel intervention. Subjects drank a low calorie cranberry beverage (450 ml) made with a juice-derived, powdered cranberry fraction (n = 22) or a placebo beverage (n = 23), daily, for 10 wk. PBMC were cultured for six days with autologous serum and PHA-L stimulation. Cold and influenza symptoms were self-reported. RESULTS: The proliferation index of γδ-T cells in culture was almost five times higher after 10 wk of cranberry beverage consumption (p <0.001). In the cranberry beverage group, the incidence of illness was not reduced, however significantly fewer symptoms of illness were reported (p = 0.031). CONCLUSIONS: Consumption of the cranberry beverage modified the ex vivo proliferation of γδ-T cells. As these cells are located in the epithelium and serve as a first line of defense, improving their function may be related to reducing the number of symptoms associated with a cold and flu. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01398150 .

Phenolic compounds or polyphenols are among the most common compounds of secondary metabolism in plants. Their biosynthesis is characteristic of all plant cells and is carried out with the participation of the shikimate and acetate-malonate pathways. In this case, polyphenols of various structures are formed, such as phenylpropanoids, flavonoids, and various oligomeric and polymeric compounds of phenolic nature. Their number already exceeds 10,000. The diversity of phenolics affects their biological activity and functional role. Most of their representatives are characterized by interaction with reactive oxygen species, which manifests itself not only in plants but also in the human body, where they enter through food chains. Having a high biological activity, phenolic compounds are successfully used as medicines and nutritional supplements for the health of the population. The accumulation and biosynthesis of polyphenols in plants depend on many factors, including physiological–biochemical, molecular–genetic, and environmental factors. In the review, we present the latest literature data on the structure of various classes of phenolic compounds, their antioxidant activity, and their biosynthesis, including their molecular genetic aspects (genes and transfactors). Since plants grow with significant environmental changes on the planet, their response to the action of abiotic factors (light, UV radiation, temperature, and heavy metals) at the level of accumulation and composition of these secondary metabolites, as well as their metabolic regulation, is considered. Information is given about plant polyphenols as important and necessary components of functional nutrition and pharmaceutically valuable substances for the health of the population. Proposals on promising areas of research and development in the field of plant polyphenols are presented.

Phenolic compounds are an important class of plant secondary metabolites which play crucial physiological roles throughout the plant life cycle. Phenolics are produced under optimal and suboptimal conditions in plants and play key roles in developmental processes like cell division, hormonal regulation, photosynthetic activity, nutrient mineralization, and reproduction. Plants exhibit increased synthesis of polyphenols such as phenolic acids and flavonoids under abiotic stress conditions, which help the plant to cope with environmental constraints. Phenylpropanoid biosynthetic pathway is activated under abiotic stress conditions (drought, heavy metal, salinity, high/low temperature, and ultraviolet radiations) resulting in accumulation of various phenolic compounds which, among other roles, have the potential to scavenge harmful reactive oxygen species. Deepening the research focuses on the phenolic responses to abiotic stress is of great interest for the scientific community. In the present article, we discuss the biochemical and molecular mechanisms related to the activation of phenylpropanoid metabolism and we describe phenolic-mediated stress tolerance in plants. An attempt has been made to provide updated and brand-new information about the response of phenolics under a challenging environment.

Polyphenols are categorized as plant secondary metabolites, and they have attracted much attention in relation to human health and the prevention of chronic diseases. In recent years, a considerable number of studies have been published concerning their physiological function in the digestive tract, such as their prebiotic properties and their modification of intestinal microbiota. It has also been suggested that several hydrolyzed and/or fission products, derived from the catabolism of polyphenols by intestinal bacteria, exert their physiological functions in target sites after transportation into the body. Thus, this review article focuses on the role of intestinal microbiota in the bioavailability and physiological function of dietary polyphenols. Monomeric polyphenols, such as flavonoids and oligomeric polyphenols, such as proanthocyanidins, are usually catabolized to chain fission products by intestinal bacteria in the colon. Gallic acid and ellagic acid derived from the hydrolysis of gallotannin, and ellagitannin are also subjected to intestinal catabolism. These catabolites may play a large role in the physiological functions of dietary polyphenols. They may also affect the microbiome, resulting in health promotion by the activation of short chain fatty acids (SCFA) excretion and intestinal immune function. The intestinal microbiota is a key factor in mediating the physiological functions of dietary polyphenols.

Tea is widely consumed all over the world. Generally, tea is divided into six categories: White, green, yellow, oolong, black, and dark teas, based on the fermentation degree. Tea contains abundant phytochemicals, such as polyphenols, pigments, polysaccharides, alkaloids, free amino acids, and saponins. However, the bioavailability of tea phytochemicals is relatively low. Thus, some novel technologies like nanotechnology have been developed to improve the bioavailability of tea bioactive components and consequently enhance the bioactivity. So far, many studies have demonstrated that tea shows various health functions, such as antioxidant, anti-inflammatory, immuno-regulatory, anticancer, cardiovascular-protective, anti-diabetic, anti-obesity, and hepato-protective effects. Moreover, it is also considered that drinking tea is safe to humans, since reports about the severe adverse effects of tea consumption are rare. In order to provide a better understanding of tea and its health potential, this review summarizes and discusses recent literature on the bioactive components, bioavailability, health functions, and safety issues of tea, with special attention paid to the related molecular mechanisms of tea health functions.

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays.