Dietary polyphenols against metabolic disorders: How far have we progressed in the understanding of the molecular mechanisms of action of these compounds?

The aim of this review was to critically assess the evidence supporting the metabolic and anti-inflammatory effects attributed to polyphenols and the potential mechanisms of action underlying these effects. The metabolic and anti-inflammatory properties of polyphenols and polyphenol-rich products have been shown mostly in rodents. These compounds appear to share multiple mechanisms of action at different body sites (gastrointestinal tract, microbiota, host organs) and the responsible molecules may be the original plant compounds, the microbial metabolites and (or) the host derived conjugates. Polyphenols may modify digestion and absorption of nutrients, microbiota composition and metabolism, and host tissue metabolic pathways but none of these mechanisms have been fully demonstrated in vivo and thus, more and better designed studies are needed. Furthermore, human clinical trials show inconsistent evidence of the metabolic and inflammation regulatory properties of polyphenols. Some of the principal limitations of these studies as well as recommendations to further progress in the understanding of the metabolic effects and mechanisms of action of polyphenols are discussed.     

Proanthocyanidin metabolites associated with dietary fibre from in vitro colonic fermentation and proanthocyanidin metabolites in human plasma

Proanthocyanidins (PAs) or condensed tannins, a major group of dietary polyphenols, are oligomers and polymers of flavan‐3‐ol and flavan‐3, 4‐diols widely distributed in plant foods. Most literature data on PAs' metabolic fate deal with PAs that can be extracted from the food matrix by aqueous‐organic solvents ( extractable proanthocyanidins). However, there are no data on colonic fermentation of non‐extractable proanthocyanidins (NEPAs), which arrive almost intact to the colon, mostly associated to dietary fibre (DF). The aim of the present work was to examine colonic fermentation of NEPAs associated with DF, using a model of in vitro small intestine digestion and colonic fermentation. Two NEPA‐rich materials obtained from carob pod (Ceratonia siliqua L. proanthocyanidin) and red grapes (grape antioxidant dietary fibre) were used as test samples. The colonic fermentation of these two products released hydroxyphenylacetic acid, hydroxyphenylvaleric acid and two isomers of hydroxyphenylpropionic acid, detected by HPLC‐ESI‐MS/MS. Differences between the two products indicate that DF may enhance the yield of metabolites. In addition, the main NEPA metabolite in human plasma was 3,4‐dihydroxyphenyl acetic acid. The presence in human plasma of the same metabolites as were detected after in vitro colonic fermentation of NEPAs suggests that dietary NEPAs would undergo colonic fermentation releasing absorbable metabolites with potential healthy effects.     

Impact of dietary polyphenols on human platelet function – A critical review of controlled dietary intervention studies

Cardiovascular disease is a chronic disease influenced by many factors, with activated blood platelets being one of them. Platelets play a central role in the formation of plaques within blood vessels, contributing to early inflammatory events. Consumption of diets rich in plant‐based products protects against the development of cardiovascular disease. Polyphenols, which are secondary plant metabolites found in a wide range of foodstuffs and beverages, may be partially responsible for these effects. Their protective properties include inhibitory effects on platelet function in vitro and in vivo. However, the bioavailability of many polyphenols is poor and it is unclear whether sufficient quantities can be obtained by dietary means to exert protective effects. Consequently, this review summarizes 25 well‐controlled human intervention studies examining the effect of polyphenol‐rich diets on platelet function. These studies report a huge variety of research methods, study designs, and study subjects, resulting in controversial assertions. One consistent finding is that cocoa‐related products, however, have platelet‐inhibiting effects when consumed in moderate amounts. To assess whether other classes of dietary polyphenols, or their metabolites, also beneficially affect platelet function requires more well‐controlled intervention studies as well as the adoption of more uniform methods to assess platelet aggregation and activation.     

Updated knowledge about polyphenols: functions, bioavailability, metabolism, and health

Polyphenols are important constituents of food products of plant origin. Fruits, vegetables, and beverages are the main sources of phenolic compounds in the human diet. These compounds are directly related to sensory characteristics of foods such as flavor, astringency and color. Polyphenols are extensively metabolized both in tissues and by the colonic microbiota. Normally, the circulating polyphenols are glucuronidated and/or sulphated and no free aglycones are found in plasma. The presence of phenolic compounds in the diet is beneficial to health due to their antioxidant, anti-inflammatory, and vasodilating properties. The health effects of polyphenols depend on the amount consumed and their bioavailability. Moreover, polyphenols are able to kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans. Some dietary polyphenols may have significant effects on the colonic flora providing a type of prebiotic effect. The anti-nutrient properties of polyphenols are also discussed in this paper. The antioxidant, anti-inflammatory, vasodilating, and prebiotic properties of polyphenols make them potential functional foods.     

Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation

After consumption of plant‐derived foods or beverages, dietary polyphenols such as quercetin are absorbed in the small intestine and metabolized by the body, or they are subject to catabolism by the gut microbiota followed by absorption of the resulting products by the colon. The resulting compounds are bioavailable, circulate in the blood as conjugates with glucuronide, methyl, or sulfate groups attached, and they are eventually excreted in the urine. In this review, the various conjugates from different intervention studies are summarized and discussed. In addition, the substantial variation between different individuals in the measured quercetin bioavailability parameters is assessed in detail by examining published human intervention studies where sources of quercetin have been consumed in the form of food, beverages, or supplements. It is apparent that most reported studies have examined quercetin and/or metabolites in urine and plasma from a relatively small number of volunteers. Despite this limitation, it is evident that there is less interindividual variation in metabolites which are derived from absorption in the small intestine compared to catabolites derived from the action of microbiota in the colon. There is also some evidence that a high absorber of intact quercetin conjugates could be a low absorber of microbiota‐catalyzed phenolics, and vice versa. From the studies reported so far, the reasons or causes of the interindividual differences are not clear, but, based on the known metabolic pathways, it is predicted that dietary history, genetic polymorphisms, and variations in gut microbiota metabolism would play significant roles. In conclusion, quercetin bioavailability is subject to substantial variation between individuals, and further work is required to establish if this contributes to interindividual differences in biological responses.     

Chemopreventive effects of tea in prostate cancer: green tea versus black tea

The polyphenol compositions of green tea (GT) and black tea (BT) are very different due to post-harvest processing. GT contains higher concentrations of monomeric polyphenols, which affect numerous intracellular signaling pathways involved in prostate cancer (CaP) development. BT polymers, on the other hand, are poorly absorbed and are converted to phenolic acids by the colonic microflora. Therefore, after consumption of GT, higher concentrations of polyphenols are found in the circulation, whereas after BT consumption the phenolic acid levels in the circulation are higher. The majority of in vitro cell culture, in vivo animal, and clinical intervention studies examine the effects of extracts of GT or purified (-)-epigallocatechin-3-gallate (EGCG) on prostate carcinogenesis. These studies provide strong evidence supporting a chemopreventive effect of GT, but results from epidemiological studies of GT consumption are mixed. While the evidence for a chemopreventive effect of BT is much weaker than the body of evidence with regard to GT, there are several animal BT intervention studies demonstrating inhibition of CaP growth. This article will review in detail the available epidemiological and human clinical studies, as well as animal and basic mechanistic studies on GT and BT supporting a chemopreventive role in CaP.     

The unresolved role of dietary fibers on mineral absorption

Dietary fiber is a complex nutritional concept whose definition and method of analysis has evolved over time. However, literature on the role of dietary fiber on mineral bioavailability has not followed pace. Although in vitro studies revealed mineral binding properties, both animal and human studies failed to show negative effects on mineral absorption, and even in some cases reported absorption enhancing properties. The existing literature suggests that dietary fibers have negative effects on mineral absorption in the gastrointestinal tract largely due to mineral binding or physical entrapment. However, colonic fermentation of dietary fibers may offset this negative effect by liberating bound minerals and promoting colonic absorption. However, existing studies are limited since they did not control for more potent mineral absorption inhibitors such as phytates and polyphenols. Animal studies have mostly been on rats and hence difficult to extrapolate to humans. Human studies have been mostly on healthy young men, who likely to have an adequate store of iron. The use of different types and amounts of fibers (isolated/added) with varying physiological and physicochemical properties makes it difficult to compare results. Future studies can make use of the opportunities offered by enzyme technologies to decipher the role of dietary fibers in mineral bioavailability.     

Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites

Flavan-3-ols, occurring in monomeric, as well as in oligomeric and polymeric forms (also known as condensed tannins or proanthocyanidins), are among the most abundant and bioactive dietary polyphenols, but their in vivo health effects in humans may be limited because of their recognition as xenobiotics. Bioavailability of flavan-3-ols is largely influenced by their degree of polymerization; while monomers are readily absorbed in the small intestine, oligomers and polymers need to be biotransformed by the colonic microbiota before absorption. Therefore, phenolic metabolites, rather than the original high molecular weight compounds found in foods, may be responsible for the health effects derived from flavan-3-ol consumption. Flavan-3-ol phenolic metabolites differ in structure, amount and excretion site. Phase II or tissular metabolites derived from the small intestine and hepatic metabolism are presented as conjugated derivatives (glucuronic acid or sulfate esters, methyl ether, or their combined forms) of monomeric flavan-3-ols and are preferentially eliminated in the bile, whereas microbial metabolites are rather simple conjugated lactones and phenolic acids that are largely excreted in urine. Although the colon is seen as an important organ for the metabolism of flavan-3-ols, the microbial catabolic pathways of these compounds are still under consideration, partly due to the lack of identification of bacteria with such capacity. Studies performed with synthesized or isolated phase II conjugated metabolites have revealed that they could have an effect beyond their antioxidant properties, by interacting with signalling pathways implicated in important processes involved in the development of diseases, among other bioactivities. However, the biological properties of microbe-derived metabolites in their actual conjugated forms remain largely unknown. Currently, there is an increasing interest in their effects on intestinal infections, inflammatory intestinal diseases and overall gut health. The present review will give an insight into the metabolism and microbial biotransformation of flavan-3-ols, including tentative catabolic pathways and aspects related to the identification of bacteria with the ability to catabolize these kinds of polyphenols. Also, the in vitro bioactivities of phase II and microbial phenolic metabolites will be covered in detail.     

Dietary Polyphenols and Human Gut Microbiota: a Review

Dietary polyphenols are substrates for colonic microbiota. They and their metabolites contribute to the maintenance of gastrointestinal health by interacting with epithelial cells, and largely by modulating the gut microbial composition. Polyphenols may act as promoting factors of growth, proliferation, or survival for beneficial gut bacteria—mainly Lactobacillus strains—and thus, exerting prebiotic actions and inhibiting the proliferation of some pathogenic bacteria such as Salmonella and Helicobacter pylori species. To date the interactions affecting metabolic pathways and numerous metabolites of dietary polyphenols have been widely documented. However, the effects of dietary polyphenols on the modulation of the intestinal ecology and on the growth of gut microbial species are still poorly understood. This paper summarizes data on the influence of dietary polyphenols on gut microbiota and the main interactions between dietary polyphenols and beneficial and pathogenic intestinal bacteria.     

Interactions of tea polyphenols with intestinal microbiota and their implication for anti-obesity

Tea polyphenols (TP) are the main components in tea. Studies in vitro have shown they have significant biological activity; however, the results are inconsistent with experiments in vivo. For the low bioavailability, most TP are thought to remain in the gut and metabolized by intestinal bacteria. In the gut, the unabsorbed TP are metabolized to a variety of derivative products by intestinal flora, which may accumulate to exert beneficial effects. Numerous studies have shown that TP can inhibit obesity and its related metabolism disorders effectively. Meanwhile, it has demonstrated that TP and their derivatives may modulate intestinal micro-ecology. The understanding of the interaction between TP and intestinal microbiota will allow us to better evaluate the contribution of microbial metabolites of TP to anti-obesity activity. This review showed implications for the use of TP as functional food with potential therapeutic utility against obesity by modulating intestinal microbiota, contributing to the improvement of human health. © 2019 Society of Chemical Industry     

The Role of Dietary Phenolic Compounds in Protein Digestion and Processing Technologies to Improve Their Antinutritive Properties

Digestion is the key step for delivering nutrients and bioactive substances to the body. The way different food components interact with each other and with digestive enzymes can modify the digestion process and affect human health. Understanding how food components interact during digestion is essential for the rational design of functional food products. Plant polyphenols have gained much attention for the bioactive roles they play in the human body. However, their strong beneficial effects on human health have also been associated with a negative impact on the digestion process. Due to the generally low absorption of phenolic compounds after food intake, most of the consumed polyphenols remain in the gastrointestinal tract, where they then can exert inhibitory effects on enzymes involved in the degradation of saccharides, lipids, and proteins. While the inhibitory effects of phenolics on the digestion of energy‐rich food components (saccharides and lipids) may be regarded as beneficial, primarily in weight‐control diets, their inhibitory effects on the digestion of proteins are not desirable for the reason of reduced utilization of amino acids. The effect of polyphenols on protein digestion is reviewed in this article, with an emphasis on food processing methods to improve the antinutritive properties of polyphenols.     

Antioxidant properties of major metabolites of quercetin

Dietary flavonoids have been related to health promotion, which has been attributed in part to their antioxidant properties as demonstrated in many in vitro studies. However, in the human organism most flavonoids are little bioavailable and largely transformed to different metabolites that are crucial to explain the health effects associated with their dietary intake, although little is known about their biological activities. Quercetin is a majority flavonoid in the human diet that has been commonly used in studies on the flavonoid and health relationships. In this study, the antioxidant activity of different conjugated metabolites of quercetin (quercetin 3′-O-sulphate, quercetin 4′-O-sulphate, quercetin 3-O-glucuronide and isorhamnetin 3-O-sulphate) prepared in the laboratory, and of some phenolic acids that may result from its colonic degradation, was investigated by two in vitro assays (ABTS and FRAP assays). As expected, substitution of the hydroxyl groups of quercetin by the conjugating substituents resulted in a decrease in the antioxidant activity with regard to the parent compound. Despite this, the conjugated metabolites still retained significant antioxidant activity and behave as significantly better radical scavengers and reducing compounds than usually recognized antioxidants like α-tocopherol. Greater antioxidant activity of the metabolites was found in the ABTS assay, conducted at pH 7.4, suggesting that quercetin derivatives could act as potential radical scavengers in physiological conditions. Similarly, antioxidant activity significantly higher than α-tocopherol was also found in the ABTS assay for 3,4-dihydroxyphenylacetic, 3-methoxy-4-hydroxyphenylacetic and 3-(3,4-dihydroxyphenyl)propionic acids, described as products of the colonic degradation of quercetin. Phenylacetic acids were more active than benzoic and phenylpropionic acids, and the activity increased with the number of phenolic hydroxyls in the molecule; methoxylated derivatives showed, in general, lower activity than the equivalent O-dihydroxylated forms but greater than that of the monohydroxylated precursor. The results obtained are expected to contribute to the understanding of the mechanisms involved in the biological effects associated with the intake of flavonoid-rich diets.     

Metabolic pathways of the colonic metabolism of flavonoids (flavonols,flavones and flavanones) and phenolic acids

Flavonoids are metabolized by the gut microflora giving rise to a wide range of phenolic acids that may exert systemic effects in the body. Nevertheless, the colonic metabolism pathways and the function of the metabolites formed are poorly studied. In the present study, the individual colonic metabolism of three subclasses of flavonoids (flavonols, flavones and flavanones) and phenolic acids was evaluated. For this, seven standards of flavonoids (quercetin, quercetin–rhamnoside, quercetin–rutinoside, myricetin, luteolin, naringenin and kaempferol–rutinoside) and two phenolic acids (protocatechuic acid and gallic acid) were submitted to an in vitro fermentation model using rat colonic microflora. Simultaneously, a nuts–cocoa cream enriched with these standards of flavonoids was incubated and the colonic metabolism of these compounds was evaluated. The results showed that the greatest number of colonic metabolites came from the fermentation of quercetin and quercetin–rhamnoside, and the maximum concentration of fermentation products was observed after 48 h of fermentation. On the other hand, a smaller number of fermentation products were observed after the colonic fermentation of kaempferol–rutinoside, naringenin, luteolin and myricetin. The phenolic acids were slightly metabolized by the colonic microflora.     

Polyphenols in chocolate: is there a contribution to human health?

Recently, polyphenols have gained much more attention, owing to their antioxidant capacity (free radical scavenging and metal chelating) and their possible beneficial implications in human health, such as in the treatment and prevention of cancer, cardiovascular disease, and other pathologies. Cocoa is rich in polyphenols particularly in catechins (flavan-3-ols) and procyanidins. Polyphenol contents of cocoa products such as dark chocolate, milk chocolate and cocoa powder have been published only recently. However, the data vary remarkably due to the quantity of cocoa liquor used in the recipe of the cocoa products but also due to the analytical procedure employed. For example, results obtained by a colourimetric method were 5–7 times higher for the same type of product than results obtained by high performance liquid chromatography (HPLC). In 1994, the per head consumption of chocolate and chocolate confectionery in the European Union ranged from 1.3 kg/year in Portugal to 8.8 kg/year in Germany. In general, consumers in the Northern countries consume on average more than people in the South. Thus, chocolate can be seen as a relevant source for phenolic antioxidants for some European population. However, this alone does not imply, that chocolate could be beneficial to human health. Some epidemiological evidence suggests a beneficial effect to human health by following a polyphenol-rich diet, namely rich in fruits and vegetables and to a less obvious extent an intake of tea and wine having a similar polyphenol composition as cocoa. In many experiments cellular targets have been identified and molecular mechanisms of disease prevention proposed, in particular for the prevention of cancer and cardiovascular diseases as well as for alleviating the response to inflammation reactions. However, it has to be demonstrated, whether polyphenols exert these effects in vivo. One pre-requisite is that the polyphenols are absorbed from the diet. For monomeric flavonoids such as the catechins, there is increasing evidence for their absorption. For complex phenols and tannins (procyanidins) these questions have to be addressed for the future. Some indication for the absorption of procyanidins derive from studies with the human colon cancer cell line Caco-2, believed to be a valuable model for passive intestinal absorption as proposed for polyphenols. However, it has to be clarified which concentration is effective and what concentrations can be expected from food intake. Another open question is related to polyphenol metabolism. For example, much effort has been invested to show antioxidative effects of free unbound polyphenols, especially of catechins and the flavonol quercetin. However, only a very small part can be found in plasma in the free form but conjugated or even metabolised to several phenolic acids and other ring scission products. From the papers reviewed, it is as yet to early to give an answer to the question, whether chocolate and/or other sources rich in catechins and procyanidins are beneficial to human health. Even though some data are promising and justify further research in the field, it has to be shown in future, whether the intake of these functional compounds and/or their sources is related to measurable effects on human health and/or the development of diseases.     

Application of a new Dynamic Gastrointestinal Simulator (SIMGI) to study the impact of red wine in colonic metabolism

Polyphenols present in wine may favorably influence human health by means of modifying the metabolic activity and/or composition of gut microbiota. The aim of this study was to evaluate the impact of red wine on colonic metabolism using a novel Dynamic Gastrointestinal Simulator (namely SIMGI), inoculated with human feces of healthy volunteers (n = 2). Main wine phenolic compounds and their metabolites, ammonium and short-chain fatty acids (SCFAs) as well as main microbial groups were monitored in samples from the three colon compartments – ascending, transverse and descending – after feeding the system with red wine (225 mL). Significant increases were found for gallic acid, protocatechuic acid, 3-O-methylgallic acid, 4-hydroxybenzoic acid, 3,4-dihydroxyphenylpropionic acid, vanillic acid, syringic acid and salicylic acid after wine feeding. Concurrently, a decrease in ammonium ion and an increase in the proportion of butanoic acid were observed. In turn, the microbiota metabolic activity was found different between the two individuals and among the three compartments, with the main changes occurring in the ascending colon. These results highlight that red wine modulates the metabolic activity of colonic microbiota in vitro, which could be physiologically relevant, and contribute to our understanding on the complex metabolic fate of dietary polyphenols and polyphenols–microbiota interactions.     

植物多酚干预肥胖发生作用机制的研究进展

肥胖及其并发症严重危害公众身体健康,且肥胖发病率逐年上升,给社会和个人带来巨大的经济和心理负担。因此,肥胖的预防及治疗在学术界已成为亟待解决的重要问题。植物多酚是植物体内种类最多的一类次生代谢产物,广泛存在于水果、蔬菜、中草药以及植物源食品中,且多酚被报道具有抗氧化、抗炎、抗菌、抗病毒和抗癌等多种生物活性。此外,大量研究表明植物多酚具有良好的预防或治疗肥胖及其并发症的效果。本文从调节机体脂质代谢,影响脂肪细胞的增殖、分化与凋亡,刺激机体产热、加速能量消耗,抗炎和促进益生菌增长以调节肠道菌群等方面系统介绍了植物多酚的减肥降脂作用及其相关机理的研究进展,以期为植物多酚的开发与推广应用提供有益参考。     

多酚类化合物基于非编码RNA调控发挥抗肿瘤及辐射增敏作用研究进展

恶性肿瘤严重危害人类生命健康，放疗是目前治疗恶性肿瘤常用的方法之一。然而电离辐射会引起肿瘤细胞的辐射抗性并损伤正常组织细胞，限制了其在临床上的应用。多酚类天然产物不仅可以提高肿瘤细胞的辐射敏感性，同时又能缓解辐射对机体产生的负面效应，在肿瘤治疗中发挥着重要作用。非编码RNA在许多疾病的发生发展中起着重要作用，近年来研究发现多酚类物质在抗肿瘤及辐射增敏方面与非编码RNA的调控存在一定关联。基于此，本文综述天然产物多酚抗肿瘤和辐射增敏的作用及其机制，并基于非编码RNA调控层面阐释其作用效果，以期为肿瘤等疾病的干预治疗及相关特医膳食食品的开发提供新思路。     

Chokeberries (Aronia melanocarpa) and Their Products as a Possible Means for the Prevention and Treatment of Noncommunicable Diseases and Unfavorable Health Effects Due to Exposure to Xenobiotics

Aronia melanocarpa berries (chokeberries) constitute a very rich source of numerous substances exerting a beneficial impact on health, including mainly polyphenols (proanthocyanidins, anthocyanins, flavonoids, and phenolic acids), possessing antioxidative, anti‐inflammatory, antiviral, anticancer, antiatherosclerotic, hypotensive, antiplatelet, and antidiabetic properties. Thus, the consumption of products made from chokeberries is of vital importance for health maintenance and protection. Nowadays, due to the growing prevalence of noncommunicable diseases and ubiquitous human exposure to numerous man‐made and naturally occurring toxic substances, some of which are dangerous even at low amounts, it is very important to look for effective means of health protection. An important role in this regard may be played by A. melanocarpa berries; however, up to now the attention of scientists, nutritionists, and health practitioners has been focused mainly on the effectiveness of chokeberry products in the prevention and treatment of noncommunicable diseases, while only little attention has been paid to the possibility of their use to counteract the adverse health effects of exposure to xenobiotics. That is why in this review article the main interest has been focused on the possibility of using chokeberries in the protection against unfavorable health effects caused by the action of substances to which humans may be exposed environmentally and/or occupationally. The available experimental data indicate that not only the fruit but also the leaves of A. melanocarpa and their products may be effective means for prevention and treatment of the effects of toxic action of some xenobiotics in humans; however, further studies on this subject are necessary.     

膳食多酚对肠道菌群影响研究进展

人体肠道是一个复杂但稳定的微生态系统,其中肠道菌群对肠道及人体健康起着重要作用。健康的肠道中各菌间保持着微妙的平衡,但诸如膳食、年龄、药物、环境或生活习惯等多种因素均会打破肠道菌群平衡,而肠道菌群失衡是人体多种疾病发生发展的重要诱因。多酚是一类重要的植物次生代谢产物,具有多种生物学活性,如抗氧化、抗病毒、抗肿瘤、抗癌、抗菌、抗炎、预防心脑血管疾病等。大量研究报道证实,通过膳食补充多酚类物质对人类健康具有多种益处,特别是摄入膳食多酚对肠道健康和肠道菌群平衡有着显著的积极影响。本文归纳了近年来膳食多酚对肠道菌群影响相关研究进展,为科学、充分地利用多酚预防和治疗肠道疾病、保护肠道健康提供理论依据与参考。