Insights into the Neuroprotective Potential of Epicatechin: Effects against Aß-Induced Toxicity in Caenorhabditis elegans.

Medical therapies to avoid the progression of Alzheimer's disease (AD) are limited to date. Certain diets have been associated with a lower incidence of neurodegenerative diseases. In particular, the regular intake of foods rich in polyphenols, such as epicatechin (EC), could help prevent or mitigate AD progression. This work aims to explore the neuroprotective effects of EC using different transgenic strains of Caenorhabditis elegans, which express human Aß1-42 peptides and contribute to elucidating the mechanisms involved in the effects of EC in AD. The performed assays indicate that this flavan-3-ol was able to reduce the signs of ß-amyloid accumulation in C. elegans, improving motility and chemotaxis and increasing survival in transgenic strain peptide producers compared to nematodes not treated with EC. The neuroprotective effects exhibited by EC in C. elegans could be explained by the modulation of inflammation and stress-associated genes, as well as autophagy, microgliosis, and heat shock signaling pathways, involving the regulation of cpr-5, epg-8, ced-7, ZC239.12, and hsp-16 genes. Overall, the results obtained in this study support the protective effects of epicatechin against Aß-induced toxicity.

Effects of a Raisin Supplement on Cognitive Performance, Quality of Life, and Functional Activities in Healthy Older Adults-Randomized Clinical Trial.

The objective of this study was to evaluate the effects of consuming 50 g of raisins on cognitive performance, quality of life, and functional activities in healthy older adults. This is a parallel randomized controlled clinical trial, in which 80 subjects over 70 years of age participated. For 6 months, the intervention group (IG; n = 40) consumed 50 g of raisins per day added to their usual diet, whereas the control group (CG; n = 40) received no supplement. All variables were measured at baseline and at 6 months. Cognitive performance assessed with the Montreal Cognitive Assessment (MOCA) test shows a difference of 3.27 points (95% CI 1.59 to 4.96), p ≤ 0.001, favorable to the IG, after the intervention. Among the cognitive performances, an improvement is observed in the IG in orientation, assessed both with the MOCA test 0.49 (95% CI 0.10 to 0.87), p = 0.014, and with the Mini-Mental State Examination (MMSE) test, 0.36 (95% CI 0.02 to 0.70), p = 0.038. In visuospatial/executive capacity and in language, improvements were also observed in the IG, 1.36 (95% CI 0.77 to 1.95), p = 0.001, and 0.54 points (95% CI 0.12 to 0.96), p = 0.014, respectively. Immediate and delayed recall, assessed with the Rey Auditory Verbal Learning Test, improved in the IG. In addition, the IG showed a better quality of life and greater autonomy in instrumental activities of daily living after 6 months. No significant changes were observed in the rest of the variables analyzed. Therefore, the consumption of 50 g of raisins produces a slight improvement in cognitive performance, quality of life, and functional activities in the elderly.

Effect of including a dietary supplement of raisins, a food rich in polyphenols, on cognitive function in healthy older adults; a study protocol for a randomized clinical trial.

BACKGROUND: Polyphenols have been shown to be effective against many chronic diseases, including neurodegenerative diseases. Specifically, the consumption of raisins, being a food rich in polyphenols, has been attributed with neuroprotective benefits. Therefore, our main objective is to evaluate the effect of including 50 g of raisins in the diet daily for 6 months, on the improvement of cognitive performance, cardiovascular risk factors and markers of inflammation in a population of older adults without cognitive impairment. METHODS: Design and intervention: This study will be a randomized controlled clinical trial of two parallel groups. Each subject included in the study will be randomly assigned to one of two study groups: control group (no supplement), intervention group (50 g of raisins daily during 6 months). STUDY POPULATION: The participants will be selected by consecutive sampling in the Primary Care consultations of urban health centers in Salamanca and Zamora (Spain), taking into account the selection criteria. STUDY VARIABLES: Two visits will be made, baseline and at 6 months. Cognitive performance will be evaluated (Mini-Mental State Examination test, Rey Auditory Verbal Learning Test, verbal fluency and montreal cognitive assessment (Moca)). It will also be analyzed the level of physical activity, quality of life, activities of daily living, energy and nutritional composition of the diet, body composition, blood pressure, heart rate, markers of inflammation and other laboratory tests of clinical relevance (glycaemia, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides). In addition, sociodemographic data, personal and family history, medication use and alcohol and tobacco consumption will be collected. DISCUSSION: In this project, it is intended to contribute to minimize the problems derived from cognitive deterioration in older people. TRIAL REGISTRATION: ClincalTrials.gov Identifier: NCT04966455 Registration date: July 1, 2021.

The effects of polyphenols against oxidative stress in Caenorhabditis elegans are determined by coexisting bacteria.

Introduction: Increasing evidence supports the role of gut microbiota in many aspects of human health, including immune, metabolic and neurobehavioral traits. Several studies have focused on how different components of the diet, such as polyphenols, can modulate the composition and function of the gut microbiota leading to health benefits. Methods: The effects on the resistance against thermally induced oxidative stress of C. elegans grown in the presence of flavonoids (quercetin or epicatechin) and fed different probiotic strains, namely Lactobacillus plantarum CLC17, Bifidobacterium longum NCIMB 8809 and Enterococcus faecium CECT 410, were explored. Results: Feeding C. elegans with the assayed bacteria in the absence of flavonoids did not significantly affect body size and fertility of the worms neither improve their resistance against oxidative stress compared to E. coli controls. However, increased resistance to stress was found when C. elegans was cultivated in the presence of both L. plantarum and flavonoids, but not with B. longum or E. faecium. An exploratory study revealed the presence of glycosylated and sulfated metabolites together with the aglycone in worms treated with quercetin and fed any of the different assayed LAB strains. However, in the assays with epicatechin a differential metabolite, tentatively identified as 5-(4'-hydroxyphenyl)-γ-valerolactone 3'-O-glucoside, was detected in the worms fed L. plantarum but not with the other bacteria. Conclusion: The obtained results indicated that the interactions bacteria/polyphenol play a key role in the effects produced in C. elegans regarding resistance against oxidative stress, although those effects cannot be only explained by the ability of bacteria to metabolize polyphenols, but other mechanisms should also be involved.

Effect of Polyphenolic Complements on Cognitive Function in the Elderly: A Systematic Review.

Polyphenols have been shown to be effective against many chronic diseases. These compounds could have a beneficial effect at the cognitive level. The exact mechanism by which they provide positive effects at the cognitive level is not well known, but it is believed that they could counteract neuroinflammation. The objective of this study is to review nutritional interventions that include foods or supplements rich in flavanols, flavonols, or stilbenes to the usual diet on cognitive deterioration in people over 50 years of age. Clinical trials published in PubMed and Web of Science from 1 March 2010 to 1 March 2020 were explored, from which 14 studies were selected. All of them showed some improvement after the intervention. In interventions with flavanols and stilbenes, relevant improvements have been observed both in healthy patients and in patients with established cognitive impairment. Most studies agree that the greatest benefits are found with high doses and longer duration treatments. The changes were fundamentally assessed through cognitive tests, and in some of the studies, through magnetic resonance imaging (fMRI). The type of cognitive test used to assess the effect of the intervention was revealed to be critical. Several studies have also shown improvements in analytical parameters and blood pressure.

Ligilactobacillus salivarius PS11610 exerts an effect on the microbial and immunological profile of couples suffering unknown infertility.

PROBLEM: Unknown or idiopathic infertility has been associated with urogenital tract dysbiosis, reducing pregnancy and delivery ratios during assisted reproductive treatments (ART). The Ligilactobacillus salivarius PS11610 strain has shown extraordinary antimicrobial activity in vitro against urogenital pathogens as well as other probiotic characteristics. Therefore, an intervention study was performed to evaluate the effect of L. salivarius PS11610 on the microbial composition of urogenital tract in infertile couples with bacterial dysbiosis. METHOD OF STUDY: Seventeen couples undergoing ART diagnosed with unknown infertility were selected. After confirming urogenital dysbiosis, they started a 6-month treatment with L. salivarius PS11610 (1 dose/12 h for female and 1 dose/24 h for male). Vaginal, seminal, glans, uterine and plasma samples were collected for determination of the microbiome and immune profile at the beginning and the end of the treatment. RESULTS: Supplementation with L. salivarius PS11610 significantly modified the urogenital microbiome composition in male and female samples, solving dysbiosis of 67% of the couples. Pathogens disappeared from the vaginal samples whereas Lactobacilli percentage increased after 3 and 6 months of treatment. Moreover, L. salivarius PS11610 changed the uterine microbiome that could be associated with a change of the uterine immune profile. Additionally, the probiotic intake could be associated with the observed change in the systemic immunological profile of couples. Finally, the pregnant and delivery ratio were improved. CONCLUSIONS: Probiotic supplementation with L. salivarius PS11610 improved the male and female urogenital tract microbiome, modulating the immune system and increasing pregnancy success in couples undergoing ART.

Randomized, Double-Blind, Placebo-Controlled Study to Assess the Effect of Two Probiotics on the Preterms' Gut Microbiota.

OBJECTIVE: To evaluate the effect of a new probiotic strain combination, Ligilactobacillus salivarius subsp infantis PS11603 and Bifidobacterium longum PS10402, on gut bacterial colonization of preterm infants. METHODS: A randomized, double-blind, placebo-controlled study was conducted in preterm infants from 28 weeks + 0days to 30 weeks + 6days of gestation. Thirty preterm infants were randomly selected after birth to receive either probiotics or placebo. Stool samples were collected before product intake and then sequentially during the first weeks of their admission. Classical microbiological, metagenomics and multiplex immunological analyses were performed to assess the bacterial and immune profile of the samples. RESULTS: Twenty-seven infants completed the study (14 vs 13, probiotic and placebo groups). A higher number of participants were colonized by Lactobacilli in the probiotic group than in the placebo group (93% vs 46%; P  = 0.013). Similar results were obtained when analysing bifidobacterial colonization (100% vs 69%; P  = 0.041). Earlier colonization was observed in the probiotics group versus the placebo group, specifically 5 weeks for Lactobacillus and 1 week for Bifidobacterium. Although no effect was observed in the faecal immunological profile, a decreasing trend could be observed in Th17 response during the first week of probiotic treatment. None of the adverse events (AEs) registered were related to product intake. CONCLUSION: Probiotic supplementation with L salivarius PS11603 and B longum subsp. infantis PS10402 enhanced an earlier colonization of Lactobacillus and Bifidobacterium in preterm infants' guts in 5 and 1 week, respectively. A higher number of infants were colonized by Lactobacilli with the probiotics' intake at the end of the study.

Ligilactobacillus salivarius PS2 Supplementation during Pregnancy and Lactation Prevents Mastitis: A Randomised Controlled Trial.

Mastitis is considered one of the main reasons for unwanted breastfeeding cessation. This study aimed to investigate the preventive effect of the probiotic strain Ligilactobacillus salivarius PS2 on the occurrence of mastitis in lactating women. In this multicountry, multicenter, randomized, double-blind, placebo-controlled trial, 328 women were assigned to the probiotic or the placebo group. The intervention started from the 35th week of pregnancy until week 12 post-partum. The primary outcome was the incidence (hazard) rate of mastitis, defined as the presence of at least two of the following symptoms: breast pain, breast erythema, breast engorgement not relieved by breastfeeding, and temperature > 38 °C. The probability of being free of mastitis during the study was higher in the probiotic than in the placebo group (p = 0.022, Kaplan-Meier log rank test) with 9 mastitis cases (6%) vs. 20 mastitis cases (14%), respectively. The hazard ratio of the incidence of mastitis between both study groups was 0.41 (0.190-0.915; p = 0.029), indicating that women in the probiotic group were 58% less likely to experience mastitis. In conclusion, supplementation of L. salivarius PS2 during late pregnancy and early lactation was safe and effective in preventing mastitis, which is one of the main barriers for continuing breastfeeding.

Wine, Polyphenols, and Mediterranean Diets. What Else Is There to Say?

A considerable amount of literature has been published claiming the cardiovascular benefits of moderate (red) wine drinking, which has been considered a distinguishing trait of the Mediterranean diet. Indeed, red wine contains relevant amounts of polyphenols, for which evidence of their biological activity and positive health effects are abundant; however, it is also well-known that alcohol, even at a low level of intake, may have severe consequences for health. Among others, it is directly related to a number of non-communicable diseases, like liver cirrhosis or diverse types of cancer. The IARC classifies alcohol as a Group 1 carcinogen, causally associated with the development of cancers of the upper digestive tract and liver, and, with sufficient evidence, can be positively associated with colorectum and female breast cancer. In these circumstances, it is tricky, if not irresponsible, to spread any message on the benefits of moderate wine drinking, about which no actual consensus exists. It should be further considered that other hallmarks of the Mediterranean diet are the richness in virgin olive oil, fruits, grains, and vegetables, which are also good sources of polyphenols and other phytochemicals, and lack the risks of wine. All of these aspects are reviewed in this article.

Caffeic and Dihydrocaffeic Acids Promote Longevity and Increase Stress Resistance in Caenorhabditis elegans by Modulating Expression of Stress-Related Genes.

Caffeic and dihydrocaffeic acid are relevant microbial catabolites, being described as products from the degradation of different phenolic compounds i.e., hydroxycinnamoyl derivatives, anthocyanins or flavonols. Furthermore, caffeic acid is found both in free and esterified forms in many fruits and in high concentrations in coffee. These phenolic acids may be responsible for a part of the bioactivity associated with the intake of phenolic compounds. With the aim of progressing in the knowledge of the health effects and mechanisms of action of dietary phenolics, the model nematode Caenorhabditis elegans has been used to evaluate the influence of caffeic and dihydrocaffeic acids on lifespan and the oxidative stress resistance. The involvement of different genes and transcription factors related to longevity and stress resistance in the response to these phenolic acids has also been explored. Caffeic acid (CA, 200 µM) and dihydrocaffeic acid (DHCA, 300 µM) induced an increase in the survival rate of C. elegans under thermal stress. Both compounds also increased the mean and maximum lifespan of the nematode, compared to untreated worms. In general, treatment with these acids led to a reduction in intracellular ROS concentrations, although not always significant. Results of gene expression studies conducted by RT-qPCR showed that the favorable effects of CA and DHCA on oxidative stress and longevity involve the activation of several genes related to insulin/IGF-1 pathway, such as daf-16, daf-18, hsf-1 and sod-3, as well as a sirtuin gene (sir-2.1).

Applications of Natural Products in Food.

The term natural products includes any substance produced by living organisms [...].

Caernohabditis elegans as a Model Organism to Evaluate the Antioxidant Effects of Phytochemicals.

The nematode Caernohabditis elegans was introduced as a model organism in biological research by Sydney Brenner in the 1970s. Since then, it has been increasingly used for investigating processes such as ageing, oxidative stress, neurodegeneration, or inflammation, for which there is a high degree of homology between C. elegans and human pathways, so that the worm offers promising possibilities to study mechanisms of action and effects of phytochemicals of foods and plants. In this paper, the genes and pathways regulating oxidative stress in C. elegans are discussed, as well as the methodological approaches used for their evaluation in the worm. In particular, the following aspects are reviewed: the use of stress assays, determination of chemical and biochemical markers (e.g., ROS, carbonylated proteins, lipid peroxides or altered DNA), influence on gene expression and the employment of mutant worm strains, either carrying loss-of-function mutations or fluorescent reporters, such as the GFP.

Assessment of the In Vivo Antioxidant Activity of an Anthocyanin-Rich Bilberry Extract Using the Caenorhabditis elegans Model.

Anthocyanins have been associated with several health benefits, although the responsible mechanisms are not well established yet. In the present study, an anthocyanin-rich extract from bilberry (Vaccinium myrtillus L.) was tested in order to evaluate its capacity to modulate reactive oxygen species (ROS) production and resistance to thermally induced oxidative stress, using the nematode Caenorhabditis elegans as an in vivo model. The assays were carried out with the wild-type N2 strain and the mutant strains daf-16(mu86) I and hsf-1(sy441), which were grown in the presence of two anthocyanin extract concentrations (5 and 10 µg/mL in the culture medium) and further subjected to thermal stress. The treatment with the anthocyanin extract at 5 µg/mL showed protective effects on the accumulation of ROS and increased thermal resistance in C. elegans, both in stressed and non-stressed young and aged worms. However, detrimental effects were observed in nematodes treated with 10 µg/mL, leading to a higher worm mortality rate compared to controls, which was interpreted as a hormetic response. These findings suggested that the effects of the bilberry extract on C. elegans might not rely on its direct antioxidant capacity, but other mechanisms could also be involved. Additional assays were performed in two mutant strains with loss-of-function for DAF-16 (abnormal DAuer Formation factor 16) and HSF-1 (Heat Shock Factor 1) transcription factors, which act downstream of the insulin/insulin like growth factor-1 (IGF-1) signaling pathway. The results indicated that the modulation of these factors could be behind the improvement in the resistance against thermal stress produced by bilberry anthocyanins in young individuals, whereas they do not totally explain the effects produced in worms in the post-reproductive development stage. Further experiments are needed to continue uncovering the mechanisms behind the biological effects of anthocyanins in living organisms, as well as to establish whether they fall within the hormesis concept.

Exploring Target Genes Involved in the Effect of Quercetin on the Response to Oxidative Stress in Caenorhabditis elegans.

Quercetin is one the most abundant flavonoids in the human diet. Although it is well known that quercetin exhibits a range of biological activities, the mechanisms behind these activities remain unresolved. The aim of this work is to progress in the knowledge of the molecular mechanisms involved in the biological effects of quercetin using Caenorhabditis elegans as a model organism. With this aim, the nematode has been used to explore the ability of this flavonoid to modulate the insulin/insulin-like growth factor 1(IGF-1) signaling pathway (IIS) and the expression of some genes related to stress response. Different methodological approaches have been used, i.e., assays in knockout mutant worms, gene expression assessment by RT-qPCR, and C. elegans transgenic strains expressing green fluorescent protein (GFP) reporters. The results showed that the improvement of the oxidative stress resistance of C. elegans induced by quercetin could be explained, at least in part, by the modulation of the insulin signaling pathway, involving genes age-1, akt-1, akt-2, daf-18, sgk-1, daf-2, and skn-1. However, this effect could be independent of the transcription factors DAF-16 and HSF-1 that regulate this pathway. Moreover, quercetin was also able to increase expression of hsp-16.2 in aged worms. This observation could be of particular interest to explain the effects of enhanced lifespan and greater resistance to stress induced by quercetin in C. elegans, since the expression of many heat shock proteins diminishes in aging worms.

Plant phenolics as functional food ingredients.

Phenolic compounds have attracted much attention in recent times as their dietary intake has been associated with the prevention of some chronic and degenerative diseases that constitute major causes of death and incapacity in developed countries, such as cardiovascular diseases, type II diabetes, some types of cancers or neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Nowadays it is considered that these compounds contribute, at least in part, for the protective effects of fruit and vegetable-rich diets, so that the study of their role in human nutrition has become a central issue in food research. This chapter reviews the current knowledge on the phenolic compounds as food components, namely their occurrence in the diet, bioavailability and metabolism, biological activities and mechanisms of action. Besides, the approaches for their extraction from plant matrices and technological improvements regarding their preparation, stability and bioavailability in order to be used as functional food ingredients are also reviewed, as well as their legal situation regarding the possibility of making "health claims" based on their presence in food and beverages.

Antioxidant Characterization and Biological Effects of Grape Pomace Extracts Supplementation in Caenorhabditis elegans.

The aim of this work was to evaluate the biological activity of four grape pomace (GP) extracts that are rich in polyphenols using C. elegans as an in vivo model. Different concentrations of the GP extracts were assessed for their effects on the resistance of C. elegans against thermally induced oxidative stress, accumulation of reactive oxygen species (ROS), and lifespan. The cultivation of C. elegans with relatively low concentrations of GP extracts increased their resistance against thermal stress and prolonged their lifespan, while high levels displayed detrimental effects. In the studied extracts, maximum protection was observed for levels of polyphenols around 7 to 9 µg gallic acid equivalents per cultivation plate. The obtained results suggested that small changes in the ROS levels could have beneficial effects, although further studies are required to fully understand the impact of the extracts and assayed doses on ROS levels to explain the mechanism that is involved in the observed effects.

Preparation and Characterization of Protocatechuic Acid Sulfates.

Protocatechuic acid (3,4-dihydroxybenzoic acid; PCA) is a phenolic acid present in plants as a secondary metabolite and is also produced in the human organism as a metabolite from the degradation of polyphenols by the intestinal microbiota, particularly of flavonoids. However, PCA, like most polyphenols, is biotransformed in the human body to different conjugates as sulfates, which are found circulating in blood and could be involved in the bioactivity of the original compound. This paper describes a simple process for the preparation of PCA monosulfates with satisfactory yields. Two compounds were obtained that were identified as PCA-3-sulfate and PCA-4-sulfate by mass spectrometry and ¹H and 13C nuclear magnetic resonance using one- and two-dimensional techniques (heteronuclear single-quantum coherence and heteronuclear multiple-bond correlation). Differential MS fragmentation behavior and UV spectra were observed for each compound, which could be used for their identification in samples of unknown composition. The described procedure can be used for the preparation of these polyphenol metabolites in view of their use in in vivo and in vitro studies, as well as standards for their analysis in biological fluids, to contribute to the elucidation of biological effects of dietary polyphenols.

Epicatechin modulates stress-resistance in C. elegans via insulin/IGF-1 signaling pathway.

The nematode Caenorhabditis elegans has been used to examine the influence of epicatechin (EC), an abundant flavonoid in the human diet, in some stress biomarkers (ROS production, lipid peroxidation and protein carbonylation). Furthermore, the ability of EC to modulate the expression of some key genes in the insulin/IGF-1 signaling pathway (IIS), involved in longevity and oxidative or heat shock stress response, has also been explored. The final aim was to contribute to the elucidation of the mechanisms involved in the biological effects of flavonoids. The results showed that EC-treated wild-type C. elegans exhibited increased survival and reduced oxidative damage of biomolecules when submitted to thermal stress. EC treatment led to a moderate elevation in ROS levels, which might activate endogenous mechanisms of defense protecting against oxidative insult. The enhanced stress resistance induced by EC was found to be mediated through the IIS pathway, since assays in daf-2, age-1, akt-1, akt-2, sgk-1, daf-16, skn-1 and hsf-1 loss of function mutant strains failed to show any heat-resistant phenotype against thermal stress when treated with EC. Consistently, EC treatment upregulated the expression of some stress resistance associated genes, such as gst-4, hsp-16.2 and hsp-70, which are downstream regulated by the IIS pathway.

Effects of Quercetin Metabolites on Triglyceride Metabolism of 3T3-L1 Preadipocytes and Mature Adipocytes.

Quercetin (Q) has rapid metabolism, which may make it worthwhile to focus on the potential activity of its metabolites. Our aim was to evaluate the triglyceride-lowering effects of Q metabolites in mature and pre-adipocytes, and to compare them to those induced by Q. 3T3-L1 mature and pre-adipocytes were treated with 0.1, 1 and 10 µM of Q, tamarixetin (TAM), isorhamnetin (ISO), quercetin-3-O-glucuronide (3G), quercetin-3-O-sulfate (3S), as well as with 3S and quercetin-4-O-sulfate (4S) mixture (3S+4S). Triglyceride (TG) content in both cell types, as well as free fatty acid (FFA) and glycerol in the incubation medium of mature adipocytes were measured spectrophotometrically. Gene expression was assessed by RT-PCR. In mature adipocytes, Q decreased TG at 1 and 10 µM, 3S metabolite at 1 and 10 µM, and 3S+4S mixture at 10 µM. 3S treatment modified the glucose uptake, and TG assembling, but not lipolysis or apoptosis. During differentiation, only 10 µM of ISO reduced TG content, as did Q at physiological doses. In conclusion, 3S metabolite but not ISO, 3G, 4S and TAM metabolites can contribute to the in vivo delipidating effect of Q.

The Mechanisms Behind the Biological Activity of Flavonoids.

Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.