Main drivers of (poly)phenol effects on human health: metabolite production and/or gut microbiota-associated metabotypes?

Iglesias‐Aguirre, Carlos E.; Cortés‐Martín, Adrián; Ávila‐Gálvez, María Ángeles; Giménez‐Bastida, Juan Antonio; Selma, María V.; González‐Sarrías, Antonio; Espı́n, Juan Carlos

doi:10.1039/d1fo02033a

Cited by 66 publications

(104 citation statements)

References 251 publications

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“…Dietary (poly)phenols have been acknowledged to have a plethora of biological properties, including cancer chemopreventive activity [ 27 ]. This activity has been reported to be mediated in animal models by the decrease in K67, Bcl-2/Bax ratio, angiogenesis, matrix metalloproteinases, and cytokines, and an increase in p21, endostatin, and caspases activation, among many other mechanisms [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…This activity has been reported to be mediated in animal models by the decrease in K67, Bcl-2/Bax ratio, angiogenesis, matrix metalloproteinases, and cytokines, and an increase in p21, endostatin, and caspases activation, among many other mechanisms [ 28 ]. However, they are poorly bioavailable, i.e., the fraction of intact (poly)phenolics ingested that reach the bloodstream is low [ 27 , 29 ]. In addition, once absorbed, phase-II enzymes (mainly glucuronyl, sulfate, and catechol-methyl transferases) extensively metabolize (poly)phenols, yielding conjugated metabolites, primarily glucuronides and sulfates, that can show some activity but much less than their food-occurring phenolic precursors [ 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

González‐Sarrías

Iglesias‐Aguirre

Cortés‐Martín

et al. 2022

IJMS

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Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

González‐Sarrías

Iglesias‐Aguirre

Cortés‐Martín

et al. 2022

IJMS

Self Cite

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“…After ingestion of ellagitannin-rich food products, individuals without urolithins production belonged to metabotype 0, with UA production as the unique final product that fits into metabotype A, and UB and/or Iso-UA belongs to metabotype B ( 14 , 18 ). Thus, this difference in microbiota composition would further influence the health benefits associated with ellagitannin-rich food ( 34 ). Notably, urolithins have been found in breast milk of mothers, who consume ellagitannin rich walnut, and it resembles Urolilithin metabotypes of the mothers as well ( 35 ).…”

Section: Colon Bacteria: the Cooks Who Brought Out The Delicacymentioning

confidence: 99%

Urolithins: The Colon Microbiota Metabolites as Endocrine Modulators: Prospects and Perspectives

et al. 2022

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Selective estrogen receptor modulators (SERMs) have been used in hormone related disorders, and their role in clinical medicine is evolving. Tamoxifen and raloxifen are the most commonly used synthetic SERMs, and their long-term use are known to create side effects. Hence, efforts have been directed to identify molecules which could retain the beneficial effects of estrogen, at the same time produce minimal side effects. Urolithins, the products of colon microbiota from ellagitannin rich foodstuff, have immense health benefits and have been demonstrated to bind to estrogen receptors. This class of compounds holds promise as therapeutic and nutritional supplement in cardiovascular disorders, osteoporosis, muscle health, neurological disorders, and cancers of breast, endometrium, and prostate, or, in essence, most of the hormone/endocrine-dependent diseases. One of our findings from the past decade of research on SERMs and estrogen modulators, showed that pomegranate, one of the indirect but major sources of urolithins, can act as SERM. The prospect of urolithins to act as agonist, antagonist, or SERM will depend on its structure; the estrogen receptor conformational change, availability and abundance of co-activators/co-repressors in the target tissues, and also the presence of other estrogen receptor ligands. Given that, urolithins need to be carefully studied for its SERM activity considering the pleotropic action of estrogen receptors and its numerous roles in physiological systems. In this review, we unveil the possibility of urolithins as a potent SERM, which we are currently investigating, in the hormone dependent tissues.

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“…This is relevant since it may significantly alter the results based on the individual's capacity to produce a certain urolithin. The stratification of the population based on their metabotype has been a target of recent investigations, with several challenges both conceptual and technical (as reviewed in [143]).…”

Section: Biological Activity Against the Pathological Processes Of Diabetesmentioning

confidence: 99%

Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes

et al. 2021

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Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.

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Main drivers of (poly)phenol effects on human health: metabolite production and/or gut microbiota-associated metabotypes?

Abstract: The final drivers for the health effects of (poly)phenol consumption have not been fully identified. Specific associations between health effects and circulating-excreted metabolites and(or) gut microbial ecologies do not prove a causal role.

Cited by 66 publications

References 251 publications

Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

Urolithins: The Colon Microbiota Metabolites as Endocrine Modulators: Prospects and Perspectives

Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes

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