Metabolite production and/or gut microbiota-associated metabotypes?

Funding Information: This research was supported by the Project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain) and by Fundación Séneca de la Región de Murcia (Spain), grant number 20880/PI/18. J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991. A.C.M. and C.E.I.-A. are the holders of predoctoral grants from MINECO (grant number BES-2016-078098) and MICINN (grant number FPU18/03961) (Spain), respectively. Publisher Copyright: © 2021 The Royal Society of Chemistry.Despite the high human interindividual variability in response to (poly)phenol consumption, the cause-and-effect relationship between some dietary (poly)phenols (flavanols and olive oil phenolics) and health effects (endothelial function and prevention of LDL oxidation, respectively) has been well established. Most of the variables affecting this interindividual variability have been identified (food matrix, gut microbiota, single-nucleotide-polymorphisms, etc.). However, the final drivers for the health effects of (poly)phenol consumption have not been fully identified. At least partially, these drivers could be (i) the (poly)phenols ingested that exert their effect in the gastrointestinal tract, (ii) the bioavailable metabolites that exert their effects systemically and/or (iii) the gut microbial ecology associated with (poly)phenol metabolism (i.e., gut microbiota-associated metabotypes). However, statistical associations between health effects and the occurrence of circulating and/or excreted metabolites, as well as cross-sectional studies that correlate gut microbial ecologies and health, do not prove a causal role unequivocally. We provide a critical overview and perspective on the possible main drivers of the effects of (poly)phenols on human health and suggest possible actions to identify the putative actors responsible for the effects.publishersversionpublishe

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives

© 2020 by the authors.Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussedThis research was funded by the projects PID2019-103914RB-I00 (MICINN, Spain), 19900/GERM/15 (Fundación Séneca de la Región de Murcia, Spain), and 201870E014 and 201770E081 (CSIC, Spain). J.A.G.B. was supported by a Juan de la Cierva contract (IJCI-2016-27633) from the Ministry of Science, Innovation and Universities (Spain) and a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838991.Peer reviewe

Tissue deconjugation of urolithin A glucuronide to free urolithin A in systemic inflammation

Urolithin A (Uro-A) is an anti-inflammatory and cancer chemopreventive metabolite produced by the gut microbiota from the polyphenol ellagic acid. However, in vivo conjugation of Uro-A to Uro-A glucuronide (Uro-A glur) dramatically hampers its activity. We describe here for the first time the tissue deconjugation of Uro-A glur to Uro-A after lipopolysaccharide (LPS)-induced inflammation, which could explain the systemic in vivo activity of free Uro-A in microenvironments subjected to inflammatory stimuli.This research has been supported by the Project 201770E081 from the Spanish National Research Council (CSIC, Spain) and by the Project AGL2015-64124-R (Ministry of Science, Innovation and Universities, Spain). J. A. G.-B. is a holder of a “Juan de la Cierva” contract from the Ministry of Science, Innovation and Universities (Spain).We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI)Peer reviewe

Evidence for health properties of pomegranate juices and extracts beyond nutrition: A critical systematic review of human studies

Background The consumption of pomegranate juices and extracts has long been linked to many health benefits beyond nutrition, described mainly by innumerable preclinical studies. However, the European Food Safety Authority (EFSA) concluded in 2010 that a cause and effect relationship could not be established between the consumption of pomegranate-derived products and all the health claims presented. There are no additional EFSA opinions on health claims specifically addressed to pomegranate in the last decade. Scope and approach This review comprehensively compiles all human studies conducted on pomegranate. The aim is to discuss these studies critically to identify possible flaws and propose guidelines that might help establish a cause and effect relationship between pomegranate-derived product consumption and health. Key findings and conclusions To date, 86 human studies have evaluated the health benefits of pomegranate juices and extracts. The most promising, albeit scarce, evidence is related to blood pressure improvement. Less evidence deals with inflammation, cancer, cognitive function, physical activity, and gut microbiota modulation (prebiotic effects). After a decade since EFSA's opinion, human evidence remains inconsistent, making it difficult to support most claimed health effects. The lack of effects and(or) data discrepancy might be attributable to design limitations, including insufficient product characterization and interindividual variability that influence pomegranate polyphenols' bioefficacy. New coordinated strategies between policy makers, research/academic institutions, and industry are needed to move forward. Therefore, this review presents a roadmap to conduct well-designed trials and cover existing gaps, which could establish a cause-effect relation between pomegranate consumption and health benefits beyond nutrition.This work was supported by the MICINN (Spain) under grant number [PID2019-103914RB-I00], and by the European Union's Horizon 2020 research and innovation programme under the Marie Curie Sklodowska-Curie Grant Agreement [No 838991]

Human studies carried out with pomegranate-based products (juice and extract)

The consumption of pomegranate juices and extracts has long been linked to many health benefits beyond nutrition, described mainly by innumerable preclinical studies. However, the European Food Safety Authority (EFSA) concluded in 2010 that a cause and effect relationship could not be established between the consumption of pomegranate-derived products and all the health claims presented. There are no additional EFSA opinions on health claims specifically addressed to pomegranate in the last decade. Scope and approach This review comprehensively compiles all human studies conducted on pomegranate. The aim is to discuss these studies critically to identify possible flaws and propose guidelines that might help establish a cause and effect relationship between pomegranate-derived product consumption and health. Key findings and conclusions To date, 86 human studies have evaluated the health benefits of pomegranate juices and extracts. The most promising, albeit scarce, evidence is related to blood pressure improvement. Less evidence deals with inflammation, cancer, cognitive function, physical activity, and gut microbiota modulation (prebiotic effects). After a decade since EFSA's opinion, human evidence remains inconsistent, making it difficult to support most claimed health effects. The lack of effects and(or) data discrepancy might be attributable to design limitations, including insufficient product characterization and interindividual variability that influence pomegranate polyphenols' bioefficacy. New coordinated strategies between policy makers, research/academic institutions, and industry are needed to move forward. Therefore, this review presents a roadmap to conduct well-designed trials and cover existing gaps, which could establish a cause-effect relation between pomegranate consumption and health benefits beyond nutrition.European Commission: PolyBiota - Polyphenols and Gut Microbiota interaction in Cardiovascular Health (838991)Peer reviewe

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

This article belongs to the Collection Feature Papers in Bioactives and Nutraceuticals.5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.This research was supported by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain). J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991. CS is supported by NIH awards GM076592 and GM118412.Peer reviewe

Physiologically relevant curcuminoids inhibit angiogenesis via VEGFR2 in human aortic endothelial cells

Angiogenesis is a complex process encompassing endothelial cell proliferation, migration, and tube formation. While numerous studies describe that curcumin exerts antitumor properties (e.g., targeting angiogenesis), information regarding other dietary curcuminoids such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BisDMC) is scant. In this study, we evaluated the antiangiogenic activities of these three curcuminoids at physiological concentrations (0.1¿5 ¿M) on endothelial cell migration and tubulogenesis and the underlying associated mechanisms on human aortic endothelial cells (HAECs). Results showed that the individual compounds and a representative mixture inhibited the tubulogenic and migration capacity of endothelial cells dose-dependently, while sparing cell viability. Notably, DMC and BisDMC at 0.1 and 1 ¿M showed higher capacity than curcumin inhibiting tubulogenesis. These compounds also reduced phosphorylation of the VEGFR2 and the downstream ERK and Akt pathways in VEGF165-stimulated cells. In silico analysis showed that curcuminoids could bind the VEGFR2 antagonizing the VEGF-mediated angiogenesis. These findings suggest that physiologically concentrations of curcuminoids might counteract pro-angiogenic stimuli relevant to tumorigenic processes.J.A.G.-B. was supported by Standard European Marie Curie Individual Fellowship from the European Commission. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No 838991, and by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain

Ellagitannins, urolithins, and neuroprotection: Human evidence and the possible link to the gut microbiota

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial signatures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotectionThis work was supported by the Projects PID 2019-103914RB-I00 from the Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033, Spain) and 21647/PDC/21, 20880/PI/18 and 19900/GERM/15 (Fundación Séneca de la Región de Murcia, Spain). C.E.I.-A. holds a predoctoral grant from MICIN (grant number FPU18/03961, Spain). J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission (European Union's Horizon, 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991).Peer reviewe

Inhibition of Quorum Sensing (QS) in Yersinia enterocolitica by an Orange Extract Rich in Glycosylated Flavanones

Flavanones, flavonoids abundant in Citrus, have been shown to interfere with quorum sensing (QS) and affect related physiological processes. We have investigated the QS-inhibitory effects of an orange extract enriched in O-glycosylated flavanones (mainly naringin, neohesperidin, and hesperidin). The QS-inhibitory capacity of this extract and its main flavanone components was first screened using the bacteriological monitoring system Chromobacterium violaceum. We next examined the ability of the orange extract and of some of the flavanones to (i) reduce the levels of the QS mediators produced by Y. enterocolitica using HPLC-MS/MS, (ii) inhibit biofilm formation, and (iii) inhibit swimming and swarming motility. Additionally, we evaluated changes in the expression of specific genes involved in the synthesis of the lactones (yenI, yenR) and in the flagellar regulon (flhDC, fleB, fliA) by RT-PCR. The results showed that the orange extract and its main flavanone components inhibited QS in C. violaceum, diminished the levels of lactones secreted by Y. enterocolitica to the media, and decreased QS-associated biofilm maturation without affecting bacterial growth. Among the tested compounds, naringin was found to inhibit swimming motility. Exposure to the orange extract and (or) to naringin was also found to be associated with induction of the transcription levels of yenR, flhDC, and fliA. This work shows the in vitro QS-inhibitory effects of an orange extract enriched in flavanones against a human enteropathogen at doses that can be achieved through the diet and suggests that consumption of these natural extracts may have a beneficial antipathogenic effectJ.A.G-B. and I.C.-I. are holders of a predoctoral JAE scholarship, and M.L. is the holder of a JAE-DOC contract, all from CSIC (Spain). P.T. is the holder of a predoctoral scholarship from the Fundación Seneca de la Región de Murcia. This research has been supported by the following projects: Consolider Ingenio 2010- Fun-C-Food CSD2007-0063, CICYT BFU2007-60576, Fundación Seneca de la Región de Murcia (Grupo de Excelencia GERM 06, 04486), and the European Community’s Seventh Framework Programme (FP7) (244956, project BEEDOC)Peer reviewe