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Funding Information: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA‐01‐0145‐FEDER‐007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Ciéncia e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, European Research Council (Starting Grant: FunKeyGut 741623). FCT (2020.04630.BD). Funding Information: This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA‐01‐0145‐FEDER‐007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged. D.B. acknowledges funding by the European Research Council (Starting Grant: FunKeyGut 741623). Authors would like to acknowledge FCT for financial support of D.C. (2020.04630.BD). Publisher Copyright: © 2022 The Authors. Comprehensive Reviews in Food Science and Food Safety published by Wiley Periodicals LLC on behalf of Institute of Food Technologists. A large number of epidemiological studies have shown that consumption of fruits, vegetables, and beverages rich in (poly)phenols promote numerous health benefits from cardiovascular to neurological diseases. Evidence on (poly)phenols has been applied mainly to flavonoids, yet the role of phenolic acids has been largely overlooked. Such phenolics present in food combine with those resulting from gut microbiota catabolism of flavonoids and chlorogenic acids and those produced by endogenous pathways, resulting in large concentrations of low molecular weight phenolic metabolites in human circulation. Independently of the origin, in human intervention studies using diets rich in (poly)phenols, a total of 137 low molecular weight phenolic metabolites have been detected and quantified in human circulation with largely unknown biological function. In this review, we will pinpoint two main aspects of the low molecular weight phenolic metabolites: (i) the microbiota responsible for their generation, and (ii) the analysis (quali- and quantitative) in human circulation and their respective pharmacokinetics. In doing so, we aim to drive scientific advances regarding the ubiquitous roles of low molecular weight phenolic metabolites using physiologically relevant concentrations and under (patho)physiologically relevant conditions in humans. publishersversion published

A large number of epidemiological studies have shown that consumption of fruits, vegetables, and beverages rich in (poly)phenols promote numerous health benefits from cardiovascular to neurological diseases. Evidence on (poly)phenols has been applied mainly to flavonoids, yet the role of phenolic acids has been largely overlooked. Such phenolics present in food combine with those resulting from gut microbiota catabolism of flavonoids and chlorogenic acids and those produced by endogenous pathways, resulting in large concentrations of low molecular weight phenolic metabolites in human circulation. Independently of the origin, in human intervention studies using diets rich in (poly)phenols, a total of 137 low molecular weight phenolic metabolites have been detected and quantified in human circulation with largely unknown biological function. In this review, we will pinpoint two main aspects of the low molecular weight phenolic metabolites: (i) the microbiota responsible for their generation, and (ii) the analysis (quali- and quantitative) in human circulation and their respective pharmacokinetics. In doing so, we aim to drive scientific advances regarding the ubiquitous roles of low molecular weight phenolic metabolites using physiologically relevant concentrations and under (patho)physiologically relevant conditions in humans.

Funding Information: Funding: This work was supported by FCT–Fundação para a Ciência e a Tecnologia (grants UIDB/04567/2020 and UIDP/04567/2020 to CBIOS, PTDC/BIA-MOL/31104/2017, and PhD grants 2020.07813.BD to Í.G. and 2020.04630.BD to D.C.). C.F.-P. and R.M. are funded by FCT Scientific Employment Stimulus contract with the reference numbers CEEC/CBIOS/NUT/2018 and CEEC/04567/CBIOS/2020, respectively. Authors also acknowledge COFAC/ILIND–Cooperativa De Formação E Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). Authors also acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is co-funded by FCT/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement. Kidney diseases constitute a worldwide public health problem, contributing to morbidity and mortality. The present study aimed to provide an overview of the published data regarding the potential beneficial effects of polyphenols on major kidney diseases, namely acute kidney injury, chronic kidney disease, diabetic nephropathy, renal cancer, and drug-induced nephrotoxicity. This study consists of a bibliographical review including in vitro and in vivo studies dealing with the effects of individual compounds. An analysis of the polyphenol metabolome in human urine was also conducted to estimate those compounds that are most likely to be responsible for the kidney protective effects of polyphenols. The biological effects of polyphenols can be highly attributed to the modulation of specific signaling cascades including those involved in oxidative stress responses, anti-inflammation processes, and apoptosis. There is increasing evidence that polyphenols afford great potential in renal disease protection. However, this evidence (especially when in vitro studies are involved) should be considered with caution before its clinical translation, particularly due to the unfavorable pharmacokinetics and extensive metabolization that polyphenols undergo in the human body. Future research should consider polyphenols and their metabolites that indeed reach kidney tissues. publishersversion published

Funding Information: Funding: This work has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA—01–0145—FEDER—007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged. Authors Aβ—Amyloid beta; CAT—catalase; NF–κB—Nuclear factor kappa–light–chain–enhancer of activated B cell; GSK— Glycogen synthase kinase; GSH—glutathione; APP—Amyloid precursor protein; ROS—Reactive Oxygen Species; TNF— Tumor necrosis factor; JNK—c–Jun N–terminal kinases; SOD—Superoxide Dismutase; Tg—transgenic; PPAR— Peroxisome proliferator–activated receptor alpha; LPS—lipopolysaccharide; MPTP—1—methyl–4—phenyl–1,2,3,6— tetrahydropyridine. 1 (Poly)phenol metabolites are named accordingly the recommendations recently published [32], however the name cited in the original publications where the effect is described is indicated in brackets. ↑—increased ↓— decreased. Funding Information: would like to acknowledge FCT for financial support of D.C (2020.04630.BD), R.M (CEEC/04567/CBIOS/2020) and S.F (UIDP/BD4/04567/2020). Funding Information: This work has received funding from the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA?01?0145?FEDER?007344), which is cofunded by Funda??o para a Ci?ncia e Tecnologia (FCT)/Minist?rio da Ci?ncia e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged. Authors would like to acknowledge FCT for financial support of D.C (2020.04630.BD), R.M (CEEC/04567/CBIOS/2020) and S.F (UIDP/BD4/04567/2020). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The rise of neurodegenerative diseases in an aging population is an increasing problem of health, social and economic consequences. Epidemiological and intervention studies have demonstrated that diets rich in (poly)phenols can have potent health benefits on cognitive decline and neurodegenerative diseases. Meanwhile, the role of gut microbiota is ever more evident in modulating the catabolism of (poly)phenols to dozens of low molecular weight (poly)phenol metabolites that have been identified in plasma and urine. These metabolites can reach circulation in higher concentrations than parent (poly)phenols and persist for longer periods of time. However, studies addressing their potential brain effects are still lacking. In this review, we will discuss different model organisms that have been used to study how low molecular weight (poly)phenol metabolites affect neuronal related mechanisms gathering critical insight on their potential to tackle the major hallmarks of neurodegeneration. publishersversion published

The world of (poly)phenols arising from dietary sources has been significantly amplified with the discovery of low molecular weight (LMW) (poly)phenol metabolites resulting from phase I and phase II metabolism and microbiota transformations. These metabolites, which are known to reach human circulation have been studied to further explore their interesting properties, especially regarding neuroprotection. Nevertheless, once in circulation, their distribution to target tissues, such as the brain, relies on their ability to cross the blood-brain barrier (BBB), one of the most controlled barriers present in humans. This represents a key step of an underexplored journey towards the brain. Present review highlights the main findings related to the ability of LMW (poly)phenol metabolites to reach the brain, considering different studies: in silico, in vitro, and in vivo. The mechanisms associated with the transport of these LMW (poly)phenol metabolites across the BBB and possible transporters will be discussed. Overall, the transport of these LMW (poly)phenol metabolites is crucial to elucidate which compounds may exert direct neuroprotective effects, so it is imperative to continue dissecting their potential to cross the BBB and the mechanisms behind their permeation. publishersversion published

Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl-γ-valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-γ-valerolactone-sulfate (3′,4′ isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the “gut-brain axis”. publishersversion published

"Multiple (poly)phenolic compounds, related with the consumption of dietary products have been described to modulate microglial cells, influencing the inflammatory response in the brain and microgliamediated neuronal apoptosis. However, low amounts of information is available about small compounds, present in human blood circulation after the metabolization of (poly)phenols. Previously we have shown some of these small metabolites, capable of crossing the blood brain barrier at physiological concentrations, and be neuroprotective.(...)"