Search Results (148)

Punica granatum L. is a nutritionally relevant fruit with a complex phytochemical profile that varies across its anatomical fractions, including peel, arils, juice, seeds, and seed oil. Although pomegranate is widely recognized for its health-promoting potential, the nutritional significance of its matrix-dependent composition, bioavailability, and gut microbiota-mediated metabolism remains insufficiently integrated. This review aimed to critically evaluate the phytochemical diversity of pomegranate and its nutrition-related multi-target biological functions, with particular emphasis on food matrices, bioaccessibility, and translational relevance. A structured review of peer-reviewed studies indexed in major scientific databases from 2000 to January 2026 was conducted. Eligible reports included analytical, preclinical, and clinical studies addressing the composition of pomegranate-derived materials and their biological effects, with attention to extraction matrix, processing, bioavailability, microbial biotransformation, and mechanisms of action. Pomegranate exhibits marked matrix-specific phytochemical diversity. Peel is particularly rich in ellagitannins, especially punicalagin and punicalin; arils and juices are enriched in anthocyanins and flavonols; and seed oil contains high levels of punicic acid. Reported biological activities include antioxidant, anti-inflammatory, antimicrobial, metabolic, anti-aging, and anticancer effects. These actions appear to result from synergistic interactions among multiple bioactive compounds rather than from a single dominant constituent. Importantly, gut microbiota-driven conversion of ellagitannins and ellagic acid into urolithins is a major determinant of systemic bioactivity and may contribute to interindividual variability in response. The health effects of pomegranate should be interpreted within a nutrition-focused, matrix-dependent framework integrating composition, processing, bioavailability, and microbiota-derived metabolism. Full article

Nutraceuticals are emerging as promising agents for the prevention and treatment of atherosclerosis, particularly in light of the limitations associated with current pharmacotherapies. Pomegranate-derived polyphenols, especially punicalagin (PC), possess multiple cardioprotective properties. However, their direct biological effects are constrained by poor absorption and low bioavailability. Instead, many of their actions are mediated by gut microbiota-derived metabolites known as urolithins. Despite this, the roles of PC and its metabolites in atherosclerosis remain inadequately defined. The objective of this study was to investigate the anti-atherogenic effects and underlying mechanisms of PC and its major metabolites—ellagic acid and urolithins A, B, C, and D—using in vitro and in vivo approaches. In vitro, these compounds broadly inhibited key pro-atherogenic processes in macrophages and endothelial cells, including reactive oxygen species production and inflammatory gene expression, with notable metabolite-specific differences. Urolithin A (UA), identified as the most effective compound, was further evaluated in LDL receptor-deficient mice fed a high-fat diet. UA supplementation improved peripheral blood immune cell profile, reduced atherosclerotic plaque burden and inflammation, and enhanced markers of plaque stability. RNA sequencing of the thoracic aorta revealed key molecular pathways underlying the protective actions of UA. Collectively, these findings highlight the therapeutic potential of PC-derived metabolites, particularly UA, in combating atherosclerosis and support the need for future human clinical studies. Full article

Polyphenols are a diverse class of bioactive phytochemicals increasingly recognized for their ability to modulate human physiology through extensive interactions with the gut microbiota. This review provides a comprehensive and updated synthesis of the bidirectional polyphenol–microbiota relationship, emphasizing how dietary polyphenols reshape microbial community structure while intestinal microorganisms metabolize polyphenols into smaller, more bioavailable derivatives. These microbial metabolites—such as urolithins, phenolic acids, and dihydroresveratrol—exert amplified biological activities compared to their parent molecules, acting on key molecular pathways linked to oxidative stress, inflammation, energy homeostasis, and metabolic regulation. Through integration of mechanistic studies, multi-omics analyses, and emerging clinical evidence, this review outlines the potential of the polyphenol–microbiota–metabolite axis as a target for precision nutrition and microbiota-informed therapeutic interventions. The manuscript highlights ongoing challenges, including inter-individual variability in polyphenol metabolism, and proposes future research directions to advance the field of personalized nutrition. Full article

Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining β-hydroxybutyrate (βHB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood–brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism. Full article

Background: Antibiotics are essential for treating infections; however, they disrupt the microbiome and key microbiome-dependent functions. Clinical evidence is mixed for probiotic supplementation following antibiotics due to product heterogeneity and inconsistencies in evaluating biological mechanisms that drive clinical consequences. Accordingly, this study investigates the effects of a multi-species synbiotic on gut microbiome composition and function, and gut barrier integrity, during and following antibiotics. Methods: In a randomized, placebo-controlled trial designed to assess proof-of-mechanism, healthy adult participants received a daily synbiotic (53.6 billion AFU multi-species probiotic and 400 mg Indian pomegranate extract; DS-01) or matching placebo for 91 days. All participants also received ciprofloxacin (500 mg orally twice daily) and metronidazole (500 mg orally three times daily) for the first 7 days. Samples were collected at baseline and Days 7, 14, 49, and 91. Endpoints included fecal microbiome composition, fecal acetate and butyrate levels, urinary Urolithin A (UroA), serum p-cresol sulfate (pCS), gut barrier integrity, and safety. Results: The multi-species synbiotic significantly increased the alpha-diversity of Bifidobacterium and Lactobacillus at all timepoints compared to placebo, including short-term (Day 7, p < 0.0001) and end-of-study (Day 91, p < 0.001). The multi-species synbiotic enhanced recovery of native beneficial microbes, including butyrate-producing species and a novel Oscillospiraceae species (UMGS1312 sp900550625, p < 0.001). Beneficial microbiome-dependent metabolites increased, including fecal butyrate (119%, p < 0.05), fecal acetate (62%, p < 0.01), and UroA (13,008%, p < 0.05), whereas detrimental metabolite pCS decreased (68%, p < 0.05) compared to placebo. Functionally, the multi-species synbiotic improved gut barrier integrity rapidly (Day 7; 305%, p < 0.05) and over the long-term (Day 91; 161%, p < 0.05) compared to placebo. Conclusions: During and after antibiotics, this multi-species synbiotic promotes recovery of gut microbiome diversity and native beneficial microbes, microbiome metabolite recovery, and gut barrier function, all of which underpin antibiotic-associated gastrointestinal symptoms. Full article

Cellular senescence, mitochondrial dysfunction, and cumulative oxidative stress (OS) are the main causes of the progressive decreases in oocyte and sperm quality that define reproductive age. There is growing evidence that these processes are controlled by systemic variables, such as metabolites produced from the gut microbiome and extracellular vesicle (EV)-mediated intercellular communication, rather than being exclusively regulated at the tissue level. Antioxidant enzymes, regulatory microRNAs, and bioactive lipids that regulate mitochondrial redox balance, mitophagy, and inflammatory signaling are transported by EVs derived from reproductive organs, stem cells, immune cells, and the gut microbiota. Concurrently, microbiome-derived metabolites such as urolithin A, short-chain fatty acids, and polyphenol derivatives enhance mitochondrial quality control, activate antioxidant pathways, and suppress senescence-associated secretory phenotypes. This narrative review integrates the most recent research on the relationship between redox homeostasis, mitochondrial function, gut microbiota activity, and EV signaling in the context of male and female reproductive aging. We propose an emerging gut–EV–mitochondria axis as a unified framework through which systemic metabolic and antioxidant signals affect gamete competence, reproductive tissue function, and fertility longevity. Finally, we discuss therapeutic implications, including microbiome modulation, EV-based interventions, and senotherapeutic strategies, highlighting key knowledge gaps and future research directions necessary for clinical translation. Full article

Punicalagin, the major polyphenol in pomegranate peel, shows broad bioactivity but suffers from poor oral bioavailability. Whether hepatic or intestinal first-pass processes dominate this limitation remains unresolved. We developed a quantitative UPLC-MS/MS workflow to dissect punicalagin’s first-pass disposition and elimination in rats. Sprague–Dawley rats received punicalagin by intravenous, portal vein, oral, or intraduodenal dosing; plasma exposure was quantified by UPLC-MS/MS and analyzed noncompartmentally. We also profiled urinary and fecal excretion of punicalagin and key metabolites (punicalin, ellagic acid, urolithin C and urolithin A) to define biotransformation and clearance. Punicalagin displayed an absolute oral bioavailability of ~3.49%. First-pass analysis revealed modest hepatic extraction (~13.94%) but near-complete intestinal extraction (95.95%), identifying intestinal first-pass metabolism as the dominant barrier to systemic exposure. Consistently, parent and metabolites were eliminated mainly in feces, whereas urine contained only trace conjugated urolithin A. Collectively, these findings demonstrate that the poor oral bioavailability of punicalagin is driven primarily by extensive intestinal first-pass metabolism rather than hepatic clearance, and that its feces-dominant elimination is compatible with widespread hydrolysis and microbiota-mediated conversion within the gut. This work provides a pharmacokinetic framework to guide strategies aimed at improving oral delivery and systemic exposure of punicalagin. Full article

Over the past decade, research on urolithins has expanded significantly due to their role as mediators between polyphenol-rich diets and human health. Understanding the relationships between ellagitannin intake, gut microbiota composition, and urolithin production is essential for evaluating their biological effects and nutraceutical potential. The primary objective of this review is to critically summarise current knowledge on urolithins, bioactive metabolites derived from ellagitannins in plant-based foods, with a focus on their biosynthesis, bioavailability, protein interactions, and potential therapeutic applications. A comprehensive literature search was conducted using PubMed, Scopus, and Google Scholar to identify studies on urolithin biosynthesis, absorption, transport mechanisms, protein binding, and incorporation into extracellular vesicles. Relevant articles were critically analysed to synthesise current evidence and highlight emerging concepts. Key findings indicate that after absorption, urolithins bind to serum albumin, which facilitates their transport to target tissues, exerting anti-inflammatory and antioxidant actions. Recent evidence also shows that urolithins can be packaged into extracellular vesicles, suggesting novel mechanisms for intracellular transport and potential therapeutic applications. This review highlights gaps in current knowledge and proposes directions for future research to optimise their therapeutic potential. Full article

Urolithin A (UA), a metabolite of dietary ellagitannins produced by the gut microbiome, is a potential dual-purpose bioactive compound that may interfere with the shared pathogenic pathways linking colorectal cancer (CRC) and type 2 diabetes mellitus (T2DM). This review summarizes recent preclinical and clinical data on UA’s mechanisms, therapeutic potential, and translational challenges. In CRC models, UA promotes G2/M cell cycle arrest, triggers both intrinsic and extrinsic caspase-mediated apoptosis, enhances CD8+ T-cell mitophagy and memory functions, suppresses Wnt/β-catenin signaling, and reduces chemoresistance, especially to 5-FU. For T2DM, UA enhances autophagic flux, mitophagy, insulin signaling, and GLUT4-mediated glucose uptake through the AMPK and PI3K/AKT pathways, reduces fasting glucose and insulin resistance in animal studies, and promotes adipose tissue browning and mitochondrial beta-oxidation. Human biomarker research is limited but indicates positive changes following interventions that increase UA. Future priorities include biomarker-driven, dose-finding trials stratified by metabotype, developing colon-targeted vs. systemic formulations, and testing combinations with chemotherapy and immunotherapy to determine safety and effectiveness. Full article

Background/Objectives: Interindividual variability in polyphenol metabolism may help explain the inconsistent effects of polyphenol intake on health outcomes. This study compared, for the first time, (i) polyphenol-related gut microbiota metabotypes (urolithins: UM0, UMA, UMB; equol: EP, ENP; lunularin: LP, LNP) and their clusters (MCs) in non-medicated premenopausal (Pre-M) and postmenopausal (Post-M) women and (ii) the impact of an 8-week intake of a polyphenol-rich plant extract mixture (PPs) on the quality of life (QoL) of Post-M. Methods: Polyphenol metabotypes were determined in urine via UPLC-QTOF-MS after a 3-day intake of PPs containing resveratrol, pomegranate (ellagitannins and ellagic acid), and red clover (isoflavones) in Pre-M (n = 120) and Post-M (n = 90) women. QoL was assessed with the short-form Cervantes Scale in a randomized, placebo-controlled crossover trial (8-week PPs vs. placebo), completed by 78 Post-M participants. Results: At baseline, Pre-M and Post-M women showed only minor differences in metabotype and MC distributions linked to menopausal status. MC3 (UMA+EP+LP) predominated in Pre-M, while MC7 (UMA+EP+LNP) was most frequent in Post-M. PPs intake in Post-M women led to modest shifts in metabotype and MC distributions toward Pre-M patterns. Quantitative metabolite production was comparable between groups, except for equol, which showed a median 2.8-fold increase after PPs intake in EP Post-M women. Clinically meaningful improvements (score reduction ≥ 6.7 points) in QoL were observed in the Psychic domain in EP women (28%, p = 0.039) and in the Menopause and Health domain, specifically in EP (24.1%, p = 0.004), MC3 (22.5%, p = 0.043), and MC4 (UMB+EP+LP; 41.3%, p = 0.022), were mainly driven by a reduction in hot flashes (p = 0.001). Conclusions: These findings support metabotyping as a tool to guide targeted dietary strategies and enhance QoL through precision health in Post-M women. Full article

Phenolic compounds are widely known for their beneficial effects on human health. However, it is essential to understand which low molecular weight metabolites are produced by the gut microbiota, when non-absorbed compounds reach the colon, and whether these metabolites are more biologically active than their precursors. In this context, this study aims to explore the gut microbiota metabolites of relevant phenolic compounds commonly found in the human diet. Therefore, ellagic acid, naringenin, and phloroglucinol were incubated with human feces for 48 h, and the ensuing metabolites were analyzed by ultra-high-performance liquid chromatography with diode array detector coupled to ion trap mass spectrometry (UHPLC-DAD-MSⁿ) and gas chromatography–mass spectrometry (GC-MS). Ellagic acid metabolism by the gut microbiota produced a diversity of urolithins, with 8-hydroxyurolithin being identified for the first time. Isomers of 4-hydroxybenzoic, 3,4-dihydroxybenozic, and p-coumaric acids were identified for the first time as naringenin metabolites, while phloroglucinic, 2-hydroxy-3-phenylpropanoic, 3-phenylpropanoic, and 2-phenylacetic acids are reported for the first time as phloroglucinol metabolites. These findings contribute to a more comprehensive understanding of the beneficial health effects of these metabolites through the evaluation of their biological activities in conjunction with their effects on the gut microbiota, thus providing the basis for the development of food supplements, novel probiotics or functional foods. Full article

The present review offers a comprehensive synthesis of the structural diversity, natural occurrence, and therapeutic promise of key ellagitannins (punicalagin, sanguiin H-6, corilagin, geraniin, oenothein B, chebulagic, and chebulinic acids) within the hydrolyzable ellagitannin pool. Distributed in medicinal and dietary plants long used in traditional medicine, ellagitannin-rich species serve as sources of both complex polyphenolic scaffolds and their bioactive metabolites, urolithins, which mediate many of their health-promoting effects. Special emphasis is placed on the multifaceted mechanisms that contribute to their potent antioxidant, anti-inflammatory, antimicrobial, and anticancer effects, extending to both non-communicable and communicable diseases. Despite their broad therapeutic spectrum, clinical translation is limited by challenges such as poor bioavailability, host-gut microbiota variability, and a lack of robust in vivo evidence. The review highlights future directions aimed at unlocking ellagitannins’ potential, including microbiota-targeted strategies for urolithin production, the design of stable prodrugs and analogs, and innovative delivery platforms. By integrating phytochemical, mechanistic and translational insights, this article positions ellagitannins as promising candidates for the development of novel polyphenol-based interventions. Full article

This scoping review synthesized evidence from 2015 to 2025 on the anti-inflammatory and anticancer potential of pecan (Carya illinoinensis) kernel extracts, focusing on bioactive composition and cell signaling pathway modulation. Pecan kernels contain diverse phenolic compounds including gallic acid, catechin, epicatechin, and ellagic acid, along with tocopherols and unsaturated fatty acids, exhibiting significant cultivar-dependent variation influenced by ripening stage, processing conditions, and orchard management practices. In vitro studies demonstrate that kernel extracts possess substantial antioxidant capacity and exert antiproliferative and cytotoxic effects against various human cancer cell lines, including colon cancer cells, with evidence of apoptosis induction. Extraction methodologies significantly influence bioactive compound recovery and biological activity, with both lipid and phenolic fractions contributing to therapeutic potential. While current evidence highlights promising anti-inflammatory and anticancer properties mediated through modulation of apoptotic pathways, research remains predominantly limited to compositional analyses and in vitro models. Future investigations should elucidate specific molecular mechanisms, identify precise signaling pathway targets, conduct in vivo validation studies, and optimize processing conditions to maximize bioactive retention for potential therapeutic applications in cancer prevention and treatment. Full article

The gut microbiota greatly influences host physiology, including immune regulation, metabolic balance, and brain health. Aging is associated with alterations in the gut microbiome, including reduced microbial diversity and increased pro-inflammatory bacteria, which are linked to age-related decline and chronic diseases. This review examines the impact of the gut microbiota on key indicators of aging, including cellular senescence, mitochondrial dysfunction, alterations in gene expression, and immune system modifications. It also examines microbiome-related diseases associated with aging, including neurodegeneration, cardiovascular issues, metabolic syndrome, and frailty. Additionally, it highlights evidence-based methods to restore a youthful microbial profile. New findings suggest that certain microbial substances, including short-chain fatty acids, urolithins, and bile acids, play a role in regulating inflammation, maintaining barrier integrity, and influencing metabolism. Age-related diseases are often associated with molecular pathways driven by an imbalance in the gut microbiome. Various intervention strategies, from dietary changes and probiotics to personalized nutrition and fecal microbiota transplantation, have shown promise in reversing signs of microbial aging and improving health outcomes in both lab and human studies. Overall, the gut microbiome serves as both a marker and a regulator of healthy aging. Treatments that restore microbial balance offer hopeful ways to extend healthy living. Future studies should focus on developing long-term, multifaceted, and personalized methods to identify causal pathways and enhance microbiota-based strategies for various aging populations. Full article