We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities in vitro. Cytotoxicity tests were performed on three cell lines (DU145, T24, and HepG2) and a human normal cell line (HK-2). The half-inhibitory concentration (IC50) of derivative UD-4c to hepatoma HepG2 cells (IC50 = 4.66 ± 0.12 μM) was significantly lower than that of sorafenib (IC50 =7.76 ± 0.12 μM), and exhibited less toxicity to HK-2 cells. Preliminary studies on the mechanism revealed that the derivative UD-4c could significantly inhibit the HepG2 cell growth and colony formation, block the HepG2 cell cycle in the G2/M phase, and induce apoptosis of HepG2 cells dose-dependently. The derivative UD-4c can be used as a potential lead compound to further develop new drugs for hepatocellular carcinoma treatment based on the evaluation of anti-cancer activity.

Castration-resistant prostate cancer (CRPC) presents a significant challenge due to its resistance to conventional androgen deprivation therapies. Urolithins, bioactive metabolites derived from ellagitannins, have recently emerged as promising therapeutic agents for CRPC. Urolithins not only inhibit androgen receptor (AR) signaling, a crucial factor in the progression of CRPC, but also play a key role in regulating oxidative stress by their antioxidant properties, thereby inhibiting increased reactive oxygen species, a common feature of the aggressive nature of CRPC. Research has shown that urolithins induce apoptosis and diminish pro-survival signaling, leading to tumor inhibition. This review delves into the intricate mechanisms through which urolithins exert their therapeutic effects, focusing on both AR-dependent and AR-independent pathways. It also explores the exciting potential of combining urolithins with androgen ablation therapy, opening new avenues for CRPC treatment.

Urolithins (Uros), a series of natural polyphenols derived from ellagic acid through gut bacteria metabolism, have gathered significant attention due to their diverse bioactivities such as maintaining mitochondrial health and anti-inflammatory and antioxidative effects. However, the ability to metabolize Uros varies among individuals. This Review provides a comprehensive insight into the synthesis, encapsulation and bioactivities of Uros, focusing on their biotransformation in vivo. We highlight the critical role of gut microbiota in the biotransformation of urolithins, including primary bacterial species such as Gordonibacter urolithinfaciens, Enterocloster bolteae and Enterococcus faecium. Furthermore, the therapeutic potential of Uros in alleviating neurodegenerative diseases, cancer, and Duchenne muscular dystrophy is discussed. Finally, several encapsulation strategies for enhancing the solubility and bioavailability of Uros are summarized. Future research direction includes identifying key genes involved in Uros biotransformation, elucidating the bioactive mechanisms of Uros, and improving their bioavailability. In conclusion, we synthesized biosynthetic pathways and bioactive properties of Uros for better utilization in health management.

Based on the pharmacophore structural characteristics of topoisomerase II (TopoII) inhibitors: (i) planar polyaromatic skeleton; (ii) the cation core; (iii) a groove-binding side chain moiety, 16 urolithin derivatives with O-dialkylaminoalkyl substitutions were designed and synthesized. Most of the synthesized compounds showed improved TopoIIα inhibitory and antiproliferative activities. 20 with the best TopoIIα inhibitory activity also exhibited excellent antiproliferative activity with IC50 values of 0.91 ± 0.01, 1.93 ± 0.04, and 2.84 ± 0.34 μM against the MDA-MB-231, HeLa, and A549 cell lines, being about 12.55, 3.95, and 2.17 times more active than VP-16 (IC50 11.42 ± 0.82, 7.63 ± 0.46, and 6.15 ± 0.43 μM, respectively). Meanwhile, 20 exhibited weak toxicity to normal cells. In addition, 20 exerted anti-migration and anti-invasion activity against MDA-MB-231 cells. Our results supported that 20 might act as TopoIIα inhibitor with the potential to become a new type of antitumor drug lead.

Urolithin A (UA) is a naturally occurring polyphenolic compound.Due to its remarkable efficacy in safeguarding the central nervous system, UA has emerged as a promising candidate for drug development targeting neurodegenerative diseases such as Alzheimer's. However, the source of UA is limited and the activity of UA to inhibit PDE2 needs to be further improved. Therefore, this study will be optimized on the basis of UA to seek PDE2 inhibitors with better activity. In this study, we designed a series of UA derivatives based on 4HTX as the target protein and UA as the lead compound, utilizing the binding crystal structures of 4HTX and BAY60-7550 as references. After thorough screening, we successfully identified the 8-hydroxyl group as the precise site of modification. Utilizing 2-bromo-5-hydroxybenzoic acid as our primary raw material, we synthesized a series of the 8-hydroxyl modified UA. Subsequently, we evaluated the inhibitory activity of these synthesized UA derivatives using a phosphodiesterase assay kit. Ultimately, we screened a total of 34 derivatives; among them, compounds 1f, 1q, 2d, and 2j exhibited significant inhibitory activity against PDE2 with half-maximal inhibitory concentrations of 3.05 μM, 0.67 μM, 0.57 μM, and 4.96 μM, respectively.

Conventional antidepressants exhibit limited efficacy and delayed onset. This study aimed to elucidate the antidepressant effects of urolithin B (UB) and its regulatory role in microglia-mediated hippocampal neuronal dysfunction.

The mouse model of depression was established using both chronic unpredicted stress (CUS) and lipopolysaccharide (LPS) injection. The therapeutic efficacy of UB was assessed through behavioral paradigms. The microglia activation, cellular cytotoxicity and apoptosis levels, and underlying molecular mechanisms were delineated utilizing proteomics analysis, immunofluorescence staining, real-time PCR and Western blotting.

UB efficiently alleviated depression-related behaviors, accompanied by suppressed microglia activation, neuroinflammation, changes of classic activation (M1)/alternative activation (M2) polarization and recovered sirtuin-1 (SIRT1) and forkhead box protein O1 (FOXO1) expression in the hippocampus. Additionally, UB reduced the cytotoxicity and apoptosis of HT22 cells and depression-related phenotypes treated by the cellular supernatant from LPS-incubated BV2 cells, which was mediated by the SIRT1-FOXO1 pathway. The proteomics analysis of the cellular supernatant content revealed abundant secreting proteins among the LPS/UB application.

This study confirmed that microglial SIRT1 mediates UB's antidepressant effects, positioning UB as a promising therapeutic candidate for depression by targeting neuroinflammatory pathways.

Ellagic acid (EA), a widely distributed natural polyphenolic acid existing in many kinds of plant-based foods, undergoes complex physical and chemical transformations during digestion and biotransformation. Particularly, EA is metabolized by gut microbiota and transformed into urolithins in the colon. These metabolites exhibit enhanced bioavailability and bioactivity. This review explores the intricate interactions between EA and gut microbiota, emphasizing their implications for human health. We discuss the role of gut microbiota in EA metabolism, resulting in distinct metabolic phenotypes associated with varying urolithin production profiles. EA and its gut-derived metabolites, urolithins, have been reported to have the potential to modulate the microbial community composition and function of gut microbiota, promoting beneficial bacteria while reducing harmful ones. Furthermore, EA and urolithins exhibit a spectrum of beneficial biological activities, including antioxidant, anti-inflammatory, and anticancer properties, along with enhancements to intestinal barrier function and modulatory effects on metabolic and cardiovascular systems, through molecular mechanisms such as activating Nrf2 and inhibiting NF-κB pathways. The review highlights and compares the potential of EA and its gut microbial metabolites in the prevention and treatment of various diseases. However, further studies are required to elucidate the underlying mechanisms of the interactions between EA and gut microbiota and their health benefits. Continued investigation into EA and its metabolites is essential for advancing our understanding of their role in promoting human health and developing novel therapeutic applications.

The epidemiological assessment of wine consumption usually has been obtained using self-reporting questionnaires. In this study, two metabolomic approaches, targeted and untargeted, were applied to 24-h urine samples from a cohort of La Rioja (Spain) (aged 52-78), comparing moderate and daily wine consumers (20 males and 13 females) without diet intervention, versus non-consumers (8 males and 35 females). Results showed that the non-targeted metabolomics approach has allowed for the annotation of sixteen compounds in 24-h urine samples from regular wine-consumers that were not detected in the urine of non-wine consumers. Additionally, the targeted metabolomics approach showed a wide range of phenol metabolites, mainly hepatic phase-II conjugates, whose concentration was significantly higher in the urine of wine consumers. As a novelty, this study focuses on discovering the main urinary biomarkers of regular wine consumption involving free-living volunteers, without dietary intervention or restrictions that might alter their regular behaviors and lifestyles.

Inflammatory bowel disease (IBD) is characterized by the upregulation of reactive oxygen species (ROS) and dysfunction of gut immune system, and microbiota. The conventional treatments mainly focus on symptom control with medication by overuse of drugs. There is an urgent need to develop a closed-loop strategy that combines in situ monitoring and precise treatment. Herein, we innovatively designed the 'cluster munition structure' theranostic microgels to realize the monitoring and therapy for ulcerative colitis (a subtype of IBD). The superoxide anion specific probe (tetraphenylethylene-coelenterazine, TPC) and ROS-responsive nanogels consisting of postbiotics urolithin A (UA) were loaded into alginate and ion-crosslinked to obtain the theranostic microgels. The theranostic microgels could be delivered to the inflammatory site, where the environment-triggered breakup of the microgels and release of the nanogels were achieved in sequence. The TPC-UA group had optimal results in reducing inflammation, repairing colonic epithelial tissue, and remodeling microbiota, leading to inflammation amelioration and recovery of tight junction between the colonic epithelium, and maintenance of gut microbiota. During the recovery process, the local chemiluminescence intensity, which is proportional to the degree of inflammation, was gradually inhibited. The cluster munition of theranostic microgels displayed promising outcomes in monitoring inflammation and precise therapy, and demonstrated the potential for inflammatory disease management.

Polyphenolic plant extracts have demonstrated anti-inflammatory and anti-catabolic effects in vitro, however their meaningful translation into humans remains elusive. Urolithin A (UA), a gut-derived metabolite of ellagitannins, has shown promise for improving muscle function and metabolic health in rodent models. This study aimed to explore the impact of UA on insulin and anabolic sensitivity in human skeletal muscle cells.

Primary human myogenic cultures were derived from skeletal muscle biopsies of eight healthy adults. After differentiation, myotubes were treated with 0.002, 1 and 50 µM UA or vehicle for 24 h. Cell viability was assessed using a resazurin assay. Basal and insulin-stimulated glucose uptake was measured using tritiated deoxy-D-glucose, whilst amino acid-stimulated protein synthesis was estimated using the surface sensing of translation (SuNSET) technique. Expression of myostatin and glucose transporters was quantified via real-time PCR.

UA treatment at ≤ 50 µM did not compromise cell viability. Treatment with 50 µM UA enhanced both basal- and insulin-stimulated glucose uptake by 21% (P < 0.05) and 24% (P < 0.01), respectively, compared to vehicle and was accompanied by a 1.8-fold upregulation of GLUT4 expression (P < 0.01). 50 µM UA reduced myostatin (MSTN) expression by 14% (P < 0.01) but did not alter amino acid-stimulated global cell protein synthesis.

This study provides evidence of UA's metabolic benefits in primary human myotubes, notably improving basal- and insulin-stimulated glucose uptake and supressing MSTN expression. These findings suggest UA could be an effective nutraceutical for mitigating insulin resistance and warrants further investigation.

Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3 -MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.

For centuries, various species from the genus Alchemilla have been utilized in traditional medicine worldwide. Among them, Alchemilla vulgaris L. (Rosaceae) stands out as a promising herbal drug candidate due to its phytochemicals displaying anti-inflammatory and antioxidant properties.

In our study, we investigated the interaction between the human gut microbiota and lady's mantle herb extract (AV) following the biotransformation of the extract's constituents and their impact on colorectal cancer cells (HT-29) and normal CCD 841 CoN epithelial cells. The A. vulgaris herb metabolites were obtained by incubating the extract (AV) with human fecal slurries from three healthy donors (D1, D2, and D3).

After incubating the AV extract with the human gut microbiota (AVD1-AVD3 samples), thirty-three metabolites were detected and characterized by LC-MS. Among them, one was identified as urolithin C. The AV and AVD1-AVD3 extracts and their metabolites exhibit various levels of antiproliferative and cytotoxic activities against cancer cells. Their biological effect might be linked to the changes and direct activity of bioavailable metabolites. Samples from AVD1, AVD2, and AVD3 increase the lactate dehydrogenase (LDH) released from damaged colon cancer cells in a dose-dependent manner. At 250 μg/mL, AVD1, AVD2, and AVD3 elevated the LDH level by 12.6%, 25.3%, and 30.0%, respectively. The biotransformed samples also showed significantly higher antiproliferative activity than the AV extract. The most active sample from donor 3 (AVD3) reached IC50 = 471 μg/mL.

The differences in anticancer effect might be linked to the changes and direct activity of bioavailable metabolites. The non-transformed AV extract affected neither normal nor cancer colon cells, indicating the beneficial effect of the biotransformation procedure on the anticancer properties of the evaluated extracts. The above results clearly indicate that microbial metabolism is a crucial factor that is potent in altering the biological activity of lady's mantle extract.

Cancer stem cells (CSCs) are responsible for chemoresistance and tumor relapse in many solid malignancies, including lung and ovarian cancer. Ellagic acid (EA), a natural polyphenol, exhibits anticancer effects on various human malignancies. However, its impact and mechanism of action on cancer stem-like cells (CSLCs) are only partially understood. In this study, we evaluated the therapeutic potential and underlying molecular mechanism of EA isolated from tropical mango against CSLCs. Herein, we observed that EA treatment reduces the stem-like phenotypes in cancer cells, thereby lowering the cell survival and self-renewal potential of ovarian and lung CSLCs. Additionally, EA treatment limits the populations of lung and ovarian CSLCs characterized by CD133+ and CD44+CD117+, respectively. A mechanistic investigation showed that EA treatment induces ROS generation by altering mitochondrial dynamics, causing changes in the levels of Drp1 and Mfn2, which lead to an increased level of accumulation of DNA damage and eventually trigger apoptosis in CSLCs. Moreover, pretreatment with EA sensitizes CSLCs to cisplatin treatment by enhancing DNA damage accumulation and impairing the DNA repair ability of the CSLCs. Furthermore, EA pretreatment significantly reduces cisplatin-induced mutation frequency and improves drug retention in CSLCs, potentially suppressing the development of acquired drug resistance. Taken together, our results demonstrate an unreported finding that EA inhibits CSLCs by targeting mitochondrial function and triggering apoptosis. Thus, EA can be used either alone or in combination with other chemotherepeutic drugs for the management of cancer.

Dietary tannins can affect rumen microbiota and enteric fermentation to mitigate methane emissions, although such effects have not yet been fully elucidated. We tested two subunits of hydrolyzable tannins named gallic acid (GA) and ellagic acid (EA), alone (75 mg/g DM each) or combined (150 mg/g DM in total), using the Rusitec system. EA and EA+GA treatments decreased methane production, volatile fatty acids, nutrient degradation, relative abundance of Butyrivibrio fibrisolvens, Fibrobacter succinogenes, Ruminococcus flavefaciens but increased Selenomonas ruminantium. EA and EA+GA increased urolithins A and B. Also, EA and EA+GA reduced bacterial richness, with limited effects on archaeal richness. For bacteria, Megasphaera elsdenii was more abundant after EA and EA+GA, while Methanomethylophilaceae dominated archaea in all treatments. EA was more effective than GA in altering rumen microbiota and fermentation but GA did not reduce VFA and nutrient degradation. Thus, dietary supplementation of EA-plant extracts for ruminants may be considered to mitigate enteric methane, although a suitable dosage must be ensured to minimize the negative effects on fermentation.

Lung cancer is one of the most frequently diagnosed cancers and non-small-cell lung cancer (NSCLC) poses major diagnoses. Urolithin A (UA) is a natural compound produced by the gut microbiota through the metabolism of polyphenol ellagitannins (ETs) and ellagic acid (EA), which has been found to inhibit epithelial-mesenchymal transition (EMT) in lung cancer cell lines. However, the mechanism of UA function in NSCLC remains elusive.

This study aimed to investigate the potential effectiveness of UA in NSCLC therapeutic and uncovering its underlying mechanisms.

Effects of UA treatment, TMSB10 gene knockdown or overexpression on NSCLC cell phenotype were evaluated by availability, transwell assays. The downstream factors and pathways of UA were investigated by proteomics. TMSB10 expression in NSCLC tissues was detected by bioinformatics analysis as well as immunohistochemistry. Confocal imaging, GST pull-down and western blotting investigated the mechanism of UA induced TMSB10 degradation.

In the present study, we demonstrated that UA shows an inhibitory role in NSCLC cell proliferation, migration, and invasion. This inhibition is attributed to the accelerated degradation of TMSB10, a biomarker among various cancers, via the autophagy-lysosome pathway. Additionally, knocked down of TMSB10 showed a similar phenotype with UA treatment. The reduction of TMSB10 protein level following decreased ATP level inhibits the F-actin formation for cell migration, thereby disrupting the equilibrium between G-actin-TMSB10 and G-actin-ATP interactions in A549 cells.

Our results reveal that UA is potential for NSCLC therapeutics through reducing the protein level of TMSB10 to deformation the F-actin.

The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer's and Parkinson's). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome-gut-organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota's role in disease development.

Ancient humans used dietary plants and herbs to treat disease and to pursue eternal life. Today, phytochemicals in dietary plants and herbs have been shown to be the active ingredients, some of which have antiaging and longevity-promoting effects. Here, we summarize 210 antiaging phytochemicals in dietary plants and herbs, systematically classify them into 8 groups. We found that all groups of phytochemicals can be categorized into six areas that regulate organism longevity: ROS levels, nutrient sensing network, mitochondria, autophagy, gut microbiota, and lipid metabolism. We review the role of these processes in aging and the molecular mechanism of the health benefits through phytochemical-mediated regulation. Among these, how phytochemicals promote longevity through the gut microbiota and lipid metabolism is rarely highlighted in the field. Our understanding of the mechanisms of phytochemicals based on the above six aspects may provide a theoretical basis for the further development of antiaging drugs and new insights into the promotion of human longevity.

Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 μM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

"Personalized nutrition" aims to establish nutritional strategies to improve health outcomes for non-responders. However, it is utopian since most people share similar nutritional requirements. "Precision health," encompassing lifestyles, may be more fitting. Dietary (poly)phenols are "healthy" but non-nutritional molecules (thus, we can live without them). The gut microbiota influences (poly)phenol effects, producing metabolites with different activity than their precursors. Furthermore, producing distinctive metabolites, like urolithins, lunularin, and equol, leads to the term "polyphenol-related gut microbiota metabotypes," grouping individuals based on a genuine microbial metabolism of ellagic acid, resveratrol, and isoflavones, respectively. Additionally, (poly)phenols exert prebiotic-like effects through their antimicrobial activities, typically reducing microbial diversity and modulating microbiota functionality by impacting its composition and transcriptomics. Since the gut microbiota perceives (poly)phenols as a threat, (poly)phenol effects are mostly a consequence of microbiota adaptation through differential (poly)phenol metabolism (e.g., distinctive reductions, dehydroxylations, etc.). This viewpoint is less prosaic than considering (poly)phenols as essential nutritional players in human health, yet underscores their health significance in a coevolutionary partnership with the gut microbiota. In the perspective on the gut microbiota and (poly)phenols interplay, microbiota metabotypes could arbiter health effects. An innovative aspect is also emphasized: modulating the interacting microbial networks without altering the composition.

Urolithin families are gut-microbial metabolites of ellagic acid (EA). Although urolithin A (UA) and urolithin B (UB) were reported to have antiproliferative activities in cancer cells, the role and related mechanisms of urolithin C (UC) in colorectal cancer (CRC) have not yet been clarified. In this study, we assess the antitumor activities of UC in vitro and in vivo and further explore the underlying mechanisms in CRC cell lines. We found that UC inhibited the proliferation and migration of CRC cells, induced apoptosis, and arrested the cell cycle at the G2/M phase in vitro, and UC inhibited tumor growth in a subcutaneous transplantation tumor model in vivo. Mechanically, UC blocked the activation of the AKT/mTOR signaling pathway by decreasing the expression of Y-box binding protein 1(YBX1). The AKT agonist SC79 could reverse the suppression of cell proliferation in UC-treated CRC cells. In conclusion, our research revealed that UC could prevent the progression of CRC by blocking AKT/mTOR signaling, suggesting that it may have potential therapeutic values.

The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.

Cancer remains a global health challenge, necessitating the exploration of novel therapeutic agents. Current treatment options are unable to overwhelm and cure the cancer burden. Hence, identifying new bioactive molecular entities with potent anticancer activity is the need of the hour. Ellagitannin Geraniin (GN) is one such evidence-based novel bioactive molecular entity (BME) available from different natural sources that can effectively combat cancer. This narrative review attempts to investigate the potential of BME-GN from 2005 to 2023 as an efficient molecular anti-cancer therapeutic against diverse cancers. We provide information on GN's pharmacological advantages, metabolite profile, and capacity to modulate multiple molecular targets involved in the hallmarks of cancer. Using the search terms "Geraniin," "Gallic acid," "Ellagitannin," "pharmacological properties," "health," "antioxidant," "apoptosis," "disease management," "anti-proliferative," "in vitro," "anti-inflammatory," "anti-angiogenic," "in vivo," and "clinical trials," We searched the scientific literature using Scopus, Web of Science, Google Scholar, and PubMed. We removed publications that included overlap or equivalent content and used the most recent review on each issue as our primary reference. From an initial pool of 430 articles, 52 studies met the search criteria. These studies collectively provide substantial in vitro, in vivo, and clinical evidence of GN's potential to combat diverse cancers. Mechanistic insights revealed its involvement in fostering apoptosis, anti-inflammatory, and modulation of key signalling pathways implicated in the hallmarks of cancer. GN's pleiotropic pharmacological and molecular therapeutic properties strongly suggest its potential as a promising anticancer agent.

Pomegranate (Punica granatum L.) is a multipurpose dietary and medicinal plant known for its ability to promote various health benefits. Metabolic syndrome (MetS) is a complex metabolic disorder driving health and socioeconomic challenges worldwide. It may be characterized by insulin resistance, abdominal obesity, hypertension, and dyslipidemia. This study aims to conduct a review of pomegranate's effects on MetS parameters using a mechanistic approach relying on pre-clinical studies. The peel, juice, roots, bark, seeds, flowers, and leaves of the fruit present several bioactive compounds that are related mainly to anti-inflammatory and antioxidant activities as well as cardioprotective, antidiabetic, and antiobesity effects. The use of the juice extract can work as a potent inhibitor of angiotensin-converting enzyme activities, consequently regulating blood pressure. The major bioactive compounds found within the fruit are phenolic compounds (hydrolysable tannins and flavonoids) and fatty acids. Alkaloids, punicalagin, ellagitannins, ellagic acid, anthocyanins, tannins, flavonoids, luteolin, and punicic acid are also present. The antihyperglycemia, antihyperlipidemia, and weight loss promoting effects are likely related to the anti-inflammatory and antioxidant effects. When considering clinical application, pomegranate extracts are found to be frequently well-tolerated, further supporting its efficacy as a treatment modality. We suggest that pomegranate fruit, extract, or processed products can be used to counteract MetS-related risk factors. This review represents an important step towards exploring potential avenues for further research in this area.

Kakadu plum (Terminalia ferdinandiana) (KP) is an indigenous fruit used as a functional ingredient in powdered form. Three KP doses (1, 2.5 and 5 g) were digested in a dynamic in vitro gut digestion model over 48 h. Faecal water digests from the colonic reactors were assessed for total soluble polyphenols (TSP), ferric reducing antioxidant power (FRAP), phenolic metabolites and short-chain fatty acids (SCFAs). Effects of digests on cell viability were tested against Caco-2 intestinal and HepG2 hepatic cells. All doses of KP fermentation produced castalagin, corilagin, chebulagic acid, chebulinic acid, and gallic acid. TSP and FRAP significantly increased in 5 g KP digests at 0 and 48 h of fermentation. SCFA concentrations significantly increased after 48 h. Cytotoxic effects of 2.5 and 5 g KP digests diminished significantly after 12 h. Overall, colonic fermentation increased antioxidant activity and polyphenolic metabolites of 5 g KP powder for 48 h.

Some tannin-rich plants such as Combretum mucronatum and Phyllanthus urinaria are widely used in Africa for the control of parasitic nematodes in both humans and livestock. Tannins have been recognized as an alternative source of anthelmintic therapies, and hence, recent studies have focused on both the hydrolyzable and condensed tannins. These groups of compounds, however, have poor oral bioavailability and are metabolized by gut microbiota into lower molecular weight compounds. The role of these metabolites in the anthelmintic activities of tannins has not been explored yet. This study investigated the effects of fecal metabolism on the anthelmintic potential of procyanidin C1 (PC1) and geraniin and the tannin-enriched extracts of C. mucronatum (CML) and P. urinaria (PUH), which contain these compounds, respectively. Metabolites were formed by anaerobic fermentation of the test compounds and extracts in a fresh human fecal suspension for 0 h, 4 h, and 24 h. Lyophilized samples were tested in vitro against hookworm larvae and whipworm (Trichuris trichiura) larvae obtained from naturally infected human populations in Pru West District, Bono East Region, Ghana, and against the wildtype strain of Caenorhabditis elegans (L4). Both extracts and compounds in the undegraded state exhibited concentration-dependent inhibition of the three nematodes. Their activity, however, significantly decreased upon fecal metabolism. Without fermentation, the proanthocyanidin-rich CML extract was lethal against hookworm L3 (LC50 = 343.5 μg/mL, 95% confidence interval (CI) = 267.5-445.4), T. trichiura L1 (LC50 = 230.1 μg/mL, CI = 198.9-271.2), and C. elegans (LC50 = 1468.1 μg/mL, CI = 990.3-1946.5). PUH, from which the ellagitannin geraniin was isolated, exhibited anthelmintic effects in the unfermented form with LC50 of 300.8 μg/mL (CI = 245.1-374.8) against hookworm L3 and LC50 of 331.6 μg/mL (CI = 290.3-382.5) against T. trichiura L1, but it showed no significant activity against C. elegans L4 larvae at the tested concentrations. Similarly, both compounds, procyanidin C1 and geraniin, lost their activity when metabolized in fecal matter. The activity of geraniin at a concentration of 170 μg/mL against C. elegans significantly declined from 30.4% ± 1.8% to 14.5% ± 1.5% when metabolized for 4 h, whereas that of PC1 decreased from 32.4% ± 2.3% to 8.9% ± 0.9% with similar treatment. There was no significant difference between the anthelmintic actions of metabolites from the structurally different tannin groups. The outcome of this study revealed that the intact bulky structure of tannins (hydrolyzable or condensed) may be required for their anthelmintic action. The fermented products from the gut may not directly contribute toward the inhibition of the larvae of soil-transmitted helminths.

To observe the therapeutic effects of urolithin A (UA) on respiratory syncytial virus (RSV)-induced lung infection in neonatal mice and explore the underlying mechanisms.

Babl/c mice (5-7 days old) were subjected to nasal instillation of RSV and received intraperitoneal injection of saline or 2.5, 5 and 10 mg/kg UA 2 h after the infection and then once daily for 2 weeks. Bronchoalveolar lavage fluid (BALF) was then collected for detection of inflammatory cells and mediators, and lung pathology was evaluated with HE staining. RSV-infected BEAS-2B cells were treated with 2.5, 5 or 10 µmol/ L UA. Inflammatory factors, cell viability, apoptosis and autophagy were analyzed using ELISA, CCK-8 assay, TUNEL staining, flow cytometry, Western blotting and immunofluorescence staining. The cellular expressions of miR-136 and Sirt1 mRNAs were detected using qRT-PCR. A dual-luciferase reporter system was used to verify the binding between miR-136 and Sirt1.

In neonatal Babl/c mice, RSV infection caused obvious lung pathologies, promoted pulmonary cell apoptosis and LC3-Ⅱ/Ⅰ, Beclin-1 and miR-136 expressions, and increased the total cell number, inflammatory cells and factors in the BALF and decreased p62 and Sirt1 expressions. All these changes were alleviated dose-dependently by UA. In BEAS-2B cells, RSV infection significantly increased cell apoptosis, LC3B-positive cells and miR-136 expression and reduced Sirt1 expression (P<0.01), which were dose-dependently attenuated by UA. Dual-luciferase reporter assay confirmed the binding between miR-136 and Sirt1. In RSV-infected BEAS-2B cells with UA treatment, overexpression of miR-136 and Ex527 treatment both significantly increased the inflammatory factors and cell apoptosis but decreased LC3B expression, and these changes were further enhanced by their combined treatment.

UA ameliorates RSV-induced lung infection in neonatal mice by activating miR-136-mediated Sirt1 signaling pathway.

Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.

This work was to investigate the effect of four prebiotic saccharides gum arabic (GA), fructooligosaccharide (FOS), konjac glucomannan (KGM), and inulin (INU) incorporation on the encapsulation efficiency (EE), physicochemical stability, and in vitro digestion of urolithin A-loaded liposomes (UroA-LPs). The regulation of liposomes on gut microbiota was also investigated by in vitro colonic fermentation. Results indicated that liposomes coated with GA showed the best EE, bioaccessibility, storage and thermal stability, the bioaccessibility was 1.67 times of that of UroA-LPs. The UroA-LPs coated with FOS showed the best freeze-thaw stability and transformation. Meanwhile, saccharides addition remarkably improved the relative abundance of Bacteroidota, reduced the abundances of Proteobacteria and Actinobacteria. The UroA-LPs coated with FOS, INU, and GA exhibited the highest beneficial bacteria abundance of Parabacteroides, Monoglobus, and Phascolarctobacterium, respectively. FOS could also decrease the abundance of harmful bacteria Collinsella and Enterococcus, and increase the levels of acetic acid, butyric acid and iso-butyric acid. Consequently, prebiotic saccharides can improve the EE, physicochemical stability, gut microbiota regulation of UroA-LPs, and promote the bioaccessibility of UroA, but the efficiency varied based on saccharides types, which can lay a foundation for the application of UroA in foods industry and for the enhancement of its bio-activities.

Urolithin A is a gut metabolite of ellagitannins and reported to confer health benefits, e.g., by increased clearance of damaged mitochondria by macroautophagy or curbed inflammation. One targeted cell type are macrophages, which are plastic and able to adopt pro- or anti-inflammatory polarization states, usually assigned as M1 and M2 macrophages, respectively. This flexibility is tightly coupled to characteristic shifts in metabolism, such as increased glycolysis in M1 macrophages, and protein expression upon appropriate stimulation. This study aimed at investigating whether the anti-inflammatory properties of U: rolithin A may be driven by metabolic alterations in cultivated murine M1(lipopolysaccharide) macrophages. Expression and extracellular flux analyses showed that urolithin A led to reduced il1β, il6, and nos2 expression and boosted glycolytic activity in M1(lipopolysaccharide) macrophages. The pro-glycolytic feature of UROLITHIN A: occurred in order to causally contribute to its anti-inflammatory potential, based on experiments in cells with impeded glycolysis. Mdivi, an inhibitor of mitochondrial fission, blunted increased glycolytic activity and reduced M1 marker expression in M1(lipopolysaccharide/UROLITHIN A: ), indicating that segregation of mitochondria was a prerequisite for both actions of UROLITHIN A: . Overall, we uncovered a so far unappreciated metabolic facet within the anti-inflammatory activity of UROLITHIN A: and call for caution about the simplified notion of increased aerobic glycolysis as an inevitably proinflammatory feature in macrophages upon exposure to natural products.

In recent years, an increasing trend has been observed in the consumption of specific polyphenols, such as flavonoids and phenolic acids, derived from green tea, berries, and other similar sources. These compounds are believed to alleviate oxidative stress and inflammation resulting from exercise, potentially enhancing athletic performance. This systematic review critically examines the role of polyphenol supplementation in improving aerobic endurance among athletes and individuals with regular exercise habits. The review involved a thorough search of major literature databases, including PubMed, Web of Science, SCOPUS, SPORTDiscus, and Embase, covering re-search up to the year 2023. Out of 491 initially identified articles, 11 met the strict inclusion criteria for this review. These studies specifically focused on the incorporation of polyphenols or polyphenol-containing complexes in their experimental design, assessing their impact on aerobic endurance. The methodology adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the risk of bias was evaluated using the Cochrane bias risk assessment tool. While this review suggests that polyphenol supplementation might enhance certain aspects of aerobic endurance and promote fat oxidation, it is important to interpret these findings with caution, considering the limited number of studies available. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023453321.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC50 value of 0.07 μM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors.

Colorectal cancer (CRC) is the world's second most common gastrointestinal malignancy. Preventing tumor cell proliferation and dissemination is critical for patient survival. Polyphenols have a variety of health advantages and can help prevent cancer. The current study examined different cellular activities of the gut-microbiota metabolite urolithin A (UA) on several colon cancer cell lines. The results revealed that UA suppressed cell growth in a dose- and time-dependent manner. In the current investigation, UA substantially affected cell migration in the wound-healing experiment and greatly decreased the number of colonies generated in each CRC cell culture. UA decreased cellular migration in CRC cells 48 h after treatment, which was significant (p < .001) compared to the migration rate in untreated cells. When compared to untreated cells, UA slowed the process of colony formation by reducing the number of colonies or altering their morphological shape. The western blot analysis investigation revealed that UA inhibits cellular metastasis by lowering the expression levels of matrix metalloproteinases 1 and 2 (MMP1 and MMP2) by more than 43% and 41% (p < .001) in HT29, 28% and 149% (p < .001) in SW480, and 90% and 74% (p < .001) in SW620, respectively, at a 100 µM dosage of UA compared to the control. Surprisingly, at a 100 µM dosage of UA, the expression levels of the tissue inhibitor of metalloproteinases 1 (TIMP1) were elevated in HT29, SW480, and SW620 cells treated with 100 µM of UA by more than 89%, 57%, and 29%, respectively. Our findings imply that UA has anticancer properties and might be used therapeutically to treat CRC. The findings provided the first indication of the influence of UA on cellular migration and metastasis in colon cancer cells. All of these data showed that UA might be used as an adjuvant therapy in the treatment of various forms of CRC.

Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plant's aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 - 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with NG-nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl2. Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca2+ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo. It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract.

The intestine tract is a vital site for the body to acquire nutrients, serving as the largest immune organ. Intestinal health is crucial for maintaining a normal physiological state. Abundant microorganisms reside in the intestine, colonized in a symbiotic manner. These microorganisms can generate various metabolites that influence host physiological activities. Microbial metabolites serve as signaling molecules or metabolic substrates in the intestine, and some intestinal microorganisms act as probiotics and promote intestinal health. Researches on host, probiotics, microbial metabolites and their interactions are ongoing. This study reviews the effects of gut bacteria and their metabolites on intestinal health to provide useful references for animal husbandry.

The involvement of malfunctioning glutamate systems in various central nervous system (CNS) disorders is widely acknowledged. Urolithin B, known for its neuroprotective and antioxidant properties, has shown potential as a therapeutic agent for these disorders. However, little is known about its protective effects against glutamate-induced toxicity in PC12 cells. Therefore, in this study, for the first time we aimed to investigate the ability of Urolithin B to reduce the cytotoxic effects of glutamate on PC12 cells.

Different non-toxic concentrations of urolithin B were applied to PC12 cells for 24 h before exposure to glutamate (10 mM). The cells were then analyzed for cell viability, intracellular reactive oxygen species (ROS), cell cycle arrest, apoptosis, and the expression of Bax and Bcl-2 genes.

The results of MTT assay showed that glutamate at a concentration of 10 mM and urolithin B at a concentration of 114 μM can reduce PC12 cell viability by 50%. However, urolithin B at non-toxic concentrations of 4 and 8 μM significantly reduced glutamate-induced cytotoxicity (p < 0.01). Interestingly, treatment with glutamate significantly enhanced the intracellular ROS levels and apoptosis rate in PC12 cells, while pre-treatment with non-toxic concentrations of urolithin B significantly reduced these cytotoxic effects. The results also showed that pre-treatment with urolithin B can decrease the Bax (p < 0.05) and increase the Bcl-2 (p < 0.01) gene expression, which was dysregulated by glutamate.

Taken together, urolithin B may play a protective role through reducing oxidative stress and apoptosis against glutamate-induced toxicity in PC12 cells, which merits further investigations.

Clostridioides difficile is a Gram-positive, anaerobic, spore-forming bacterium responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activity, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.IMPORTANCETherapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.