This study demonstrated the potential of ellagic acid-rich fruit byproducts, particularly pomegranate peel, as functional ingredients. During digestion, pomegranate peel exhibited superior antioxidant activity owing to its high phenolic content. Twenty-four phenolic compounds were released, with pomegranate peel maintaining higher bioactivity than chestnut and walnut peels. In vitro colonic fermentation with urolithin A-producing microbiota revealed that pomegranate peel stimulated butyrate synthesis (11.94 mM) and urolithin A production (6.31 μM), highlighting the prebiotic role of ellagic acid. Gut microbiota modulation by pomegranate peel increased Bacteroides and Bifidobacterium (a potential key for ellagic acid conversion) while suppressing Alistipes. Functional analyses confirmed its effect on carbohydrate, lipid, and amino acid metabolism. In contrast, chestnut and walnut peels exhibited lower bioactivity and microbial selectivity. These findings positioned pomegranate peel as a superior ingredient for gut health and microbial metabolism optimization, offering targeted nutritional benefits over conventional byproducts.

Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.

The relationship between diet and human physical and mental health is highly interconnected and has been significantly correlated with the occurrence of various diseases, including neurological disorders, cancer, and chronic inflammatory diseases. Moreover, diet has been demonstrated to play a pivotal role in governing gut microbiota composition, making it one of the most influential factors. The diet is crucial in connecting humans and their gut microorganisms. The nutrients ingested supply energy to the body and serve as substrates for the metabolic processes of the gut microorganisms. Consequently, the gut flora and their metabolites reciprocally impact the host's metabolism, thereby influencing the physiological state of the human body. Extensive investigations on human and mouse models have revealed that diet potentially underlies various effects on human health and disease.

The intestinal barrier serves as a boundary between the mucosal immune system in the lamina propria and the external environment of the intestinal lumen, which contains a diverse array of microorganisms and ingested environmental factors, including pathogens, food antigens, toxins, and other foreign substances. This barrier has a central role in regulating the controlled interaction between luminal factors and the intestinal immune system. Disruptions of intestinal epithelial cells, which serve as a physical barrier, or the antimicrobial peptides and mucins they produce, which act as a chemical barrier, can lead to a leaky gut. In this state, the intestinal wall is unable to efficiently separate the intestinal flora and luminal contents from the intestinal immune system. The subsequent activation of the immune system has an important role in the pathogenesis of inflammatory bowel disease, as well as in metabolic dysfunction-associated steatohepatitis, primary sclerosing cholangitis, and colorectal cancer. Dysregulated intestinal barrier integrity has also been described in patients with chronic inflammatory diseases outside the gastrointestinal tract, including rheumatoid arthritis and neurodegenerative disorders. Mechanistic studies of barrier dysfunction have revealed that the subsequent local activation and systemic circulation of activated immune cells and the cytokines they secrete, as well as extracellular vesicles, promote proinflammatory processes within and outside the gastrointestinal tract. In this Review, we summarise these findings and highlight several new therapeutic concepts currently being developed that attempt to control inflammatory processes via direct or indirect modulation of intestinal barrier function.

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.

The Type VI secretion system (T6SS) is a key virulence mechanism utilized by many Gram-negative bacteria to mediate the microbial competition and host pathogenesis. Despite the identification of diverse T6SS effectors targeting eukaryotic or prokaryotic cells, the trans-kingdom T6SS effectors that simultaneously target both eukaryotic and prokaryotic cells remain rarely reported. In this study, it is demonstrated that Yersinia pseudotuberculosis (Yptb) T6SS secretes a DNase effector, TkeA, which induces apoptosis in host cells. The translocation of TkeA into host cells causes nuclear DNA damage. This, in turn, activates the DNA-sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. The activation of the cGAS-STING pathway by TkeA subsequently triggers apoptosis in host cells via extrinsic pathways, with tumor necrosis factor (TNF) signaling playing a critical role. Additionally, TkeA enhances bacterial competition by targeting rival bacteria, thereby promoting host colonization. These findings reveal that the transkingdom T6SS effector TkeA executes a "one weapon, two battlefields" strategy, acting as a trans-kingdom effector that enhances interbacterial competition while inducing apoptosis in host cells through the activation of the cGAS-STING-TNF axis. This highlights a previously unrecognized dimension of bacterial virulence strategies and expands the understanding of host-pathogen interactions involving T6SS effectors.

Neuroinflammation is a key factor in age-related cognitive decline and memory impairment. UAS03, a potent synthetic analogue of Urolithin-A, has demonstrated anti-inflammatory and antioxidant properties. This investigation examined the neuroprotective effect of UAS03 on lipopolysaccharide (LPS) induced neuroinflammation, and its associated cognitive impairments, memory deficits, and depression-like behaviors. Intracerebroventricular administration of LPS (12 μg/kg) was performed to induce neuroinflammation in mice, followed by a 7 day treatment with UAS03 at 10 and 30 mg/kg doses. Mice were evaluated for depressive and anxiety-like behavior, spatial memory, and learning functions using a series of neurobehavioral test paradigms. Histopathological and molecular analyses were conducted using hematoxylin-eosin and cresyl violet staining, immunohistochemistry, ELISA, and Western blotting techniques. We have found that, UAS03 significantly enhanced cognitive and memory functions impaired by LPS while concurrently reducing depressive symptoms. Furthermore, the compound attenuated neuronal damage and decreased the expression of IBA-1 and GFAP in hippocampal region. Through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, UAS03 effectively mitigated markers of oxidative stress and reduced levels of pro-inflammatory factors, including IL-1β, TNF-α, and COX-2. Cumulatively, this study provides compelling evidence that UAS03 exerts neuroprotective effects by regulating essential pathways involved in anti-inflammatory and neuroprotective mechanisms, suggesting its potential as a preventative measure against age-related cognitive decline and memory impairments associated with neuroinflammation.

Common gastrointestinal (GI) symptoms such as abdominal pain, indigestion, and constipation affect a significant portion of the global population and can substantially impair quality of life. Despite these widespread issues, research specifically investigating the effects of walnuts on gut function and GI symptoms remain limited.

This study investigates the effects of walnuts on gastrointestinal symptoms in healthy adults.

An experimental baseline-end study with an equivalent group design was employed.

The experimental group consumed 42 grams of walnuts daily, and their gastrointestinal symptoms were compared with those of a control group that did not consume walnuts over a 3-week period.

Sixty university students were recruited as volunteer subjects, consisting of 30 males and 30 females.

Participants were randomly assigned to either an experimental group or a control group.

The independent variable was walnut consumption, and the dependent variable was gastrointestinal health, assessed using the Gastrointestinal Symptom Rating Scale (GSRS) and a qualitative questionnaire to collect participants' perceived changes in GI symptoms.

A t-test with a p-value of less than 0.05 and verbatim analysis were utilized.

This mixed-methods study provides evidence for the beneficial effects of walnuts in promoting normal digestive function.

The study provides alternative evidence for the beneficial effects of walnuts in promoting normal digestive function.

Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.

Ulcerative colitis (UC) is characterized clinically by intestinal inflammation and gut microbiota dysbiosis. The consumption of biologics, although effective in inflammation control, may lead to adverse effects and is inconvenient for at-home administration. Goat milk-derived extracellular vesicles (GMEVs) have been proposed as a supplement to prevent intestinal inflammation. However, their therapeutic potential for colitis remains elusive. This study aimed to explore the preventive effect of GMEVs on colitis and its underlying mechanisms through the microbiota-immune axis using a dextran sodium sulfate (DSS)-induced colitis mouse model. We found that a pre-treatment of 20 mg/kg/d GMEVs effectively prevented body weight loss, colon shortening, the depletion of colonic goblet cells, and the disappearance of crypts, while enhancing the intestinal mucosal barrier. Consistent with these phenotypes, GMEV pre-treatment increased levels of IL-22 and IL-10 and decreased levels of IL-1β, TNF-α, IL-6, and iNOS. However, GMEVs themselves had no effect on normal mice. Paralleling the alleviation of intestinal inflammation, GMEV pre-treatment also restored the reduction in unclassified Muribaculaceae, Dubosiella, and Lactobacillus and suppressed the expansion of Alistipes and Proteobacteria following DSS treatment. Additionally, GMEV intake significantly downregulated the expression of proteins in the NF-κB signaling pathway induced by DSS. In summary, GMEVs could prevent colitis by regulating intestinal inflammation, the intestinal mucosal barrier, gut microbiota, organ damage, and the immune microenvironment. This study demonstrated that GMEVs have potential application prospects for UC prevention.

This study aimed at investigating the effects of pomegranate juice (POMJ) consumption on inflammatory biomarkers and gene expression in patients with inflammatory bowel disease (IBD) in clinical remission. In this randomized, placebo-controlled trial, 16 subjects with IBD in remission consumed POMJ or placebo for 12 weeks. POMJ consumption significantly reduced fecal calprotectin (FC) and plasma endotoxin levels. Transcriptomic analysis of peripheral blood mononuclear cells revealed upregulation of genes involved in mucosal immunity, including aryl hydrocarbon receptor (AHR), neutrophil cytosolic factor 4 (NCF4), and nuclear factor, interleukin 3 regulated (NFIL3). Urolithin metabotypes were predominantly of the B type, associated with intestinal dysbiosis. No significant changes were observed in serum inflammatory markers or colonic mucosal cytokine expression. POMJ consumption reduced markers of intestinal inflammation and modulated gene expression related to mucosal immunity and barrier function in patients with IBD. These findings suggest the potential of POMJ as a beneficial dietary intervention for maintaining remission in IBD, highlighting the promise of targeted nutritional strategies in managing chronic inflammatory conditions. Further research is needed to elucidate the long-term clinical implications of these molecular changes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03000101.

The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host-microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1-Nrf2 PPI inhibitors. Comprehensive structure-activity relationship (SAR) exploration identified compound 19 as the optimal inhibitor with an IC50 of 0.55 μM for disrupting the Keap1-Nrf2 interaction and a Kd of 0.50 μM for binding to Keap1. Further studies demonstrated that 19 effectively activated the Nrf2-regulated cytoprotective system and provided protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in both in vitro and in vivo models. These findings highlight the potential of β-amino acid substituted naphthalene sulfonamide Keap1-Nrf2 inhibitor 19 as a prospective therapeutic agent for UC via Keap1 targeting.

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.

Bacteroides is a crucial mucosal symbiotic bacterium in mammals, with Bacteroides thetaiotaomicron (B. thetaiotaomicron) being particularly noteworthy as a glyco-specialist due to its significant nutritional impact. However, the potential effects of B. thetaiotaomicron on host health remain underexplored.

This study aimed to investigate the patterns of microbial community changes and the molecular mechanisms mediated by microbial metabolites in alleviating piglet diarrhea through B. thetaiotaomicron intervention.

Cold stress was induced in piglets to trigger stress-induced diarrhea. The control group and B group were administered a blank medium and 1 × 108 CFU of B. thetaiotaomicron, respectively, on days 1, 3, and 5. The diarrhea rate and growth performance of the piglets were recorded during the experimental period. Based on 16S rRNA gene amplicon sequencing, microbial ecological networks analysis, and metabolomics analysis, the composition and changes of the colonic microbiota and metabolites were analyzed. The antibacterial capacity and anti-inflammatory molecular mechanisms of B. thetaiotaomicron metabolites were analyzed through in vitro antibacterial assays and inflammatory cell models.

B. thetaiotaomicron administration alleviated diarrhea and improved the growth performance of piglets. It modulated the composition and interactions of the intestinal microbiota, with microbial metabolites primarily enriched in the tryptophan metabolism pathway-especially indole and its derivatives, which were closely associated with host phenotypes. In vitro co-culture experiments showed that B. thetaiotaomicron metabolites inhibited the growth of pathogenic bacteria. Further experiments demonstrated that these metabolites, including indole, enhanced epithelial barrier function and attenuated TNF-α-induced inflammation and apoptosis in Caco-2 cells, highlighting the involvement of the AHR-Nrf2 signaling pathway in mediating these protective effects.

In conclusion, this study offers a theoretical framework for understanding the role of the symbiotic bacterium B. thetaiotaomicron in the gut microbiota ecosystem during diarrhea and its interactions with the host's intestinal tract.

This review addresses critical gaps in knowledge and provides a literature overview of the molecular pathways connecting gut microbiota dysbiosis to increased intestinal permeability (commonly referred to as "leaky gut") and its contribution to metabolic disorders. Restoring a healthy gut microbiota holds significant potential for enhancing intestinal barrier function and metabolic health. These interventions offer promising therapeutic avenues for addressing leaky gut and its associated pathologies in metabolic syndrome.

In metabolic disorders such as obesity and type 2 diabetes (T2D), beneficial microbes such as those producing short-chain fatty acids (SCFAs) and other key metabolites like taurine, spermidine, glutamine, and indole derivatives are reduced. Concurrently, microbes that degrade toxic metabolites such as ethanolamine also decline, while proinflammatory, lipopolysaccharide (LPS)-enriched microbes increase. These microbial shifts place a higher burden on intestinal epithelial cells, which are in closest proximity to the gut lumen, inducing detrimental changes that compromise the structural and functional integrity of the intestinal barrier. Such changes include exacerbation of tight junction protein (TJP)s dysfunction, particularly through mechanisms such as destabilization of zona occludens (Zo)-1 mRNA or post-translational modifications. Emerging therapeutic strategies including ketogenic and Mediterranean diets, as well as probiotics, prebiotics, synbiotics, and postbiotics have demonstrated efficacy in restoring beneficial microbial populations, enhancing TJP expression and function, supporting gut barrier integrity, reducing leaky gut and inflammation, and ultimately improving metabolic disorders. This review summarizes the mechanisms by which gut microbiota contribute to the development of leaky gut and inflammation associated with metabolic syndrome. It also explores strategies for restoring gut microbiota balance and functionality by promoting beneficial microbes, increasing the production of beneficial metabolites, clearing toxic metabolites, and reducing the proportion of proinflammatory microbes. These approaches can alleviate the burden on intestinal epithelial cells, reduce leaky gut and inflammation, and improve metabolic health.

Fluxapyroxad, the most extensively utilized succinate dehydrogenase inhibitor (SDHI) fungicide, lacks comprehensive research on potential risks associated with chronic toxicity. To investigate its effects on chronic colonic inflammation and elucidate the underlying mechanisms, a mouse model was employed to assess oral exposure to fluxapyroxad at no observed adverse effect level (NOEL) for 13 weeks, in vitro and in silico models were utilized as well. The results revealed reduced body weight gain, colon length reduction, crypt damage, goblet cell loss in the colon, impaired intestinal barrier integrity, and an elevation of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α following fluxapyroxad exposure in mice. These findings suggested that fluxapyroxad induced chronic colonic inflammation. Furthermore, fluxapyroxad decreased interleukin 22 levels and antibacterial peptide secretion by inhibiting Aryl hydrocarbon receptors (AhR) activation, which was confirmed in vitro experiments. Molecular docking analysis indicated that fluxapyroxad spontaneously formed halogen bonds and bound hydrophobic interactions with AhR, which might act as an AhR inhibitor. These results indicated that AhR inhibition may represent one of the primary mechanisms for chronic colonic inflammation induced by fluxapyroxad exposure. This study shed light on the association between low acute pesticide exposure to fluxapyroxad and chronic colonic inflammation development while contributing to pesticide safety assessment.

The poor intestinal health induced by management, stress, or infection remains a substantial challenge restricting the rapid development of the pig industry. Some natural plant bioactive components (NPBCs) have garnered considerable interest owing to their multifarious benefits, including enhancing intestinal morphology, digestion and absorption, barrier function, immune function, and regulating the gut microbiota. However, there are critical factors, such as the lack of standardized production technologies, lower stability and bioavailability, and unclear mechanisms of NPBCs, severely limiting their feeding efficacy and their application in animal production. Here, we conducted a comprehensive review of the recent advances regarding the impacts of NPBCs on pig gut health. Additionally, we highlighted the key areas that warrant further in-depth investigation. Taken together, NPBCs could be green, safe, and effective feed additives by constructively overcoming their limitations, and they are expected to have broader applications in animal husbandry.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

Cholestatic liver injury is a hepatobiliary disorder primarily characterized by cholestasis, which significantly contributes to liver damage. The Yinzhihuang (YZH) oral preparation is an effective clinical treatment for cholestatic liver injury; however, the specific mechanism of action has not been clarified.

This study investigated YZH's pharmacological mechanisms associated with the microbe‒gut‒liver axis in cholestatic mice, offering new perspectives for the treatment of cholestasis.

YZH's protective effects were evaluated by evaluating serum liver injury indices and liver staining in an alpha-nephthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis mouse model. Colon hematoxylin‒eosin (H&E) and alcian blue staining and FITC‒dextran leakage assays were performed to assess intestinal barrier integrity. Fluorescence in situ hybridization was employed to analyze bacterial translocation. Additionally, 16S rRNA sequencing, fecal microbiota transplantation, and bile acid metabolomics analysis were conducted to examine the relationships among the microbiome, bile acid metabolism, and YZH formula.

We found that YZH administration alleviated symptoms of ANIT-induced hepatic pathological injury and fibrosis. In addition, YZH reduced the transfer of gut bacteria to liver tissue by maintaining an intact intestinal barrier. Notably, YZH influenced the intestinal microbiota composition, upregulated the abundance of bile acid metabolism-associated probiotic bacteria, including Clostridiales, Lachnospiraceae and Bifidobacterium pseudolongum; and downregulated the abundance of Escherichia-Shigella and Serratia, thereby promoting bile acid excretion.

YZH protects against cholestatic liver damage by promoting bile excretion and maintaining intestinal mucosal barrier integrity. Furthermore, YZH alleviates cholestasis in a gut microbiota-dependent manner, and upregulation of probiotics may be crucial for YZH's influence on bile acid metabolism.

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 human gut microbiota is diverse and abundant and plays important roles in regulating health by participating in metabolism and controlling physiological activities. The gut microbiota and its metabolites have been shown to affect the functioning of the gut and central nervous system through the microbiota-gut-brain axis. It is well established that microbiota play significant roles in the pathogenesis and progression of Parkinson's disease (PD). Disorders of the intestinal microbiota and altered metabolite levels are closely associated with PD. Here, the changes in intestinal microbiota and effects of metabolites in patients with PD are reviewed. Potential mechanisms underlying intestinal microbiota disorders in the pathogenesis of PD are briefly discussed. Additionally, we outline the current strategies for the treatment of PD that target the gut microbiota, emphasizing the development of promising novel strategies.

Neurodevelopmental disorders (NDDs) encompass a range of disruptive conditions with varying prevalence rates and multiple contributing factors. Recent studies have suggested a potential connection between NDDs and the gut-brain axis. Furthermore, there is evidence indicating that nutritional supplements might have an impact on gastrointestinal (GI) and behavioral symptoms. This study aimed to explore the effects of nutritional supplements on the gut microbiota and behavioral symptoms in individuals with NDDs.

A systematic search of databases such as PubMed, Scopus, Web of Science, Embase, and APA PsycINFO was conducted, utilizing relevant keywords until February 2025. In addition, the search for gray literature was carried out on Google Scholar and ProQuest. The risk of bias was assessed using the ROBINS-I tool for non-randomized studies and the RoB-1 tool for randomized controlled trials. Due to the heterogeneity of the studies, a Synthesis without Meta-analysis (SWiM) approach was employed.

The overall findings from the studies indicated positive effects of supplementation in reducing the Gastrointestinal Severity Index (GIS) score and alleviating GI symptoms. Supplementation with probiotics and vitamins increased good microbiomes (GM) and decrease in bad microbiomes (BM) among individuals with autism spectrum disorder (ASD). Moreover, the Firmicutes to Bacteroidetes ratio (F/R ratio) exhibited significant changes after supplementation. Additionally, improvements were observed in various assessment scores, including ATEC, ABC, CARS, and PGI-2.

Nutritional supplementation in individuals with NDDs can have a positive influence by modulating the microbiome, reducing dysbiosis, and enhancing gut barrier integrity. Shifting in the F/R ratio can be considered as the reason for improving gastrointestinal and behavioral symptoms by influencing neurotransmitter activity and neuroinflammation. Targeting the gut-brain axis with interventions that focus on gut microbiota offers a promising adjunct therapy for the management of NDD. Registration of the review protocol. PROSPERO registration no. CRD42023460449.

Metabolic dysfunction leading to non-alcoholic fatty liver disease (NAFLD) exhibits distinct molecular and immune signatures that are influenced by factors like gut microbiota. The gut microbiome interacts with the liver via a bidirectional relationship with the gut-liver axis. Microbial metabolites, sirtuins, and immune responses are pivotal in different metabolic diseases. This extensive review explores the complex and multifaceted interrelationship between sirtuins and gut microbiota, highlighting their importance in health and disease, particularly metabolic dysfunction and hepatocellular carcinoma (HCC). Sirtuins (SIRTs), classified as a group of NAD+-dependent deacetylases, serve as crucial modulators of a wide spectrum of cellular functions, including metabolic pathways, the inflammatory response, and the process of senescence. Their subcellular localization and diverse functions link them to various health conditions, including NAFLD and cancer. Concurrently, the gut microbiota, comprising diverse microorganisms, significantly influences host metabolism and immune responses. Recent findings indicate that sirtuins modulate gut microbiota composition and function, while the microbiota can affect sirtuin activity. This bidirectional relationship is particularly relevant in metabolic disorders, where dysbiosis contributes to disease progression. The review highlights recent findings on the roles of specific sirtuins in maintaining gut health and their implications in metabolic dysfunction and HCC development. Understanding these interactions offers potential therapeutic avenues for managing diseases linked to metabolic dysregulation and liver pathology.

The T-2 toxin, originating from a Fusarium species, is a mycotoxin that can adversely affect animal health. Melatonin (MT) is a natural hormone recognized for its properties that reduce inflammation and act as an antioxidant. However, MT's capacity to alleviate intestinal harm from T-2 toxin remains incompletely explored. Employing postweaning piglets, this research investigates MT's prophylactic impact on T-2 toxin-induced enterotoxicity. The results indicate that MT improved growth performance in piglets exposed to T-2 toxins while also enhancing intestinal barrier function. Such effects probably stem from MT's ability to reduce colonic oxidative stress and inflammation. Further findings suggest that these changes are closely associated with MT-induced remodeling of intestinal microbiota and an increase in short-chain fatty acid (SCFA) levels in the intestine. MT therefore alleviates T-2 toxin intestinal damage; gut microbiota are the key to this process.

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.

Host-microorganism encounters take place in many different ways and with different types of outcomes. Three major types of microorganisms need to be distinguished: (1) pathogens that cause harm to the host and must be controlled; (2) environmental microorganisms that can be ignored but must be controlled at higher abundance; and (3) symbiotic microbiota that require support by the host. Recent evidence indicates that the aryl hydrocarbon receptor (AHR) senses and initiates signalling and gene expression in response to a plethora of microorganisms and infectious conditions. It was originally identified as a receptor that binds xenobiotics. However, it was subsequently found to have a critical role in numerous biological processes, including immunity and inflammation and was recently classified as a pattern recognition receptor. Here we review the role of the AHR in host-pathogen interactions, focusing on AHR sensing of different microbial classes, the ligands involved, responses elicited and disease outcomes. Moreover, we explore the therapeutic potential of targeting the AHR in the context of infection.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, mainly involved in detoxification. However, in the intestine, metabolites derived from the diet, which are converted by a wide range of bacteria can also activate the AHR. This intestinal AHR activation plays a key role in maintaining the gut barrier by, for example, upregulating antimicrobial peptides and anti-inflammatory cytokines. Since the gut barrier influences the gut-liver axis by regulating the leaking of metabolites, bacteria, and endotoxins into circulation and particularly into the liver, the AHR is a key factor in the gut-liver axis. Vice versa, certain liver pathologies also influence the gut microbiome, thereby altering bacteria-derived activation of the AHR. Additionally, bile acids can impact the gut via the liver and thereby also affect the AHR. The aryl hydrocarbon receptor (AHR) interacts with several molecular factors, one of which is the nuclear factor erythroid-derived 2-like 2 (NRF2), a transcription factor primarily associated with regulating antioxidant stress responses. The interplay between AHR and NRF2 has been investigated in the context of various diseases; this review highlights the significance of this interaction within the framework of the gut-liver axis.

Smoking is one of the most important predisposing factors of intestinal inflammatory diseases. Heated tobacco product (HTP) is a novel tobacco category that is claimed to deliver reduced chemicals to humans those reported in combustible cigarette smoke (CS). However, the effect of HTP on the intestine is still unknown.

Our study aims to explore the potential effects of HTP on intestine. In the framework of Organization for Economic Co-operation and Development guidelines 413 guidelines, Sprague-Dawley rats were exposed to HTP aerosol and CS for 13 weeks. The atmosphere was characterized and oxidative stress and inflammation of the intestine were investigated after exposure. Furthermore, the feces we performed with 16S sequencing and metabolomics analysis.

HTP aerosol and CS led to obvious intestinal damage evidenced by increased intestinal proinflammatory cytokines and oxidative stress in male and female rats After HTP and CS exposure, the abundance that obviously changed were Lactobacillus and Turiciacter in male rats and Lactobacillus and Prevotella in female rats. HTP mainly induces the metabolism of amino acids and fatty acyls such as short-chain fatty acids and tryptophan, while CS is involved in the main metabolism of bile acids, especially indole and derivatives. Although different metabolic pathways in the gut are mediated by HTP and CS, both inflammation and oxidative stress were ultimately induced.

HTP aerosol and CS-induced intestinal damage are mediated by different gut microbiota and metabolites, while both lead to inflammation and oxidative stress.

The concentration of various harmful components in heated tobacco product aerosol is reported lower than that of traditional cigarette smoke, however, its health risk impact on consumers remains to be studied. Our research findings indicate that heated tobacco products and cigarette smoke inhalation induced intestinal damage through different metabolic pathways mediated by the gut microbiome, indicating the health risk of heated tobacco products in the intestine.

Spinal cord injury (SCI) is a potentially fatal condition that often results in loss of motor and sensory functions, thereby significantly burdening global health initiatives. Urolithin A (UA), an intestinal microbial metabolite of ellagic acid, is known for its potent anti-inflammatory properties in chronic inflammation contexts. UA treatment in humans induces a molecular signature of improved mitochondrial and cellular health. Yet, its effects on acute inflammation following SCI remain unclear. In this study, we developed an impact-induced mouse model for SCI and treated the injured mice with UA (50 mg/kg/d, till 8 weeks) via intragastric administration. Furthermore, we subjected BV2 cells to lipopolysaccharide and adenosine 5'-triphosphate to simulate the post-injury inflammatory response. Our results demonstrated that pre-treatment with UA (10 μM) effectively inhibited NLRP3 inflammasome activation in LPS-primed BV2 cells. This inhibition was evidenced by reduced cleaved Caspase-1 and mature IL-1β release, diminished ASC speck formation, and decreased gasdermin D (GSDMD)-mediated pyroptosis. Additionally, UA treatment restored mitochondrial activity and ROS production attenuated by NLRP3 activation, increased LC3-II expression, and enhanced LC3 co-localization with mitochondria. 3-Methyladenine (3-MA), an autophagy inhibitor, can partially reverse the stimulatory effect of UA on mitophagy, as well as the inhibitory effect of UA on pyroptosis. This study highlighted the protective role of UA against SCI through its promotion of mitophagy, which in turn inhibits NLRP3 inflammasome activation and pyroptosis.

The gut microbiome plays a pivotal role in human health, influencing digestion, immunity, and disease prevention. Beneficial gut bacteria such as Akkermansia muciniphila, Adlercreutzia equolifaciens, and Christensenella minuta contribute to metabolic regulation and immune support through bioactive metabolites like short-chain fatty acids (SCFAs). Dietary patterns rich in prebiotics, fermented foods, and plant-based bioactive compounds, including polyphenols and flavonoids, promote microbiome diversity and stability. However, challenges such as individual variability, bioavailability, dietary adherence, and the dynamic nature of the gut microbiota remain significant. This review synthesizes current insights into gut bacteria's role in health, emphasizing the mechanisms by which dietary interventions modulate microbiota. Additionally, it highlights advancements in microbiome-targeted therapies and the transformative potential of personalized nutrition, leveraging microbiota profiling and artificial intelligence (AI) to develop tailored dietary strategies for optimizing gut health and mitigating chronic inflammatory disorders. Addressing these challenges requires a multidisciplinary approach that integrates scientific innovation, ethical frameworks, and practical implementation strategies.

Postbiotics are defined as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". They represent an attractive alternative to probiotics as they could be used in a broader range of applications, where probiotic stability is limiting. To date knowledge on the mechanism of action of inanimate microorganisms is relatively scarce. In this study, we investigated the impact of heat treatment on NRF2 activation by several candidate probiotic strains from the Nestlé Culture Collection (NCC), including species encompassed in the Bifidobacterium genus and the Lactobacillaceae family. We identified an NRF2-activating bioactive molecule, 4-oxo-2-pentenoic acid (OPA), specifically released during heat treatment of Bifidobacterium breve NCC 2950. We explored cellular pathways that can be modulated by OPA, such as antiinflammatory signals and organismal defense against oxidative stress in zebrafish in vivo. We identified a new B. breve NCC 2950-derived postbiotic that, based on the mode of action, may have important applications for nutritional strategies to benefit human health.

Population aging has become a primary global public health issue, and the prevention of age-associated diseases and prolonging healthy life expectancies are of particular importance. Gut microbiota has emerged as a novel target in various host physiological disorders including aging. Comprehensive understanding on changes of gut microbiota during aging, in particular gut microbiota characteristics of centenarians, can provide us possibility to achieving healthy aging or intervene pathological aging through gut microbiota-directed strategies.

This review aims to summarize the characteristics of the gut microbiota associated with aging, explore potential biomarkers of aging and address microbiota-associated mechanisms of host aging focusing on intestinal barrier and immune status. By summarizing the existing effective dietary strategies in aging interventions, the probability of developing a diet targeting the gut microbiota in future is provided.

This review is focused on three key notions: Firstly, gut microbiota has become a new target for regulating health status and lifespan, and its changes are closely related to age. Thus, we summarized aging-associated gut microbiota features at the levels of key genus/species and important metabolites through comparing the microbiota differences among centenarians, elderly people and younger people. Secondly, exploring microbiota biomarkers related to aging and discussing future possibility using dietary regime/components targeted to aging-related microbiota biomarkers promote human healthy lifespan. Thirdly, dietary intervention can effectively improve the imbalance of gut microbiota related to aging, such as probiotics, prebiotics, and postbiotics, but their effects vary among.

Ulcerative colitis (UC) is a relapsing disease with an increasing morbidity and prevalence. Dietary polysaccharides have recently become a research hotspot because of their therapeutic effects and safety on UC. Our previous research elucidated that pectic polysaccharide from Phyllanthus emblica L. (PEP-1) could alleviate dextran sodium sulfate-induced UC mice. Herein, metabolomics and transcriptomics were further applied to disclose the underlying mechanisms behind PEP-1's anti-inflammatory effects. PEP-1 intervention altered the serum metabolite contents and pathways represented by decreasing xanthine and sphinganine levels. Changes in gene expressions correlated with metabolite variations led by the suppression of the expression of the inflammatory factors, colorectal cancer promoter, and NF-κB pathway as well as the enhancement of tight junctions. This study demonstrated that the ameliorating effect of chronic UC was partially ascribed to the alteration of the serum metabolites and changes in gene expression.

The INFOGEST semi-dynamic digestion model more closely aligns the kinetics of nutrient digestion with structural changes in the food matrix during gastric digestion, which can significantly influence polyphenol bioaccessibility. In this study, the static and semi-dynamic INFOGEST models were compared to assess polyphenol bioaccessibility across various matrix scenarios, using different apple fractions. Each digesta, regardless of the model used, underwent re-solubilization, centrifugal filtration, and UHPLC-ESI-QTOF-MS/MS analysis to approximate transepithelial absorption and facilitate untargeted polyphenol screening and semi-quantification. The semi-dynamic model was initially optimized using whole apple. Overhead stirring with a paddle led to greater browning and degradation of phenolic acids and dihydrochalcones than magnetic stirring, the latter showing bolus stratification and closer physiological conditions for oxygenation and intragastric chyme homogenization. The suitability of a 2 kcal/min gastric emptying rate was tested with pomace, resulting in 8.25 min total gastric emptying time due to low caloric content. Compared to the gastric emptying time of whole apple (139.5 min), the caloric-driven emptying of pomace produced similar polyphenol bioaccessibility but a three-fold higher coefficient of variation (19.5 % vs. 69.4 %). Finally, using several apple fractions, the semi-dynamic setup with magnetic stirring and a fixed gastric emptying rate of 139.5 min showed greater extraction of hydroxybenzoic acids and dihydrochalcones from apple and of hydroxybenzoic and hydroxycinnamic acids from pomace than the static model. However, flavanols in juice degraded more extensively under semi-dynamic conditions. Minimal differences were observed between models for an apple polyphenol extract, indicating that in the absence of matrix, the static setup might be preferred.

Probiotics have been proposed as a potential strategy for managing ulcerative colitis (UC). However, the underlying mechanisms mediating microbiota-host crosstalk remain largely elusive. Here, we report that Limosilactobacillus reuteri (L. reuteri), as a probiotic, secretes cytoplasmic membrane vesicles (CMVs) that communicate with host cells, alter host physiology, and alleviate dextran sulfate sodium (DSS)-induced colitis. First, L. reuteri-CMVs selectively promoted the proliferation of the beneficial bacterium Akkermansia muciniphila (AKK) by upregulating the expression of glycosidases (beta-N-acetylhexosaminidase and alpha-N-acetylglucosaminidase) involved in glycan degradation and metabolic pathways and restored the disrupted gut microbiota balance. Second, L. reuteri-CMVs were taken up by intestinal epithelial cells (IECs), elevated the expression of ZO-1, E-cadherin (Cdh1), and Occludin (Ocln), decreased intestinal permeability, and exerted protective effects on epithelial tight junction functionality. RNA sequencing analysis demonstrated that L. reuteri-CMVs repaired intestinal barrier by activating the HIF-1 signaling pathway and upregulating HMOX1 expression. Third, L. reuteri-CMVs increased the population of double positive (DP) CD4+CD8+ T cells in the intestinal epithelial layer, suppressing gut inflammation and maintaining gut mucosal homeostasis. Finally, L. reuteri-CMVs exhibited satisfactory stability and safety in the gastrointestinal tract and specifically targeted the desired sites in colitis mice. Collectively, these findings shed light on how L. reuteri interact with the host in colitis, and provide new insights into potential strategies for alleviating colitis.

Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal barrier integrity. Most individuals harbor a microbiota capable of uroA production; however, the mechanisms underlying the dehydroxylation of its catechol-containing precursor (uroC) are unknown. Here, we use a combination of untargeted bacterial transcriptomics, proteomics, and comparative genomics to uncover an inducible uroC dehydroxylase (ucd) operon in Enterocloster species. We show that the ucd operon encodes a predicted molybdopterin-dependent enzyme complex that dehydroxylates urolithins at a specific position (9-OH). By interrogating publicly available metagenomics datasets, we observed that uroC-metabolizing Enterocloster species and ucd operon genes are prevalent in human feces. In ex vivo experiments with human fecal samples, only samples actively transcribing ucd could produce uroA, possibly explaining differences in urolithin metabolism between individuals. Collectively, this work identifies Enterocloster species and the ucd operon as important contributors to uroA production and establishes a multi-omics framework to further our mechanistic understanding of polyphenol metabolism by the human gut microbiota.