Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut-brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut-brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.

The current limitations of oral nanomedicines such as aminosalicylates, immunosuppressants, corticosteroids, and antibiotics include the toxic byproducts from nanocarrier synthesis, poor targeting and retention within the inflamed colon, delayed release at inflammation sites, susceptibility to gastric degradation, reduced efficacy under hypoxic conditions, MUC2 homeostasis disruption, and insufficiently addressing the disease's root causes. This research presents an innovative approach of using non-toxic, biodegradable, and biocompatible Maillard reaction-based nanoparticles (MPs) for targeted oral drug delivery in IBD therapy. Through the development of mucoadhevise chitosan-bovine serum albumin Maillard nanoparticles shielded with biocompatible, non-toxic, non-immunogenic, gastroprotective pectin (P@CMPs) encapsulating with chrysin, a flavonoid with anti-inflammatory and hyperoxia properties whose bioavailability is negatively affected by gastric degradation. P@CMPs had a spherical, uniform 300 nm hydrodynamic diameter, confirmed by TEM and FESEM. Chrysin encapsulation efficiency and loading capacity were ∼96 % and 16 %, respectively, demonstrating effective nanoparticle formulation The P@CMPs is designed to withstand the gastrointestinal environment, ensuring targeted delivery and prolonged retention in inflamed colonic regions. In a dextran sodium sulfate-induced colitis mouse model, P@CMPs markedly mitigated inflammation, suppressed proinflammatory cytokine levels, and augmented the expression of MUC2, a crucial factor for maintaining the integrity of the gut barrier. By employing non-toxic, biocompatible and biodegradable materials, our P@CMPs approach offers a promising avenue for advancing IBD treatment, addressing various challenges and precise oral delivery within the gastrointestinal system.

Peptide drugs offer considerable potential for treating a diverse range of diseases. Yet, their clinical application is generally restricted to injectable therapies. The main challenge hindering their broader use through globally accessible, patient-friendly, and non-invasive delivery routes such as oral or buccal, lies in their poor ability to cross biological barriers effectively. Here, we demonstrate that enzymes can be harnessed to transiently reduce these barriers and improve absorption. As a proof of concept, we employ a mucin-specific protease (mucinase) and a phospholipase to increase mucus diffusivity and epithelial cell membrane permeability, respectively. In a canine model, we show that enteric capsules containing both enzymes, and the peptide drug desmopressin achieved a relative bioavailability of 155 % compared to the drug alone. Additionally, a buccal patch loaded with phospholipase and semaglutide displayed a 5-fold higher bioavailability and lower variability (71.5 % reduction in the coefficient of variation) compared to the commercially available oral tablet. These results suggest that enzymatic modulation of biological barriers holds promise as a strategy to improve non-invasive delivery of peptides and potentially other macromolecular drugs.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by impaired intestinal mucosal barrier function, leading to persistent inflammation and tissue damage. Current therapies often fail to address barrier dysfunction, highlighting the need for innovative treatments. This study developed a novel therapeutic strategy by combining decellularized porcine small intestinal submucosa (D-SIS) with fibroblast growth factor 20 (FGF-20) to promote mucosal repair and restore barrier integrity in a TNBS-induced colitis rat model. The D-SIS-based hydrogel, supplemented with hyaluronic acid (HA), was designed to enhance FGF-20 stability and enable sustained drug release. Results showed that the FGF-20-loaded hydrogel (MAF) exhibited excellent rheological properties, erosion resistance, and controlled drug release, making it suitable for rectal administration. In vitro cell experiments demonstrated that MAF enhanced Caco-2 cell proliferation, migration, and tight junction protein expression, restoring epithelial barrier integrity. In the colitis model, MAF significantly reduced disease activity index (DAI) scores, attenuated inflammation, and restored mucosal morphology. Additionally, MAF promoted goblet cell regeneration, enhanced mucus secretion, and upregulated intestinal stem cell markers, indicating its ability to repair both epithelial and mucus barriers. In conclusion, the MAF hydrogel represents a promising therapeutic approach for UC by combining the regenerative properties of FGF-20 with the bioactive support of D-SIS.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract caused by dysfunction of the immune system in genetically susceptible individuals. As current pharmacologic and surgical treatments remain suboptimal, increasing attention has been directed toward exosomes derived from mesenchymal stem/stromal cells (MSCs) as alternative therapeutic approaches. MSCs are multipotent stromal cells that can be isolated from various human tissues such as bone marrow, adipose, umbilical cord and periodontal ligament. Exosomes are cell-derived membrane-bound vesicles enclosing RNAs, proteins, growth factors, and cytokines. Previous studies indicate that the anti-inflammatory, immunomodulatory, and regenerative effects of MSCs are largely mediated by MSC-derived exosomes (MSC-Exos). Therefore, this review outlines current insights into the molecular mechanisms of MSC-Exos in IBD treatment to support the future development of MSC-Exos as a therapeutic strategy, thus providing novel observations into the clinical applications of MSC-Exos in IBD management.

Growing research is devoted to the development of plant-derived products as new therapeutic drugs to reduce side effects. Plant-derived exosome-like nanoparticles (ELNs) have shown promising potential in the treatment of colitis.

As a proof of concept, the efficacy of ELNs from edible Zanthoxylum bungeanum (ZbELNs) in protecting macrophages from inflammation was determined by in vitro experiments. Moreover, we assess the therapeutic effect of ZbELNs to colitis in a mouse model.

ZbELNs were found to have an ideal particle size (160.0 nm) and contain a large number of lipids, some functional proteins or metabolites, and many small RNA molecules. The in vitro experiment results revealed that ZbELN pretreatment increased cell vitality and decreased the levels of pro-inflammatory cytokines. Furthermore, the in vivo experiments indicated that oral administration of ZbELNs can significantly reduce disease activity index, increase colon length, and inhibit colon wall thickening, thereby alleviating acute colitis in dextran sulfate sodium-induced model mice. In addition, ZbELN treatment can reduce the degree of histological damage in the colon and suppress pro-inflammatory cytokines levels in mice serum. Notably, miRNA-1 and miRNA-21 in ZbELNs showed similar therapeutic effects on macrophage inflammation.

These findings suggest that ZbELNs are a novel natural nanomedicine with promising therapeutic potential for the treatment of colonic diseases.

Bisphenol A (BPA), recognized as an endocrine disruptor, is widely present in various aquatic ecosystems. Marine bivalves constitute a significant portion of molluscan diversity and occupy a crucial niche in marine ecosystems. Nonetheless, toxicological studies focusing on the dysregulation of the intestinal barrier and microbiota in marine bivalves under BPA exposure still need to be refined and deepened. This research aims to assess the toxicity of BPA at concentrations of 1, 10, 100 μg/L on the intestinal tissues of Meretrix petechialis, focusing on behavioral responses, intestinal morphology, intestinal oxidative stress and antioxidant homeostasis, intestinal barrier function and intestinal microbial community. Our results demonstrated that BPA exposure caused behavioral changes in M. petechialis, significantly increased the number of buried clams and decreased the ingestion rate. Furthermore, BPA exposure disrupted the intestinal structure and induced inflammation and immune dysregulation in clams. Immunofluorescence staining showed that BPA disrupted the distribution of occludin and ZO-1 proteins in the intestine and significantly reduced their expression. Mucus secretion and tight junction genes were downregulated, which may be attributed to BPA-induced oxidative stress and the dysregulation of antioxidant homeostasis in the intestine. Besides, 16S rRNA sequencing revealed BPA not only influenced the beta diversity of intestinal bacteria but also the overall composition of the intestinal microbiome, with potential effects on metabolism predicted by PICRUSt2. Taken together, our results indicated that higher concentrations of BPA may pose safety concerns and enhanced our comprehension of the toxicological processes responsible for BPA-related intestinal toxicity in marine bivalves.

Breast milk is crucial for infant health, offering essential nutrients and immune protection. However, despite increasing exposure risks from nanoparticles (NPs), their potential infiltration into human breast milk remains poorly understood. This study provides a comprehensive chemical profile of NPs in human breast milk, analyzing their elemental composition, surface charge, hydrodynamic size, and crystallinity. NPs were detected in 42 out of 53 milk samples, with concentrations reaching up to 1.12 × 1011 particles/mL. These particles comprised nine elements, with O, Si, Fe, Cu, and Al being the most frequently detected across all samples. We establish a mechanistic axis for NP infiltration, involving penetration of the intestine/air-blood barriers, circulation in blood vessels, crossing the blood-milk barrier via transcytosis or immune cell-mediated transfer, and eventual accumulation in milk. Structure-activity relationship analysis reveals that smaller, neutral-charged NPs exhibit stronger infiltration capacity, offering potential for regulating NP behavior at biological barriers through engineering design. This study provides the chemical profiles of NPs in human breast milk and uncovers their infiltration pathways.

Porcine epidemic diarrhea (PED) incurs substantial economic losses to the pig industry. During viral infection of cells, the activity of NF-κB is upregulated. As an endogenous inhibitor, FoxO4 plays a crucial role in antagonizing NF-κB activity, inhibiting the NF-κB-mediated MLCK signaling pathway, altering the expression of cellular tight junctions (TJs) and pro-inflammatory cytokines, and protecting intestinal epithelial cells from damage. However, there are limited reports on this inhibitory and protective effect in PEDV-infected IPEC-J2 cells. Therefore, this experiment employed methods such as homologous recombination, qRT-PCR, Western blotting, co-immunoprecipitation, laser confocal microscopy, and cell transmembrane resistance assays to investigate the effect of FoxO4 on indicators related to cell damage through the NF-κB/MLCK pathway in infected cells. The results demonstrated the successful construction of FoxO4 and NF-κB factor p65 expression vectors, confirming the interaction between the two in IPEC-J2 cells. FoxO4 effectively antagonizes the expression of NF-κB/MLCK pathway factors in infected cells, and through this action, it reduces the permeability of infected cells, maintains the integrity of the cell membrane, upregulates the expression of TJ proteins, antagonizes the expression of pro-inflamma-tory factors, and exerts effects in promoting cell apoptosis and antagonizing viral replication.This study further elucidates the molecular mechanisms underlying cell damage caused by PEDV and offers new potential targets for protecting intestinal epithelial barrier function.

Diarrhea in piglets causes intestinal inflammation and epithelial damage. Weaned piglets fed with Bacillus subtilis (B.S) have enhanced intestinal mucosal immunity and reduces diarrhea in piglets. However, the immune system of newborn piglets is immature, and B.S cannot effectively activate the intestinal mucosal reaction when given directly. This research explored the impact of the maternal supplementation of B.S-Dia during the final 35 days of gestation on piglet intestinal development and mucosal immunity. The results demonstrated that B.S-Dia administration significantly increased the body weight, jejunal villus height, and crypt depth in the piglets. In addition, B.S-Dia also significantly increased the proliferative activity of intestinal epithelial cells, as evidenced by proliferating cell nuclear antigen (PCNA) staining and the elevated mRNA expression of the proliferation-related gene (c-Myc). Furthermore, B.S-Dia supplementation also reinforced the intestinal mucosal barrier by increasing goblet cell numbers and upregulating the mRNA expression of antimicrobial peptides, such as Muc2 and Lyz-1. Finally, elevated levels of IL-4 and IFN-γ, along with an increased abundance of CD3+ T cells, revealed that the intestinal mucosal immunity of piglets was improved after B.S-Dia administration. Our study indicates that feeding B.S-Dia to sow spromotes intestinal development and improves intestinal mucosal immunity in piglets.

Intestinal inflammation and increased permeability have been linked to metabolic dysregulation in patients with compromised intestinal barrier function. Among the pathways, garnering attention is the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Upon binding to double-stranded DNA (dsDNA), cGAS catalyzes the conversion of ATP and GTP into cyclic GMP-AMP (cGAMP). Subsequently, cGAMP binds to STING, triggering the activation of tank-binding kinase 1 (TBK1), which activates interferon regulatory factor 3 (IRF3), thus inducing the production of type I interferon. Activated TBK1 can also induce the activation of nuclear factor κB (NF-κB), thus mediating the production of proinflammatory cytokines. The effects of this process vary among innate and adaptive immune cells, as well as intestinal epithelial cells (IECs). This review aims to elucidate the impact and role of the cGAS-STING pathway on intestinal barrier function.

Deoxynivalenol (DON) is one of the most prevalent mycotoxins globally, causing a variety of toxic effects in both humans and animals. Numerous studies have demonstrated the considerable efficacy of natural medicines in treating and preventing DON-induced damage. Therefore, it is crucial to predict and screen highly efficient natural medicines and further investigate their mechanisms. In this study, we employed bioinformatics approaches to explore DON's pathogenic mechanism and targets. Utilizing drug prediction and screening databases, we conducted reverse prediction and screening of differentially expressed genes (DEGs) and key targets to obtain optimal natural medicines, ultimately identifying quercetin as the most promising candidate. Subsequently, network pharmacology analyses revealed that quercetin alleviated DON-induced intestinal damage by modulating inflammatory targets and the TNF/NF-κB pathways. Our experiments demonstrated that quercetin treatment improved DON-induced growth inhibition and intestinal damage in mice, while successfully reversing the abnormal expression of key target genes. Furthermore, quercetin restored the intestinal microbial imbalance induced by DON. Overall, these findings suggest that quercetin is a promising natural medicine capable of alleviating DON-induced intestinal dysfunction by regulating inflammation-related factor levels and gut microbiota, thereby providing new insights for the future prevention and treatment of mycotoxins.

Sini Decoction (SND), a time-honored formulation in traditional Chinese medicine, consists of three key ingredients: aconite, licorice, and ginger rhizome. It has been used for more than a thousand years to relieve symptoms associated with acute gastroenteritis, dyspepsia, and abdominal discomfort, but its therapeutic efficacy in ulcerative colitis (UC) and the mechanisms involved have not been validated. In this study, a comprehensive approach integrating network pharmacology, molecular docking, molecular dynamics simulation and experimentation was used to assess the efficacy of SND in the treatment of UC and to explore its molecular mechanisms.

The bioactive compounds associated with ulcerative colitis (UC) were identified using the TCMSP database, with potential targets predicted via the Swiss Target Prediction database. Protein-protein interaction networks were constructed using the STRING database and Cytoscape and the most important genes were identified. Subsequently, molecular docking was combined with molecular dynamics simulations using molecular docking to assess the binding affinity of the main active ingredient of SND to AKT1. To evaluate the therapeutic effects of SND, we utilized a dextran sodium sulfate-induced UC mouse model. Additionally, fecal samples were collected for analysis of the intestinal microbiota to explore the influence of SND on gut flora composition.

Fifteen bioactive components from SND were identified, and their activities were validated. The results indicated that AKT serine/threonine kinase 1 is a core target of SND for the treatment of UC. The anti-inflammatory, intestinal barrier-protective, and microbiota-regulating effects of SND were confirmed in animal models, alongside evidence of its inhibitory effect on AKT1.

The active ingredients of SND were screened, with a focus on AKT1 inhibition, to reduce inflammation in UC, protect the intestinal barrier, and regulate the intestinal microbiota, demonstrating significant therapeutic potential.

Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.

Cell-cell adhesions mediated by adherens junctions, structures connecting cells to each other and to the cortical cytoskeleton, are essential for epithelial physical and biological integrity. Nonetheless, how such structures resist mechanical stimuli that prompt cell-cell rupture is still not fully understood. Here we challenge the conventional views on cell-cell adhesion stability, highlighting the importance of viscous dissipation at the cellular level. Using microdevices to measure the rupture energy of cell-cell junctions and synthetic cadherins to discriminate cadherin binding energy from downstream cytoskeletal regulation, we demonstrate that the balance between cortical tension and cell shape recovery time determines a transition from ductile to brittle fracture in cell-cell contact. These findings suggest that junction toughness, defined as the junction disruption energy, is a more accurate measure of junctional stability, challenging the current emphasis on bond energy and tension. Overall, our results highlight the role and the regulation of energy dissipation through the cytoskeleton during junction deformation for epithelial integrity.

The immature gastrointestinal development of infants and young animals made them more vulnerable to stress-related damage, which affected the gut-liver axis and consequently impaired their health and growth. This study used weaned piglets as a model to investigate how dietary sesamin regulated the gut-liver axis and impacted young animal health. We assessed gut-liver tissue morphology, measured key indicators of intestinal barrier damage, mucosal repair, antioxidant and immune pathways in the gut-liver system and serum, and analyzed microbial composition. We further explored the interactions between sesamin and the gut-liver axis through PLS-PM and molecular docking analysis. Results showed that sesamin enhanced intestinal barrier function, reduced liver damage, decreased oxidative stress, promoted anti-inflammatory immune responses, and enriched beneficial microbes, thereby promoting overall growth. Sesamin can enhance the health of young animals by regulating the function of the gut-liver axis.

Diquat is a widely used bipyridyl herbicide that is extensively applied in agricultural production and water management due to its high efficacy in weed control. However, its environmental persistence and the toxic effects it induces have raised widespread concern. Studies show that Diquat primarily enters the body through the digestive tract, leading to poisoning. The core mechanism of its toxicity involves reactive oxygen species (ROS)-induced oxidative stress, which not only directly damages the intestinal barrier function but also exacerbates inflammation and systemic toxicity by disrupting the balance of the gut microbiota and the normal production of metabolic products. This review systematically summarizes the physicochemical properties of Diquat, with a focus on analyzing the mechanisms by which it damages the gut tissue structure, barrier function, and microbiota after digestive tract exposure. The aim is to provide theoretical support for a deeper understanding of Diquat's toxic mechanisms and its digestive tract-centered toxic characteristics, laying a scientific foundation for the development of effective interventions and protective strategies against its toxicity.

Impaired gut barrier function plays a pivotal role in the pathophysiology of irritable bowel syndrome (IBS), particularly in IBS with diarrhea. Mucoprotectants, such as xyloglucan, gelatin tannate and pea protein tannins, offer a novel therapeutic approach by restoring intestinal permeability and reducing inflammation. This review assesses preclinical and clinical evidence supporting mucoprotectants in IBS with diarrhea management. Preclinical studies indicate their efficacy in reducing intestinal permeability and inflammation, while clinical trials demonstrate improvements in stool consistency, abdominal pain and bloating. Despite these promising results, comparative studies are needed to establish the superiority of specific mucoprotectants and their optimal use in clinical practice.

Inflammatory Bowel Disease (IBD) is a complex intestinal disorder that typically triggers inflammatory responses, immune dysregulation, and gut microbiota imbalance. Lignoformic acid (LFA) is a lignin-derived compound containing benzene rings and hydroxyl functional groups. It has antioxidant properties and can regulate intestinal pH. This study aimed to investigate the improve effects of LFA on dextran sulfate sodium (DSS)-induced chronic colitis in mice. The results showed that LFA treatment significantly improved body weight and Disease Activity Index (DAI) in mice and alleviated colon damage. In terms of oxidative stress and anti-inflammatory effects, the expression of antioxidant enzymes such as Glutathione Peroxidase (GSH-PX) and Superoxide Dismutase (SOD) was dose-dependently enhanced in DSS-induced mice. LFA reduced the expression of Tumor Necrosis Factor-alpha (TNF-α) by modulating the TLR4/MyD88/NF-κB signaling pathway. Furthermore, LFA dose-dependently increased the abundance of beneficial bacteria, including Akkermansia and Lachnospiraceae, and promoted the production of short-chain fatty acids (SCFAs). These findings suggest that LFA could serve as a therapeutic agent for colitis by enhancing intestinal barrier integrity, regulating inflammation, and restoring gut microbiota balance.

The intestinal epithelium, which is protected by mucosal surfaces composed of mucins and other glycoproteins, functions as a selective barrier that absorbs nutrients while preventing the translocation of harmful substances. To understand the mechanisms between mucosal disruption and tissue inflammation, we orally administrated a mucus-disrupting agent, dextran sodium sulfate, to Drosophila melanogaster and screened 63 differentially expressed genes (DEGs). Through a database search using bioinformatics tools (CHEA3 and WebGestalt), we identified ELK1 as a potential key transcription factor for the selected DEGs, and among the 63 DEGs, ELK1-related genes, B3GAT3, FIBP, and TENT2 (GlcAT-S, Fibp, and Wisp in Drosophila), were selected as the relevant genes that respond to mucus disruption. We confirmed that enterocyte (EC)-specific GlcAT-S knockdown by RNAi significantly reduced gut length and increased intestinal stem cell proliferation in Drosophila. Additionally, in EC-specific GlcAT-S-knockdown flies, it was observed that the mucus-production-related genes, Muc68D and Mur29B, were specifically reduced, whereas the inflammatory cytokines egr and upd3 were overexpressed. This study provides evidence that GlcAT-S is involved in the regulation of intestinal inflammation in Drosophila and plays a protective role against mucus disruption. Our findings suggest that GlcAT-S may be a potential therapeutic target for the treatment of intestinal inflammatory diseases such as IBD.

Enzymolysis can effectively reduce the allergenicity of α-lactalbumin (ALA). Herein, complex enzymes targeted enzymolysis technology was developed to reduce the allergenicity of ALA, and the allergenicity of hydrolysates (WM) were investigated from multiple perspectives. The results showed that compared with the single enzyme hydrolysates, the degree of hydrolysis and antigen reduction rate of WM were increased by 5.57 % and 25.31 %, and linear allergenic epitopes were further eliminated. The spatial conformation of WM was disrupted, manifested by decreasing in α-helix content and surface hydrophobicity. In addition, WM could alleviate allergic symptoms in mice, reduced the binding ability with IgE and IgG1 and the release of mast cells degranulation, maintained the balance of Th1/Th2 cells and intestinal barrier function. Spearman's correlation analysis further revealed the correlation between the relative abundance of marker genus and allergy related indicators. This study will provide theoretical basis for the development of low allergenic dairy-based materials.

The increasing interest in utilizing three-dimensional (3D) in vitro models with innovative biomaterials to engineer functional tissues arises from the limitations of conventional cell culture methods in accurately reproducing the complex physiological conditions of living organisms. This study presents a strategy for replicating the intricate microenvironment of the intestine by cultivating intestinal cells within bioinspired 3D interfaces that recapitulate the villus-crypt architecture and 3D tissue arrangement of the intestine. Intestinal cells cultured on these biomimetic substrates exhibited phenotypes and differentiation characteristics resembling intestinal-specific cell types, effectively replicating intestinal tissue. Notably, tissue proliferation and differentiation were achieved within 72-120 h-significantly faster than the several weeks required by conventional bioengineered materials, which often pose risks of tissue necrosis or cross-contamination. Additionally, the differentiated cells on these villi-crypts mimicking bio-interfaces exhibit higher production of natural antimicrobial peptides, resulting in reduced pathogenic infection compared to control samples. Furthermore, our method stands out for simplicity in fabrication, eliminating the need for cleanroom procedures and complex microfabrication techniques.

In Nature, bacterial clustering by host-released peptides or nucleic acids is an evolutionarily conserved immune defense strategy employed to prevent adhesion of pathogenic microbes, which is prerequisite for most infections. Synthetic anti-adhesion strategies present as non-lethal means of targeting bacteria and may potentially be used to avoid resistance against antimicrobial therapies. From bacteria-agglutinating biomolecules discovered in nature to synthetic designs involving peptides, cationic polymers and nanoparticles, the modes of actions appear broad and unconsolidated. Herein, we present a critical review and update of the state-of-the-art in synthetic bacteria-clustering designs with proposition of a more streamlined nomenclature and classification. Overall, this review aims to consolidate the conceptual framework in the field of bacterial clustering and highlight its potentials as an avenue for discovering novel antibacterial biomaterials.

Nanoplastics pollution is a global issue, with the digestive tract being one of the first affected organs, requiring further research on its impact on intestinal health. This study involved orally exposing mice to polystyrene nanoplastics (PS-NPs) at doses of 0.1, 0.5, or 2.5 mg/d for 42 days. The effects on intestinal health were thoroughly assessed via microbiomics, metabolomics, transcriptomics, and molecular biology. Our study demonstrated that the administration of all three doses of PS-NPs resulted in increased colonic permeability, heightened colonic and peripheral inflammation, reduced levels of antimicrobial peptides, and shortened colonic length. These effects may be attributed to a reduction in the abundance of probiotic bacteria, such as Clostridia_UCG-014, Roseburia, and Akkermansia, alongside an increase in the abundance of the pathogenic bacterium Desulfovibrionaceae induced by PS-NPs. Furthermore, we underscored the crucial role of histidine metabolism in PS-NPs-induced colonic injury, characterized by a significant reduction of L-histidine, which is closely related to microbial ecological dysregulation. Corresponding to microbiota deterioration and metabolic dysregulation, transcriptome analysis revealed that PS-NPs may disrupt colonic immune homeostasis by activating the TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In conclusion, this study provided novel insights into the mechanisms by which PS-NPs disrupt intestinal homeostasis through integrated multiomics analysis, revealing critical molecular pathway and providing a scientific basis for future risk assessment of nanoplastics exposure.

Stachyose has traditionally been considered to exert prebiotic effects primarily through its interaction with gut microbiota. However, this study reveals a novel mechanism by which stachyose alleviates cyclophosphamide (CY)-induced small intestinal mucosa disruption by regulating the intestinal exosomal miRNAs, without relying on the gut microbiota. Specifically, stachyose significantly mitigates CY-caused damage to the intestinal permeability, oxidative stress, and the structure of intestinal villi and crypts in pseudo-germ-free (PGF) mice. The immunofluorescence staining and qPCR analyses show that stachyose treatment restores CY-caused abnormal changes on the levels of tight junction proteins including MUC2, Occludin, Claudin-1, and ZO-1, and pro-inflammatory cytokines including TNF-α, IL-1β, and IL-2. Furthermore, by conducting fecal miRNA transplantation experiment, we further demonstrated that, similar to stachyose, stachyose-shaped intestinal miRNAs protect against CY-induced intestinal mucosal damage in PGF mice. In summary, this study provides new scientific evidence for the direct interaction between nondigestible stachyose and the proximal small intestine. It also opens new avenues for further investigation into the systemic nutritional functions of stachyose, particularly the health benefits of stachyose in the upper gastrointestinal tract.

Partially hydrolyzed guar gum (PHGG) protects against intestinal barrier dysfunction and can ameliorate some intestinal diseases. However, whether PHGG has a role in protecting intestinal barrier function (IBF) during sepsis remains unclear. This study aimed to investigate the role and probable mechanism of PHGG in the intestinal mucosa in sepsis. A rat sepsis model was constructed using cecal ligation and puncture (CLP). FITC-dextran 4 (FD-4) flux, serum inflammatory mediator levels, tight junction (TJ) levels, jejunum mucosa pathology, and epithelial intercellular junction ultrastructure were monitored to evaluate the effect of PHGG on IBF. Caco-2 monolayers were used to study the impact and mechanism of PHGG on lipopolysaccharide (LPS)-induced barrier dysfunction in vitro. The expression of zonula occludens protein-1 and occludin and the location of P65 were studied by immunofluorescence. Nuclear factor kappa B (NF-κB) and myosin light chain kinase 3 (MLCK) pathway-related protein expression was verified by quantitative reverse transcriptase polymerase chain reaction or western blotting. The results indicated that the jejunal mucosa structure was destroyed, the villi were disrupted and shortened, and neutrophil infiltration was evident in the septic rats. Compared to Sham group, spetic rats had increased Chiu's score, serum inflammatory mediator levels, and FD-4 flux but decreased TJ and gap junction density. In addition, the expression of MLCK, p-MLC, and TJ proteins and the expression of P65 in the nucleus were increased in septic rats. Furthermore, compared to those in the Control group, LPS-treated Caco-2 cells showed lower cell viability and transepithelial electrical resistance, while had higher FD-4 flux and the expression of MLCK, p-MLC, TJ proteins and P65 in the nucleus. PHGG pretreatment reversed the above effects induced by CLP or LPS treatment. Moreover, SN50, an NF-κB inhibitor, attenuated the above effects of LPS on Caco-2 cells. Overall, PHGG reduced inflammation, increased TJ protein expression and localization, and relieved damage to the TJ structure and intestinal permeability through suppression of the NF-κB/MLCK pathway. This study provides new insights into the role of PHGG in sepsis therapy.

The influence of gut microbiota on Type 2 Diabetes Mellitus (T2DM) is an emerging area of research. This review investigates the relationship between gut microbiota dysbiosis, bacterial translocation, and T2DM. It aims to elucidate how microbial imbalances contribute to the progression of T2DM through bacterial translocation and to evaluate dietary and therapeutic strategies to manage these effects.

Recent studies highlight that dysbiosis in T2DM patients often leads to increased systemic inflammation, impaired glucose metabolism, and disrupted gut barrier integrity. These disruptions promote elevated levels of harmful bacterial components, such as lipopolysaccharides, in the bloodstream. This, in turn, is linked to worsening insulin resistance and metabolic dysfunction. Advances in molecular methods and biomarkers have provided deeper insights into bacterial translocation and its impact on diabetes. Dietary interventions, including nutraceutical agents, high-fiber and low-glycemic index diets, as well as the use of probiotics and prebiotics, have shown promise in restoring gut health and mitigating bacterial translocation.

Maintaining a balanced gut microbiota and intestinal barrier integrity is crucial for managing T2DM. Therapeutic strategies, including dietary modifications and nutraceuticals, have demonstrated potential in reducing bacterial translocation and systemic inflammation. Continued research is needed to refine these approaches and explore novel treatment modalities for improving metabolic health in T2DM patients.

Intestinal barrier damage is frequently caused by antibiotic therapy, potentially leading to bacterial translocation and toxin leakage, which triggers inflammation and increases the risk of various diseases. In this study, Tamarind seed polysaccharides (TSP) with different molecular weights were administered to mice during the recovery phase from clindamycin-induced intestinal barrier damage. The results indicated that TSP restored the shortened colon length, reduced the enlarged cecum index, and decreased the elevated level of inflammatory infiltration. Biochemical testing revealed that TSP decreased the levels of intestinal permeability biomarkers and inflammatory factors that were elevated by clindamycin treatment. Transcriptomics and non-targeted metabolomics analyses respectively uncovered changes in colon gene expression and fecal metabolites. The joint analysis of these omics data identified critical pathways, including arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings suggest that TSP could be a promising dietary supplement for protecting the intestinal barrier and alleviating inflammation.

Efferocytosis, the process by which apoptotic cells (ACs) are recognized and cleared by phagocytes, is a critical mechanism in maintaining intestinal immune homeostasis and promoting the resolution of inflammation. Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation, wherein defective efferocytosis contributes to the accumulation of ACs, secondary necrosis, and sustained mucosal damage. This review delineates the molecular mechanisms underlying efferocytosis and systematically examines its functional roles across five key intestinal phagocytic cell types: macrophages, dendritic cells (DCs), neutrophils, intestinal epithelial cells (IECs), and Paneth cells (PCs). Particular emphasis is placed on the dysregulation of efferocytosis capacity in IBD pathogenesis and the consequences of impaired apoptotic cell clearance in both professional and non-professional phagocytes. Furthermore, we evaluate emerging therapeutic strategies designed to restore or enhance efferocytosis, including modulation of macrophage polarization, LC3-associated phagocytosis pathways, nanotechnology-enabled delivery systems, and stem cell-based interventions. A comprehensive understanding of cell-type-specific efferocytosis in the intestinal microenvironment offers promising directions for the development of targeted, inflammation-resolving therapies for IBD.

The mucosal barrier serves as a crucial defense against external pathogens and allergens, being widely distributed across the respiratory, gastrointestinal, urogenital tracts, and oral cavity. Its disruption can lead to various diseases, including inflammatory bowel disease, asthma, urinary tract infections, and oral inflammation. Current mainstream treatments for mucosa-associated diseases primarily involve glucocorticoids and immunosuppressants, but their long-term use may cause adverse effects. Therefore, the development of safer and more effective therapeutic strategies has become a focus of research. Natural products, with their multi-target and multi-system regulatory advantages, offer a promising avenue for the treatment of mucosal diseases. This review summarizes the potential applications of natural products in diseases of mucosal barrier dysfunction through mechanisms such as immune modulation, inflammation inhibition, tight junction protein restoration, and gut microbiota regulation, with the aim of providing insights for the exploration of novel therapeutic strategies.

Polycystic ovary syndrome (PCOS) is a prevalent gynecologic endocrine disorder characterized by menstrual irregularities, elevated androgen levels, and ovulatory dysfunction. Its etiology is multifactorial. Emerging evidence indicates that PCOS patients exhibit diminished gut microbiota (GM) diversity and altered microbial ratios, contributing to the metabolic derangements observed in these individuals. This review elucidates the role of GM in the pathogenesis and metabolic disorders of PCOS, encompassing insulin resistance (IR), hormonal imbalances, bile acid metabolic disorders, Interleukin-22-mediated immune dysregulation, and brain-gut axis disturbances. Additionally, it synthesizes current therapeutic strategies targeting the GM, aiming to furnish a theoretical framework for prospective clinical interventions.

Background: Glutamate, a nutritionally non-essential amino acid, is a key intermediate in nitrogen metabolism. Despite more studies on its functional role in intestine health, it remains unknown how glutamate regulates nitrogen metabolism in animals fed a low-protein diet. Methods: Herein, we investigated the effects of glutamate supplementation on colonic amino acid transport, barrier protein expression, microbiota alterations, fecal nitrogen emissions, hepatic amino acid transport, and protein synthesis in weaned rats. Results: We found that protein restriction diminished the mucus thickness, reduced goblet cell numbers, and the expression of EAAT3, y+LAT2 in the colon. In contrast, glutamate supplementation reversed these effects, increasing the colon length and enhancing the expression of ZO-1, Occludin, and Claudin-1 in the colon. At the genus level, glutamate increased the abundance of Lactococcus and Clostridia_sensu_stricto_18. Additionally, glutamate supplementation resulted in an increased apparent nitrogen digestibility, reduced the ratio of fecal nitrogen to total nitrogen intake, and increased the ratio of fecal microbial nitrogen to total nitrogen intake. Protein restriction decreased the mRNA level of ATP1A1, EAAT3, SNAT9/2, and ASCT2, and the protein level of p-mTOR, mTOR, p-mTOR/mTOR, and p-p70S6K/p70S6K as well as p-4EBP1/4EBP1 in the liver. These effects were reversed by glutamate supplementation. Conclusions: In conclusion, glutamate supplementation upregulates amino acid transporters and barrier protein expression in the colon, modulates microbiota composition to reduce fecal nitrogen excretion, and enhances amino acid transport and protein synthesis in the liver by activating the mTOR/p70S6K/4EBP1 pathway, which influences nitrogen metabolism in weaned rats fed a low-protein diet.

The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca2+ influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.

Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.

This study investigated the protective effects of Garcinia biflavonoid 1 (GB1) against dextran sulfate sodium (DSS)-induced ulcerative colitis and its underlying mechanisms. Using wild-type (WT) and NLRP3 knockout (Nlrp3-/-) mice, we demonstrated that GB1 administration significantly ameliorated colitis symptoms, as evidenced by improved body weight, disease activity index (DAI) scores, colon length, and histological damage in WT mice. Mechanistically, GB1 downregulated pro-inflammatory mediators (IL-6, NF-κB, and CD11b) while attenuating the expression of NLRP3 inflammasome components (ASC, Caspase-1, and IL-1β). Notably, these protective effects were abolished in Nlrp3-/- mice, confirming the essential role of NLRP3 in GB1-mediated mitigation of colitis. Furthermore, GB1 reinforced intestinal barrier integrity by preserving tight junctions, reducing permeability, and attenuating mucosal inflammation. Collectively, our findings highlight GB1 as a promising therapeutic candidate for colitis treatment, primarily through NLRP3 inflammasome suppression and intestinal barrier restoration.

Inflammatory bowel disease (IBD) is a prevalent condition worldwide, characterized by complex etiologies, limited efficacy of clinical drug treatments, and potential adverse effects. In this study, we designed 269 nm selenium nanoparticles with double-cell targeting for ulcerative colitis treatment. Somatostatin (SST) and mannooligosaccharide (MOS) were employed to functionalize an Eucommia ulmoides polysaccharide selenium nanoparticle (EUP-SeNP), resulting in the formulation of SST/MOS@EUP-SeNP. Nanoparticles were engineered to target intestinal epithelial cells and macrophages through specific cell surface receptors, enabling dual-targeted treatment. In addition, sodium alginate (SA) microspheres incorporating SST/MOS@EUP-SeNP were prepared for oral administration, protecting the nanoparticles from gastric fluid. The results showed that SA/SST/MOS@EUP-SeNP could preferentially target the inflamed colon tissue and adhere to the colon, enhance the intestinal barrier function, regulate the level of colon inflammation, enhance antioxidant capacity, and regulate the composition of intestinal microbes to effectively relieve the colitis induced by sodium glucan sulfate (DSS). Meanwhile, SA/SST/MOS@EUP-SeNP had excellent biocompatibility both in vivo and in vitro. To some extent, this study can provide a reference for the treatment of IBD.