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Composition and structure of oleogels significantly influence their digestive behaviour, impacting triacylglycerol breakdown and the bioavailability of incorporated compounds. Texture profile analysis showed that sterol-based oleogels (STOs) exhibited 20 times higher hardness than beeswax-based oleogels (BWOs), which showed stronger cohesion due to elasticity sustained by adhesive forces. Tribological assessments revealed similar initial coefficients of friction (COF) for both oleogels. However, fluctuations were observed in BWOs and a gradual decrease in STOs over time, enhancing lubrication, while BWOs recorded higher adhesion. These findings provide insights into their distinct digestive behaviour, with both oleogels undergoing structural disintegration and STOs displaying a higher lipolysis degree. Non-cytotoxicity was confirmed under Caco-2 cells. β-carotene bioaccessibility was influenced by the oleogels' structural modification and values of 4.0 ± 0.7 % for STOs and 2.6 ± 1.1 % for BWOs were recorded. Results highlight the need to optimize formulations to improve bioactive's bioavailability, emphasizing the role of structured gels in modulating digestion dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ethnopharmacological Relevance: Ulcerative colitis (UC), a chronic inflammatory bowel disease, has become a significant public health challenge due to the limited effectiveness of available therapies. Huoxiang Zhengqi (HXZQ), a well-established traditional Chinese formula, shows potential in managing UC, as suggested by clinical and pharmacological studies. However, the active components and mechanisms responsible for its effects remain unclear., Aim of Study: This study aimed to identify the bioactive components of HXZQ responsible for its therapeutic effects on UC and to elucidate their underlying mechanisms., Materials and Methods: The effect of HXZQ against dextran sodium sulfate (DSS)-induced colitis was investigated. Ingredients in HXZQ were characterized and analyzed in colitic mice using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). In vitro, biological activity of compounds was assessed using lipopolysaccharide (LPS)-induced Ana-1 cells and bone marrow-derived macrophages (BMDMs), tumor necrosis factor-alpha (TNF-α)-induced Caco-2 cells, and isolated intestinal crypts from colitic mice. These results were confirmed in vivo. The targets of the components were identified through bioinformatics analysis and validated via molecular docking, enzyme inhibition assays, and in vivo experiments. Hematoxylin and eosin (HE) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative real-time polymerase chain reaction (qPCR) were employed to confirm the pharmaceutical effects., Results: A clinical equivalent dose of HXZQ (2.5 mL/kg) effectively treated DSS-induced colitis. A total of 113 compounds were identified in HXZQ, with 35 compounds detected in colitic mice. Glycyrrhizic acid (GA) and patchouli alcohol (PA) emerged as key contributors to the anti-colitic effects of HXZQ. Further investigation revealed that HXZQ and its active components decreased the levels of pro-inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) in colon, likely by inhibiting nuclear factor kappa-B (NF-κB) signaling pathway. This inhibition indirectly activated the intestinal farnesoid X receptor (FXR) signaling pathway, correcting bile acid imbalances caused by colitis. Additionally, these components significantly enhanced the expression of tight junction proteins ZO-1 and Occludin, as well as the adhesion protein E-cadherin, and reduced goblet cell loss, thereby repairing intestinal barrier injury. Mechanistically, GA and PA were found to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, leading to increased local active corticosterone levels in the intestine to exert anti-inflammatory effects. Notably, the inhibition of 11β-HSD1 with the selective inhibitor BVT2733 (BVT) ameliorated colitis in mice., Conclusions: HXZQ exhibits therapeutic effects on UC, primarily through GA and PA inhibiting 11β-HSD1. This suggests new natural therapy approaches for UC and positions 11β-HSD1 as a potential target for colitis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Magnolia officinalis Rehder & E.H. Wilson is traditionally used in the treatment of gastrointestinal disorders, diarrhea, and cough. Its main active ingredient, magnolol, exhibits protective effects on the lungs and gastrointestinal tract, including the inhibition of inflammation in these organs., Aim of the Study: This work aims to explore the molecular mechanism by which magnolol suppressed Chronic obstructive pulmonary disease (COPD) intestinal damage by improving the intestinal epithelial barrier., Materials and Methods: The study focused on investigating the mitigation effect of magnolol on intestinal injury and epithelial barrier in a COPD rat. Caco-2 cells were induced with TNF-α or IL-1β to establish the barrier injury model in order to explore the direct protective effect of magnolol on the intestinal barrier and elucidate the molecular mechanism by which it activates peroxisome proliferators-activated receptors-γ (PPARγ)., Results: Magnolol significantly improves pulmonary function and tissue damage in COPD rats by inhibiting inflammation, protease imbalance, and oxidative stress. It also suppresses colon tissue damage and inflammation, and protects colon epithelial barrier function by suppressing the decline of tight junction proteins, reducing colon epithelial permeability. In Caco-2 cells, magnolol directly reduces monolayer permeability, increases TEER, and upregulates tight junction protein expression induced by TNF-α or IL-1β. Drug Affinity Responsive Target Stability (DARTS) and thermal shift assays show that magnolol effectively binds to SRC, activating PPARγ signaling in Caco-2 cells and colon tissues of COPD rats. Furthermore, magnolol enhances the binding of PPARγ and RXRα, promoting their activation and entry into the nucleus. The PPARγ inhibitor GW9662 can reverse the effects of magnolol on PPARγ activation and tight junction protein upregulation in IL-1β or TNF-α induced Caco-2 cells., Conclusions: This work demonstrates that magnolol enhances lung and intestinal functions in COPD rats, and elucidates its mechanism of action in protecting the intestinal epithelial barrier by activating PPARγ., Competing Interests: Declaration of competing interest The authors state unequivocally that there are no known conflicts of interest related to this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

5-Fluorouracil (5-FU) is a primary chemotherapeutic agent for gastrointestinal cancers, known to improve survival but also cause significant intestinal damage, affecting patient quality of life. This study investigated the IL-23-IL-22 axis's role in moderating 5-FU-induced intestinal damage. We analyzed paracancerous tissue damage in colon cancer patients with different Tumor Regression Grade (TRG) and found a direct correlation between TRG and tissue damage severity, indicating that higher chemotherapy effectiveness is linked to increased tissue damage. In a 5-FU-treated mouse model, we observed severe intestinal damage and a reduction in proliferative cells. Transcriptome sequencing and immunofluorescence revealed that myeloid cells in damaged tissues produced IL-23, which activated ILC3s to secrete IL-22, promoting tissue repair and homeostasis. IL-22 supplementation in deficient mice significantly mitigated damage, underscoring the IL-22/IL-23 axis's potential as a therapeutic target to reduce chemotherapy-induced damage and enhance recovery. This research advances understanding of the biochemical responses to chemotherapy and suggests new avenues for developing therapies to maintain intestinal integrity during cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objectives: The aim is to analyze differentially expressed genes (DEGs) in mice with sepsis-related intestinal mucosal barrier damage and to explore the diagnostic and protective mechanisms of this condition at the transcriptome level., Methods: Small intestinal tissues from healthy male C57BL/6J mice subjected to Cecal ligation and puncture (CLP) and sham operation were collected. High-throughput sequencing was performed using the paired-end sequencing mode of the Illumina HiSeq platform. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted on the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified with Cytoscape. These hub genes were then validated using quantitative real-time polymerase chain reaction (RT-qPCR)., Results: A total of 239 DEGs were identified, with 49 upregulated and 130 downregulated genes. KEGG enrichment analysis showed that these DEGs were primarily involved in cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, viral protein interactions with cytokines and their receptors, and the IL-17 signaling pathway. The top 10 hub genes were selected using the cytoHubba plugin. Experimental validation confirmed that the expression levels of TBX21, CSF3, IL-6, CXCR3, and CXCL9 matched the sequencing results., Conclusion: TBX21, CSF3, IL-6,CXCR3, and CXCL9 may be potential biological markers for the diagnosis and treatment the sepsis-associated intestinal mucosal barrier., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Currently, there is limited research on the impact of abdominal infection on intestinal damage under microgravity conditions. Cordyceps polysaccharide (CPS), the main active ingredient of Cordyceps, has demonstrated various pharmacological effects, including anti-inflammatory, antioxidant, and immunomodulatory properties. Moxifloxacin (MXF) is a fourth-generation quinolone antibiotic that is believed to have a dual regulatory effect on immune system activation and suppression. Our objective was to investigate the effects of MXF plus CPS on the intestinal barrier damage due to abdominal infection under microgravity., Methods: The hindlimb unloading model in rats was employed to simulate microgravity. The rat model of abdominal infection was established by cecal ligation and puncture (CLP). MXF, CPS and the combination of the two drugs were used to treat CLP-rats in simulated microgravity. We assessed histopathological changes of ileum by hematoxylin and eosin staining. The intestinal ultrastructure was observed under transmission electron microscopy. Additionally, the expression of intestinal barrier proteins RegIII α/γ and MUC2 was detected by Western blot analysis, while the localization of these proteins within the ileum was examined using immunohistochemistry. Cytometric bead array (CBA) was employed to detect cytokine including IL-6, TNF-α, IL-1β, IL-1α, CXCL-1, MCP-1, IL-17A, IL-18, and IL-33. Flow cytometry analysis was conducted to determine the percentages of Treg cells, M1 macrophages, M2 macrophages, T cells and CD8 + T cells., Results: The results showed that compared with the normal gravity groups, the simulated microgravity groups exhibited a significant decrease in RegIII α/γ protein expression, an increase in M1 macrophage frequency, and elevated levels of TNF-α, IL-1α, MCP-1 and IL-6. Notably, the combined application of MXF and CPS effectively mitigated intestinal barrier damage in CLP-rats exposed to microgravity, as evidenced by alleviated ultrastructural and pathological impairments in ileum, along with increased expression of key intestinal barrier proteins MUC2 and RegIII α/γ. Furthermore, the combination therapy enhances the proportion of T cells, CD8 + T cells, and M2 macrophages in septic rats exposed to simulated microgravity while reducing the frequency of Treg cells and M1 macrophages. MXF plus CPS also led to a reduction of proinflammatory cytokines and chemokines, including IL-6, TNF-α, IL-1β, IL-1α, CXCL-1, MCP-1, IL18, and IL33., Conclusion: Our study showed that MXF plus CPS exhibited a protective effect on intestinal barrier damage due to abdominal infection under microgravity, potentially attributed to its anti-inflammatory properties and immune regulatory mechanisms. These findings may provide insights into the development of drugs targeting abdominal infections in the space environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Advanced glycation end products (AGEs) in processed foods are closely linked to intestinal injury. However, the long-term effects of exposure to free Nɛ-carboxymethyl lysine (CML), a prevalent AGE molecule, on intestinal barrier integrity have been rarely evaluated. This study investigated the temporal effects of CML exposure on intestinal barrier permeability in C57BL/6N mice at diet-related doses over 12, 14, and 16 weeks. No significant changes were observed at 12 weeks, but CML exposure significantly increased intestinal permeability at 14 and 16 weeks, accompanied by elevated serum LPS levels, colonic histological damage, and reduced tight junction protein expression at 16 weeks. CML exposure also altered gut microbiota composition and intestinal bile acid (BA) profiles, specifically reducing TDCA, GDCA, and GCDCA levels. Given the important role of colonic BA receptor signaling in maintaining the intestinal barrier integrity, the impact of CML on BA receptor signaling was assessed. CML exposure significantly downregulated BA receptor TGR5-YAP signaling in mice, while no significant effects were observed in vitro, suggesting that the changes observed in TGR5-YAP signaling in vivo may not result from the direct effects of CML. Spearman's correlation analysis revealed strong associations between altered gut microbiota, BA levels, TGR5-YAP signaling, and intestinal barrier injury. This study highlighted the chronic health risks of long-term CML intake and provided new insights into the links between CML-induced intestinal toxicity, gut microbiota, BA profiles, and BA receptor signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Xylooligosaccharides (XOS) ameliorate insulin resistance (IR) in gestational diabetes mellitus (GDM) probably by propagating Akkermansia muciniphila (Akk). This study aimed to investigate the effects and mechanisms of XOS, Akk and combination on IR in GDM mice/pseudo-germ-free (PGF) mice. Female mice were fed with AIN-93 (n = 19) and high fat diet (HFD) (n = 206). After 4 weeks, HFD-fed mice were further allotted to HFD, GDM, GDM + XOS, GDM + Akk, GDM + XOS + Akk, GDM + PGF, GDM + PGF + XOS, GDM + PGF + Akk, and GDM + PGF + XOS + Akk groups (n ≥ 19). GDM was induced by intraperitoneally injecting streptozotocin and PGF was established by intragastrically administrating antibiotic cocktails. XOS (500 mg/kg·BW) or/and Akk (4 × 10 8 CFU) were gavaged once a day for 10 days. Fasting blood glucose (FBG), insulin, oral glucose tolerance test (OGTT) and insulin signaling pathway were determined. Gut microbiota were detected by 16S rRNA sequencing and absolute quantities of Akk by qRT-PCR. Intestinal tissues were stained by Hematoxylin-Eosin and Periodic acid-Schiff-Alcian blue staining. Occludin and Zonula occludens-1 (ZO-1) in intestine, Natural killer group 2 member D (NKG2D) on intestinal epithelial lymphocytes (IELs) and NKG2D ligands (NKG2DL) on intestinal epithelial cells (IECs) were detected by Western blotting. In GDM mice, XOS, Akk and XOS + Akk reduced (p < 0.05) the area under the curve of OGTT (AUC), insulin and homeostasis model assessment of insulin resistance (HOMA-IR), and increased (p < 0.05) protein kinase B (Akt) phosphorylation in liver and insulin receptor substrate 1 (IRS-1) phosphorylation in muscle. Furthermore, XOS + Akk reduced (p < 0.05) FBG and increased (p < 0.05) Akt phosphorylation in muscle and IRS-1 phosphorylation in liver. XOS, Akk and XOS + Akk reshaped gut microbiota with XOS + Akk exhibiting the greatest effectiveness. XOS increased (p < 0.05) Akk and clearance of gut microbiota abolished such effect. XOS, Akk and XOS + Akk reduced (p < 0.05) the small intestine Chiu's score and the colon Dieleman's scores, increased (p < 0.05) ZO-1 and Occludin, and reduced (p < 0.05) NKG2D on IELs and NKG2DLs (H60, MULT-1, Rae-1ε) on IECs. Moreover, XOS + Akk reduced (p < 0.05) MULT-1 in duodenum. Collectively, XOS and Akk synergistically ameliorate IR by reshaping gut microbiota, improving intestinal barrier and regulating NKG2D/NKG2DL signaling in GDM mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Different physiological and pathological situations can produce alterations in the cell's endoplasmic reticulum (ER), leading to a condition known as ER stress, which can trigger an intricate intracellular signal transduction system known as the unfolded protein response (UPR). UPR is primarily tailored to restore proteostasis and ER equilibrium; otherwise, if ER stress persists, it can cause programmed cell death as a cytoprotective mechanism and drive inflammatory processes. Therefore, since intestinal cells strongly rely on UPR for their biological functions and unbalanced UPR has been linked to inflammatory, metabolic, and immune disorders, here we discussed the role of the UPR within the intestinal tract, focusing on the UPR contribution to inflammatory bowel disease development. Importantly, we also highlighted the promising potential of UPR components as therapeutic targets for intestinal inflammatory diseases., (© 2025 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti-inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides-induced improvement of increased intestinal permeability., Methods: Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats., Results: Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2-deoxy-d-glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon-like peptide-1 (GLP-1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose-dependent manner. The liraglutide-induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP-1 receptor antagonist attenuated 2-deoxy-d-glucose-induced improvement of colonic hyperpermeability in splenectomized rats., Conclusion: The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP-1 acts centrally in the brain to improve colonic hyperpermeability in a spleen-independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain-gut regulation in intestinal barrier function., (© 2024 John Wiley & Sons Ltd.)

Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline PKD1 mutations. In the kidney, Pkd1 loss impairs epithelial cell integrity and increases macrophage infiltration, contributing to cyst growth. Despite its role as the body's largest inflammatory cell reservoir, it has yet to be elucidated whether a similar phenotype presents in the intestines. We hypothesize that loss of Pkd1 leads to a leaky intestinal epithelial barrier and increased inflammation, before rapid cystogenesis. Control and inducible, global Pkd1 knockout ( Pkd1 KO) mice were euthanized at 3 and 6 mo of age (early and late stage) to evaluate kidney disease progression, small and large intestinal integrity, and inflammation. Early-stage Pkd1 KO mice displayed mild cystic kidneys and tubular injury with preserved kidney function. Intestinal epithelial barrier was tighter in KO mice, which was associated with higher expression of cell-cell epithelial integrity markers. However, there was no evidence of local or systemic inflammation in either genotype. Late-stage Pkd1 KO mice had severely cystic, impaired kidneys with increased expression of integrity markers, tubular injury, and inflammation. Intestinal epithelial barrier was leakier in late-stage Pkd1 KO mice, accompanied by gene reduction of integrity markers, increased inflammation, and elevated water and sodium channel expression. Gut motility and fecal water excretion were increased in Pkd1 KO compared with flox mice irrespective of age. Overall, kidney injury appears to precede intestinal injury in ADPKD, whereby the intestinal barrier becomes leaky as cystogenesis progresses. NEW & NOTEWORTHY Though autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder, this is the first study to explore a kidney-gut contribution to disease progression. We identified a tightened intestinal epithelial barrier in early PKD, which becomes leaky as kidneys become more cystic, accompanied by a sustained loss of fecal water. Given the only approved ADPKD therapeutic yields adverse aquaretic events, this study emphasizes the need to evaluate extrarenal water loss in patients before prescribing.

Forkhead box protein P3 (FOXP3) positive regulatory T lymphocytes are indispensable in the inflammatory homeostasis of the gastrointestinal tract and represent a significant subset of regulatory cells in inflammatory, autoimmune, and neoplastic conditions. This study aimed to elucidate the potential of FOXP3 expression in diagnosing and pathogenesis of celiac disease (CD) by comparing duodenal biopsies of CD cases with non-CD ones, some of which had increased intraepithelial lymphocytes (IELs). Two hundred sixty-one duodenal tissues of patients who applied to adult gastroenterology were reevaluated for immunohistochemical analysis. After excluding patients on a gluten-free diet (n = 44), the CD (n = 97) and non-CD (n = 120) groups were divided based on clinical complaints that could be associated with CD (intestinal or extraintestinal), serologic and histologic findings. The specific threshold was determined by receiver operating characteristic (ROC) analysis, and its relationship with CD diagnosis and clinicopathological data was evaluated. ROC analysis offered a ">14" cut-off value for diagnosing CD, for which AUC (Area Under The Curve): 0.968, p < 0.0001, sensitivity: 92.8, specificity: 91.7, positive and negative predictive values were 90 % and 94 %, respectively. High FOXP3 expression was associated with higher IEL, diagnosis of CD, more severe histologic (higher Marsh score) and endoscopic (scalloping) findings, and higher anti-tissue transglutaminase and anti-endomysium IgA titers (p < 0.001). It also correlates with IEL in CD patients and is unaffected by the increase in IEL and the presence of gastric Helicobacter Pylori in the non-CD group. FOXP3 is a sensitive and specific marker for diagnosing CD despite inflammatory conditions resulting from non-CD causes., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an important role in the maturation of PCs. Since there is an intimate interaction between PCs and ISCs, we speculated that the loss of Mist1 could impact these two neighboring cell types. Here, we report that mice lacking Mist1 had fewer but larger PCs with shrunken secretory granules, accompanied by an increase in goblet cells and tuft cells. Mist1 loss significantly decreased the number of proliferative crypt cells, especially columnar basal cells (CBCs). In addition, Mist1-deficient enteroids needed supplemental Wnt3a to support their growth. Results from RNA sequencing (RNA-seq) demonstrated an apparent deficiency of innate immunity in Mist1-knockout mice. Intriguingly, Mist1 loss increased the survival rate of mice subjected to whole abdominal irradiation (WAI). Moreover, radiation injury was ameliorated in Mist1-knockout mice compared with their wild-type littermates based on histological analysis and enteroid culture, which might be a consequence of increased contents of the endoplasmic reticulum (ER) and the increased activity of mTORC1 in Paneth cells. In summary, our data uncover that Mist1 plays an important functional role in PCs and regulates the maintenance of ISCs and their response to radiation injury. © 2025 The Pathological Society of Great Britain and Ireland., (© 2025 The Pathological Society of Great Britain and Ireland.)

The goal of this study was to determine whether the influence of a high-fat high-sugar diet (Western diet) on intestinal function and health was reversible. We measured transepithelial short circuit current ( I sc ), across freshly isolated segments of jejunum from male C57Bl/6J mice randomly assigned to one of the following groups for the study duration: high-fat high-sugar diet for 24 wk (HFHS), HFHS diet for 12 wk then switched to standard chow and water for a further 12 wk (Std), and lean controls (standard chow and water for 24 wk). At the completion of the study, segments of jejunum were frozen for Western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum and tissue assays were performed. Basal I sc was significantly decreased (by 42%, P < 0.05) in HFHS versus leans. This decrease in I sc was fully reversed by switching to Std diet. The HFHS-induced decrease in I sc was attributed to a significant loss of calcium-activated chloride channel (ClC2) expression. Changes in inflammatory state (TNF-α) and intestinal health [myeloperoxidase (MPO) activity] were associated with body weight changes. Our data suggests that the reduced basal jejunal I sc in HFHS mice is reversible. Better understanding of Western diet-mediated intestinal disturbances may permit for improved treatment options for gastrointestinal abnormalities in obese individuals. NEW & NOTEWORTHY Our data suggests that the reduced basal jejunal I sc (decreased secretory function) in Western diet-fed mice is reversible. A better understanding of Western diet-mediated intestinal disturbances may permit improved treatment options for gastrointestinal abnormalities in obese individuals.

The present study introduces a novel therapeutic approach for ulcerative colitis (UC) utilizing American ginseng vesicles encapsulated within a hyaluronic acid (HA) hydrogel matrix. UC, a prevalent form of inflammatory bowel disease, is characterized by chronic inflammation of the colonic mucosa, leading to significant morbidity and compromised quality of life. Existing therapeutic modalities such as 5-Aminosalicylic acid (5-ASA) are associated with substantial side effects and a high recurrence rate. Thus, there is an unmet need for alternative treatments that offer enhanced efficacy with reduced adverse effects. Leveraging the anti-inflammatory properties of American ginseng vesicles HA -hydrogels of HA hydrogel (5-ASA + ANPs@HA), this study presents a targeted drug delivery system designed to provide localized therapy for UC. We synthesized the hydrogel matrix by HA and 1,4-butanediol diglycidyl ether (BDDE) at concentrations of 1 % NaOH and 0.8 %, v/v, respectively. The water content of the hydrogel was about 80 % to 90 %, and 82 % of Rb1 was released in 61 min. Our results demonstrate a significant reduction in disease symptoms, a substantial decrease in pro-inflammatory cytokines, and marked enhancement in mucosal healing following treatment with the 5-ASA + ANPs@HA. Collectively, these results suggest that the 5-ASA + ANPs@HA represents a promising therapeutic strategy for UC, warranting further investigation for clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The success of graphene oxides has gained extensive research interests in developing novel 2D nanomaterials (NMs). WS 2 nanosheets (NSs) are novel transition metal-based 2D NMs, but their toxicity is unclear. In this study, we investigated the oral toxicity of WS 2 NSs to mouse intestines. Male mice were administrated with vehicles, 1, 10, or 100 mg/kg NSs via intragastric route, once a day, for 5 days. The results indicate that the NSs did not induce pathological or ultrastructural changes in intestines. There were minimal changes of trace elements that the exposure did not induce W accumulation, and only Co levels were dose-dependently increased. Lipid droplets were observed in all groups of mice, but lipidomics data indicate that WS 2 NSs only significantly decreased four lipid species, all belonging to phosphatidylcholine (PC). The levels of proteins regulating autophagic lipolysis, namely, LC3, lysosomal associated membrane protein 2 (LAMP2) and perilipin 2 (PLIN2), were increased, but it was only statistically significantly different for LC3. The results of this study suggest that repeated intragastric exposure to WS 2 NSs only induced minimal influences on pathological injury, trace element balance, autophagy, and lipid profiles in mouse intestines, indicating relatively high biocompatibility of WS 2 NSs to mouse intestine via oral route., (© 2024 John Wiley & Sons Ltd.)

The gut barrier is the first line of defense against harmful substances and pathogens in the intestinal tract. The balance of proliferation and apoptosis of intestinal epithelial cells (IECs) is crucial for maintaining the integrity of the intestinal mucosa and its function. However, oxidative stress and inflammation can cause DNA damage and abnormal apoptosis of the IECs, leading to the disruption of the intestinal epithelial barrier. This, in turn, can directly or indirectly cause various acute and chronic intestinal diseases. In recent years, there has been a growing understanding of the vital role of dietary ingredients in gut health. Studies have shown that certain amino acids, fibers, vitamins, and polyphenols in the diet can protect IECs from excessive apoptosis caused by oxidative stress, and limit intestinal inflammation. This review aims to describe the molecular mechanism of apoptosis and its relationship with intestinal function, and to discuss the modulation of IECs' physiological function, the intestinal epithelial barrier, and gut health by various nutrients. The findings of this review may provide a theoretical basis for the use of nutritional interventions in clinical intestinal disease research and animal production, ultimately leading to improved human and animal intestinal health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study aimed to investigate the effects of nicotinamide (NAM) applied to diets with different crude protein levels on immune function, antioxidant capacity, and intestinal flora in growing-finishing pigs. Forty barrows (37.0±1.0 kg) were randomly allocated to one of four dietary treatments (n=10 per group). The diets in the two phases consisted of a basal diet with 30 mg/kg NAM, a basal diet with 360 mg/kg NAM, a low-protein diet with 30 mg/kg NAM, and a low-protein diet with 360 mg/kg NAM. The results showed that dietary addition of 360 mg/kg NAM decreased IL-12, malondialdehyde, IgG and IgM contents in the plasma and increased total superoxide dismutase activity and total antioxidant capacity in the colonic mucosa (P < .05). Supplementing the diet with 360 mg/kg NAM increased mRNA expression of the nucleotide-binding oligomerization domain containing 2 and nuclear factor erythroid 2-related factor 2 and protein expression of nuclear factor kappa-B and toll-like receptor 4 in the colonic mucosa (P < .05). The concentrations of acetic acid and butyric acid in the colonic contents and the abundance of Actinobacteriota in the colon at the phylum level were significantly decreased by feeding low-protein diets (P < .05). Additionally, the addition of 360 mg/kg NAM to diets increased (P < .05) the Sobs, Ace, and Chao indices of colonic microorganisms in pigs. Overall, the rational use of NAM can improve inflammatory status, enhance antioxidant capacity and intestinal barrier function, and increase colonic microbial diversity in growing-finishing pigs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Taxifolin, a natural dihydroflavonol compound, possesses notable anti-inflammatory properties and regulatory effects on intestinal microbiota. In this study, gelatinized-retrograded corn starch (GCS) was utilized as a carrier for colonic delivery of taxifolin, and its therapeutic efficacy against dextran sulfate sodium (DSS)-induced colitis in mice were systematically investigated. Taxifolin can integrate into the helical structure of starch, and the formation of GCS-Taxifolin complexes (GCS-Tax) significantly delayed the release of taxifolin in vitro. After oral administration of GCS-Tax, fecal excretion of taxifolin increased from 0.42 % to 10.89 % within 24 h compared to free taxifolin. Moreover, GCS-Tax facilitated the production of short-chain fatty acid in mice and effectively alleviated DSS-induced colitis symptoms, including weight loss, bloody stools, and colonic tissue damage. Additionally, GCS-Tax significantly suppressed proinflammatory factors such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS), while elevating anti-inflammatory interleukin-10 (IL-10) level in mice serum. Furthermore, it restored intestinal mucosal barrier function by upregulating the expression of Mucin 2, Occludin, and zonula occludens-1 (ZO-1), reducing Beclin 1 expression, and exhibited hepatoprotective effects by enhancing total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities. High-throughput sequencing analysis revealed that GCS-Tax improved intestinal flora diversity, reducing inflammation-related Bacterium 1 and Staphylococcus, while promoting the abundance of beneficial bacteria like Lachnospiraceae., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Postweaning intestinal damage in piglets is a challenging issue in the livestock industry. Short-chain fatty acids (SCFAs) are important metabolic products of the gut microbiota and are widely recognized for their role in maintaining normal colonic function and regulating the intestinal immune system. However, the effects of branched short-chain fatty acid (BSCFA) isobutyrate on intestinal health remain largely unknown. This study aims to explore the potential of isobutyrate for alleviating postweaning intestinal damage., Results: This study indicates that isobutyrate can alleviate diarrhea in weaned piglets, enhance their growth performance, and optimize the gut microbiota. This is mainly achieved through increasing the relative abundance of probiotic bacteria such as Lactobacillus, Megasphaera, and Prevotellaceae&#95;UCG-003, while concurrently reducing the relative abundance of potentially harmful bacteria such as Clostridium&#95;sensu&#95;stricto-1 and Escherichia-Shigella. It promotes the production of SCFAs, including acetate, isobutyrate, and butyrate. Furthermore, it activates G-protein-coupled receptors (GPR43/109A), inhibits the TLR4/MyD88 signaling pathway, strengthens the intestinal barrier function, and regulates the expression of related cytokines., Conclusion: In summary, exogenous isobutyrate can be considered a promising feed additive for improving the intestinal microbiota and regulating intestinal health in piglets. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Objective: Physalis Peruviana Linnaeus (PPL) is an herbaceous species characterized by a wide variety of bioactive compounds to which anti-inflammatory properties have been attributed. This makes this fruit a possible complementary therapy for diseases that involve chronic inflammation, such as inflammatory bowel diseases (IBD). In the present study, the effect of a PPL extract on the expression of inflammatory markers in the Caco-2 cell line was evaluated., Methods: An in vitro gastric digest (50 g PPL pulp) was performed, obtaining an extract that was used to challenge Caco-2 cells for 24 and 72 hours. This extract was characterized by LC-MS/MS. Then, the relative mRNA expression of NF-kB, TLR4, IL-18 and MCP-1 was determined through qRT-PCR and the protein levels of TNF-α, IL-6, IL-8, IL-18 and MCP-1 through Luminex Immunoassay., Results: From the characterization of the extract, compounds with bioactive potential such as isothiocyanates, indoles and coumarins were found. Treatment of Caco-2 cells with PPL extract (80 µg/ml), particularly for 72 hours, produced a reduction of IL-18 and MCP-1 mRNA expression ( p < 0.01), in addition to IL-18 ( p < 0.01), IL-8 ( p < 0.0001) and MCP-1 ( p < 0.01) protein levels, however, no effects on NF-kB p65 ( p = 0.09) and TLR4 ( p = 0.20) mRNA expression were observed., Conclusion: The results obtained in this study open the possibility that the regular consumption of 50 g of PPL could constitute a possible complementary therapy for the treatment of IBD, improving the quality of life of these patients.

Emerging cellulose nanomaterials (CNMs) may have commercial impacts in multiple sectors, being their application particularly explored in the food sector. Thus, their potential adverse effects in the gastrointestinal tract should be evaluated before marketing. This work aimed to assess the safety of two CNMs (CNF-TEMPO and CMF-ENZ) through the investigation of their cytotoxicity, genotoxicity (comet and micronucleus assays), and capacity to induce reactive oxygen species in human intestinal cells, and their mutagenic effect using the Hprt gene mutation assay. Each toxicity endpoint was analysed after cells exposure to a concentration-range of each CNM or to its digested product, obtained by the application of a standardized static in vitro digestion method. The results showed an absence of cytotoxic effects in intestinal cells, up to the highest concentration tested (200 µg/mL or 25 µg/mL, for non-digested and digested CNMs, respectively). Of note, the cytotoxicity of the digestion control limited the top concentration of digested samples (25 µg/mL) for subsequent assays. Application of a battery of in vitro assays showed that CNF-TEMPO and CMF-ENZ do not induce gene mutations or aneugenic/clastogenic effects. However, due to the observed DNA damage induction, a genotoxic potential cannot be excluded, even though in vitro digestion seems to attenuate the effect. The lowest digested CNF-TEMPO concentration induced chromosomal damage in Caco-2 cells, leading to an equivocal outcome. Ongoing research on epigenotoxic effects of these CNMs samples may strengthen the lines of evidence on their safety when ingested, paving the way for their innovative application in the food industry., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s).)

The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cadmium (Cd) disrupts the immune system and intestinal barrier, increasing infection risk and gut dysbiosis. Its impact on intestinal fungi, particularly the opportunistic pathogen Candida albicans, which can cause systemic infections in immunocompromised patients, is not well understood. Our study revealed that C. albicans exhibited high tolerance and maintained its morphogenetic switching in response to Cd. As C. albicans is not naturally found in the mouse gut, we attempted intestinal colonization of C. albicans-SC5314 strain using standard procedures. However, the intestinal fungal load decreased and was undetectable by 15th day. To assess the effects of sub-chronic Cd exposure, both oral and intravenous methods were used. Oral exposure to C. albicans (10 5  CFU/ml) resulted in a 10-fold increase in intestinal translocation in Cd-exposed mice (0.98 mg/kg) compared to controls. Cd exposure also downregulated intestinal tight junction proteins and increased FITC-dextran permeability, indicating that Cd disrupts the intestinal barrier and facilitates C. albicans translocation. Moreover, Cd-exposed mice showed significant morbidity and higher fungal loads in organs after intravenous non-lethal dose of C. albicans, along with a subdued cytokine response. These findings highlight the significant impact of Cd on fungal pathogenicity and immune response, pointing to the broader health risks of Cd exposure., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged, as defined by unique gene expression profiles, indicating potentially novel biological functions. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions. Our analysis of subtype-specific gene expression and pathway enrichment showed variances in tuft cell subtypes between healthy individuals and those with inflammatory bowel disease (IBD). The frequency of TC1 and TC2 differed between healthy controls and IBD. Relative to healthy controls, TC1 and TC2 in IBD tissue showed an upregulation of gene expression, favoring increased metabolism and immune function. These findings provide foundational knowledge about the complexity of the human colon tuft cell population and hint at their potential contributions to gut health. They provide a basis for future studies to explore the specific roles these cells may play in gut function during homeostasis and disease. We demonstrate the value of in silico approaches for hypothesis generation in relation to the putative functions of low-frequency gut cells for subsequent physiological analyses. NEW & NOTEWORTHY This study reveals the nuanced and novel landscape of human colonic tuft cells through integrative scRNA-seq analysis. Four distinct tuft cell subtypes were identified, varying markedly between healthy and individuals with IBD. We uncovered human colonic tuft cell subtypes with unexpected antimicrobial and progenitor-like gene expression signatures. These insights into tuft cell diversity offer new avenues for understanding gut health and disease pathophysiology.

The discovery that vitamin D 2 is being generated by anaerobic microbial metabolism in the alimentary tract, raises the question whether such a source of vitamin D could contribute to vitamin D supply for the animal hosting this microbial production system. In ruminants, this microbial generation in the forestomach allows vitamin D 2 to be readily absorbed when it reaches the small intestine, contributing to vitamin D 2 and 25-hydroxyvitamin D 2 [25(OH)D 2 ] found in their tissues. In monogastric animals like humans, the microbial generation of vitamin D 2 is occurring in the large intestine. There is evidence that vitamin D hydroxy metabolites, delivered to the lumen of the colon can be absorbed. However, the parent vitamin D is more lipophilic than its metabolites, and like lipophilic vitamin K 2 being produced by bacteria in the hindgut, may be poorly absorbed by the colon mucosa. It is now apparent that colon mucosal cells have the proteins megalin and cubilin in their basal membrane. These glycoproteins perform endocytosis of circulating proteins including vitamin D binding protein [DBP]. Inside the cell, DBP binds to cytoplasmic actin and thus provides an array of high affinity binding sites for vitamin D and its functional metabolites. Any traces of vitamin D 2 that may diffuse into the colon mucosal cells from the lumen would thus be retained and accumulate on the DBP-actin. It would then be a substrate for functional hydroxylase metabolism for local endocrine action in these cells, and subsequent delivery of 25(OH)D 2 by diffusion to apo-DBP in the circulation., Competing Interests: Declaration of competing interest The author has no competing interests to declare., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

The integrity of colonic gland cells is a prerequisite for normal colonic function and maintenance. To evaluate the underlying injury mechanisms in colonic gland cells induced by excessive fluoride (F), forty-eight female Kunming mice were randomly allocated into four groups and treated with different concentrations of NaF (0, 25, 50, and 100 mg F - /L) for 70 days. As a result, the integrity of the colonic mucosa and the cell layer was seriously damaged after F treatment, as manifested by atrophy of the colonic glands, colonic cell surface collapse, breakage of microvilli, and mitochondrial vacuolization. Alcian blue and periodic acid Schiff staining revealed that F decreased the number of goblet cells and glycoprotein secretion. Furthermore, F increased the protein expression of TLR4, NF-κB, and ERK1/2 and decreased IL-6, interfered with NF-κB signaling, following induced colonic gland cells inflammation. The accumulation of F inhibited proliferation via the JAK/STAT signaling pathway, as characterized by decreased mRNA and protein expression of JAK, STAT3, STAT5, PCNA, and Ki67 in colon tissue. Additionally, the expression of CDK4 was up-regulated by increased F concentration. In conclusion, excessive F triggered colonic inflammation and inhibited colonic gland cell proliferation via regulation of the NF-κB and JAK/STAT signaling pathways, leading to histopathology and barrier damage in the colon. The results explain the damaging effect of the F-induced inflammatory response on the colon from the perspective of cell proliferation and provide a new idea for explaining the potential mechanism of F-induced intestinal damage., Competing Interests: Declarations. Ethics Approval: All ethical procedures for animal experiments were reviewed and supported (SCXK (YU) 2021-0009). Competing Interests: The authors declare no competing interests. Consent for Publication: Not applicable. Consent to Participate: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease impacting both the respiratory and gastrointestinal systems, with its pathogenesis closely linked to the lung-gut axis theory. In this study, we established a rat model of COPD using a fumigation method combined with intra-airway administration of lipopolysaccharide (LPS) to investigate the effects of lactulose on lung and intestinal tissues, focusing on related inflammatory markers and the TLR4/NF-κB signaling pathway. We further explored the therapeutic effects and mechanisms of lactulose on the lung-intestinal tissues in COPD rats, aiming to expand its potential application in chronic respiratory diseases. Subsequently, damage to lung and colon tissue was assessed using hematoxylin and eosin (HE) staining techniques, and ultrastructural changes in lung tissue cells were observed using transmission electron microscopy. Additionally, the study detected the expression of TNF-α, IL-1β, MUC5AC, TLR4, and NF-κB in lung tissue, along with the expression of MUC2, TLR4, and NF-κB in colon tissue, to evaluate the degree of tissue damage. The research findings indicated that the integrity of the airway and colon mucosal barrier in COPD rats was compromised. Intervention with lactulose significantly reduced pathological damage to lung and intestinal tissue and improved the microstructure of lung tissue. In addition, lactulose downregulated the expression of TNF-α, IL-1β, and MUC5AC in lung tissue, upregulated the expression of MUC2 in colon tissue, and inhibited the activity of the TLR4/NF-κB signaling pathway in lung and colon tissue, effectively mitigating inflammatory damage. Our findings demonstrated that lactulose effectively alleviates COPD-associated inflammation by inhibiting the TLR4/NF-κB signaling pathway within the lung-gut axis, underscoring its promise for treating multi-organ inflammation. This study provides a novel diagnostic and therapeutic perspective for the systemic management of COPD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sanguinarine constitutes the main components of Macleaya cordata, and exhibits diverse biological and pharmacological activities. This study investigated the effects of sanguinarine chloride hydrate (SGCH) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. Five groups were designed to investigate the effects of SGCH on the pathological symptoms, the mRNA expression levels of inflammatory cytokines, colonic mucosal barrier damage, microbiota composition, and SCFAs metabolism in UC mice. The administration of SGCH in DSS-induced UC mice resulted in the amelioration of pathological symptoms, as evidenced by an increase in body weight, a decrease in disease activity index score, elongation of colon length, reduction in spleen index, and improvement in colon injury. SGCH can regulate the expression of inflammatory cytokines (IL-6, TNF-α, IL-1β and IL-10) and tight junction proteins (ZO-1 and Occludin) associated with UC. SGCH exhibited a significant decrease in NF-κB P65 mRNA expression levels, accompanied by a significantly reduced protein level of NF-κB P-P65/P65. Further studies revealed SGCH effectively reversed the decrease in intestinal microbiota diversity induced by UC, thereby promoting the growth of beneficial bacteria such as Akkermansia, Alistipes, and norank&#95;o&#95;Clostridia&#95;UCG-014. Correlation analysis demonstrated a positive association between butanoic acid, propanoic acid, isobutyric acid, isovaleric acid, valeric acid, hexanoic acid with Colidextribacter, while Coriobacteriaceae&#95;UCG-002 exhibited a negative correlation with butanoic acid, acetic acid and propanoic acid. In conclusion, the administration of SGCH can ameliorate clinical symptoms in UC mice, regulate the expression of inflammatory cytokines and tight junction proteins, modulate intestinal microbiota metabolism and SCFAs production., Competing Interests: Declaration of competing interest All authors of this manuscript state that they do not have any conflict of interest, and there is nothing to disclose. This study did not involve human participants. The animal study was approved by Ethical Review Committee of Laboratory Animal Welfare of Yunnan Agricultural University. The study was conducted in accordance with the local legislation and institutional requirements., (Copyright © 2024. Published by Elsevier B.V.)

Researchers have reported that soluble undenatured type II collagen (SC II) and hydrophobic phytochemicals (HPs) can ameliorate osteoarthritis (OA) through several mechanisms. However, the solubility of HPs, the stability of SC II, and the bio-accessibility of both need to be greatly improved before they can be successfully used for this purpose. In this study, two common HPs, curcumin (CUR, a hydrophobic polyphenol) and astaxanthin (AST, a carotenoid), were first loaded into SC II, which was then complexed with chondroitin sulfate (CS) to form ternary complexes: SC II-HP-CS. The results showed that SC II had the highest loading capacity for CUR (19.00 ± 0.76 μg/mg) and AST (21.15 ± 1.67 μg/mg) at pH 2.0. The CUR and AST bound to the SC II through non-covalent interactions (mainly hydrophobic interaction) and they both existed in an amorphous form within the complexes. In addition, the binding affinity and hydrophobic interaction between SC II and CUR was higher than those of AST. The thermal stability of the SC II-CUR-CS (T d  = 118.0 ± 2.1 °C) and SC II-AST-CS (T d  = 118.8 ± 3.5 °C) complexes were significantly higher than that of the SC II-CUR (T d  = 104.27 ± 0.28 °C) and SC II-AST (T d  = 103.8 ± 1.6 °C) complexes. SC II-HP complexes dissolved in gastric fluids, resulting in serious degradation of the SC II, while SC II-HP-CS complexes existed in an insoluble form to protect the triple helix structure of SC II (24-46 % retained). The CUR release (94.2 ± 5.8 %) and the free radical scavenging activity (84.6 ± 5.3 %) of SC II-CUR-CS was relatively high after 6 h of intestinal digestion, while AST in SC II-AST and SC II-AST-CS had low solubility and antioxidant activity. Therefore, the ternary complex of SC II-HP-CS was more advantageous as multifunctional delivery systems for the encapsulation, protection, and controlled release of hydrophobic polyphenols, which may provide guidance for the synergistic use of hydrophobic polyphenols and SC II to improve OA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Dachaihu decoction (DCH) is a famous and ancient TCM formula, extensively utilized for over 1800 years in treating gastrointestinal and inflammatory conditions. Our previous study showed that DCH ameliorated intestinal damage and modulated the gut microflora in septic rats. However, the material basis for these effects and the underlying mechanism of action remains ill-defined. We aimed to explore the pharmaceutical ingredients of DCH and its mechanism in mitigating sepsis-induced intestinal epithelial barrier disruption (IEBD)., Materials and Methods: Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) was used to identify DCH composition. A septic rat model and Caco-2 cells were employed to investigate DCH's effects on IEBD. Transcriptomics and network pharmacology were used to predict potential mechanisms, which were further validated by molecular docking and dynamics simulations. The Modified Murine Sepsis Score (mMSS) and histological assessments were performed. Serum fluorescence intensity of FD4 and the expression of Occludin were evaluated to assess intestinal barrier integrity. And p-PI3K P85, PI3K P85, p-AKT, AKT, Bax and Bcl-2 were determined by Western blot. Cell viability was determined using CCK-8 assay, IL-6 and TNF-α by ELISA and quantitative Real-time PCR (RT-qPCR). The integrity and permeability of single layer of Caco-2 cells were assessed via transepithelial resistance (TEER), alkaline phosphatase (ALP) activity and FD4 permeability., Results: UHPLC-HRMS identified 180 compounds in DCH. DCH significantly reduced mMSS, improved pathological conditions in the ileum, decreased FD4 serum fluorescence, and enhanced Occludin expression. Transcriptomic and network pharmacology analyses identified the PI3K/AKT pathway as a critical mechanism of action. Molecular docking and dynamics simulations confirmed strong binding of DCH components to PIK3R1. DCH upregulated p-PI3K and p-AKT in ileum tissue of septic rats. DCH improved cell viability, decreased IL-6 and TNF-α, promoted cell survival and Occludin level, and upregulated p-PI3K and p-AKT in LPS-stimulated Caco-2 cells. DCH also maintained TEER, ALP activity and decreased FD4 permeability and these effects were reversed by PI3K inhibitor, LY294002. DCH also downregulated Bax expression and increased Bcl-2 levels in both septic rats and LPS-stimulated Caco-2 cells., Conclusion: DCH ameliorates sepsis-induced IEBD via PI3K/AKT pathway activation, offering a novel therapeutic perspective for sepsis-related intestinal dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Qing Chang Suppository (QCS), a traditional Chinese medicine formula, has been shown to effectively alleviate mucosal inflammation in patients with ulcerative colitis (UC). While the mechanism of QCS appears to be related to the regulation of CD4 + T cell subset responses, direct evidence demonstrating that QCS inhibits Th1 and Th17 cell activation in UC (particularly based on human data) remains lacking. Additionally, the precise mechanisms through which QCS affects these cells have yet to be fully elucidated., Aim of Study: This study aimed to investigate the effects of QCS on Th1 and Th17 cell responses in UC and to explore the underlying mechanisms., Materials and Methods: Twenty-eight patients with mild-to-moderate UC were recruited and treated with QCS for 12 weeks. Symptoms were assessed every two weeks, with sigmoidoscopies performed at baseline and at week 12. Intestinal mucosal biopsies and peripheral blood (PB) were collected at these time points. At the end of the trial, patients were categorized into responder and non-responder groups based on a modified Mayo disease activity index score. Healthy controls (HCs) were defined as subjects without IBD or colorectal carcinoma but with colon polyps. The frequencies of IFN-γ + CD4 + T cells and IL-17A + CD4 + T cells in PB and colonic mucosa were measured using flow cytometry. The expression levels and localization of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A were determined via immunofluorescence, and JNK signaling activation was assessed through immunoblotting and immunohistochemistry. All parameters were compared across the three groups., Results: At week 12, responders showed a significant reduction in colonic mucosal inflammation compared to baseline, accompanied by decreased frequencies of IFN-γ + CD4 + T and IL-17A + CD4 + T cells in both PB and the colonic epithelial layer. Notably, Th1 and Th17 cell activity around intestinal epithelial cells (IECs) was nearly undetectable, as evidenced by the diminished expression of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A. Additionally, JNK phosphorylation in these cells was significantly reduced. In contrast, non-responders exhibited no meaningful improvement; colonic pathology remained unchanged, and elevated levels of IFN-γ + CD4 + T and IL-17A + CD 4 + T cells persisted in both the PB and colonic epithelial layer. The presence of Th1 and Th17 cells and their associated cytokines around IECs remained substantial, and there was no significant change in JNK activation., Conclusion: QCS attenuates mucosal inflammation in UC patients by inhibiting the differentiation and effector functions of Th1 and Th17 cells, primarily through the regulation of the JNK signaling pathway., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bacterial toxins are emerging as promising hallmarks of colorectal cancer (CRC) pathogenesis. In particular, Cytotoxic Necrotizing Factor 1 (CNF1) from E. coli deserves special consideration due to the significantly higher prevalence of this toxin gene in CRC patients with respect to healthy subjects, and to the numerous tumor-promoting effects that have been ascribed to the toxin in vitro. Despite this evidence, a definitive causal link between CNF1 and CRC was missing. Here we investigated whether CNF1 plays an active role in CRC onset by analyzing pro-carcinogenic key effects specifically induced by the toxin in vitro and in vivo., Methods: Viability assays, confocal microscopy of γH2AX and 53BP1 molecules and cytogenetic analysis were carried out to assess CNF1-induced genotoxicity on non-neoplastic intestinal epithelial cells. Caco-2 monolayers and 3D Caco-2 spheroids were used to evaluate permeability alterations specifically induced by CNF1, either in the presence or in the absence of inflammation. In vivo, an inflammatory bowel disease (IBD) model was exploited to evaluate the carcinogenic potential of CNF1. Immunohistochemistry and immunofluorescence stainings of formalin-fixed paraffin-embedded (FFPE) colon tissue were carried out as well as fecal microbiota composition analysis by 16 S rRNA gene sequencing., Results: CNF1 induces the release of reactive oxidizing species and chromosomal instability in non-neoplastic intestinal epithelial cells. In addition, CNF1 modifies intestinal permeability by directly altering tight junctions' distribution in 2D Caco-2 monolayers, and by hindering the differentiation of 3D Caco-2 spheroids with an irregular arrangement of these junctions. In vivo, repeated intrarectal administration of CNF1 induces the formation of dysplastic aberrant crypt foci (ACF), and produces the formation of colorectal adenomas in an IBD model. These effects are accompanied by the increased neutrophilic infiltration in colonic tissue, by a mixed pro-inflammatory and anti-inflammatory cytokine milieu, and by the pro-tumoral modulation of the fecal microbiota., Conclusions: Taken together, our results support the hypothesis that the CNF1 toxin from E. coli plays an active role in colorectal carcinogenesis. Altogether, these findings not only add new knowledge to the contribution of bacterial toxins to CRC, but also pave the way to the implementation of current screening programs and preventive strategies., Competing Interests: Declarations. Ethics approval: This study was carried out according to the European Guidelines for the Care and the Use for Laboratory Animals (authorization n° 787/21-PR). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, life span, and stress resistance. In Caenorhabditis elegans, DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, insulin-3 (INS-3), plays a crucial role in modulating the response to various environmental stressors in C. elegans. ins-3 mutants display increased resistance to heat, oxidative stress, and starvation; however, this advantage is countered by slower reproductive development under favorable conditions. We find that ins-3 expression is downregulated in response to environmental stressors, whereas, the neurohormone tyramine, which is released during the acute flight response, increases ins-3 expression. We show that tyramine induces intestinal calcium (Ca2+) transients through the activation of the TYRA-3 receptor. Our data support a model in which tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine via the activation of a TYRA-3-Gαq-IP3 pathway. The release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO. These studies offer mechanistic insights into a brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stressors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Veuthey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ulcerative colitis is a chronic idiopathic inflammatory disease that impacts the mucous membrane of the colon. Lately, the incidence and prevalence of UC has been increasing globally. However, there are significant side effects of existing drugs for UC intervention. Accordingly, there is a pressing demand to explore novel bioactive substances for addressing UC. Natural product saponins have attracted great attention due to their obvious anti-colitis potential. Capilliposide A is a triterpenoid saponin, which is derived from Lysimachia capillipes Hemsl., exhibits good anti-inflammatory activity. Nonetheless, the impact and mechanism of CPS-A on ulcerative colitis remains obscure. This study aimed to investigate the therapeutic effects of CPS-A on the dextran sulphate sodium induced colitis mouse model and explore its mechanism. The efficacy and safety of CPS-A were evaluated in a well-established dextran sodium sulfate (DSS)-induced colitis mice model. Disease progression was monitored via clinical symptoms, histopathological examination, quantification of inflammatory cytokines, and epithelial barrier function evaluation. Plasma samples and intestinal contents were collected for non-targeted metabolomics and 16sRNA sequencing, respectively, to jointly evaluate the mechanism of action. CPS-A alleviated colitis by improving weight, Disease activity index score, histopathology, goblet cell, colon length, and expression of inflammatory factors. Moreover, CPS-A effectively preserved the integrity of the intestinal barrier by enhancing the expression of tight junction proteins and mucin in the colonic tissue of mice. Furthermore, CPS-A exerted a regulatory effect on the composition of the gut microbiota, promoting bacterial richness and diversity. It not only suppressed the abundance of detrimental bacteria while enhancing the abundance of advantageous bacteria, but also modulated the metabolites derived from the intestinal flora. Importantly, correlation analysis shows that these indicators are highly correlated. This study revealed that CPS-A exhibits a favorable therapeutic efficacy against colitis, primarily attributed to its ability to modulate the gut microbiota their associated metabolites as the key mechanisms of action., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immune injury is the main side effect caused by cyclophosphamide and the disruption of the intestinal barrier may be an important cause. Yupingfeng granules have been reported to have immunomodulatory effects and polysaccharides are important components of them. This study aimed to investigate the ameliorative effect of polysaccharides from Yupingfeng granules (YPFP) on cyclophosphamide induced immune injury and reveal their potential mechanisms based on its protective effect on the intestine. YPFP were isolated and preliminarily characterized. Pharmacodynamic evaluation revealed that YPFP treatment could effectively mitigate lesions of immune organs, ameliorate white blood cells and downregulate IL-10 level. Further, the protective effect of intestinal barrier on the basis of intestinal tight junctions, MUC-2, microflora, endogenous metabolites, pathways and immune cells was discussed to outline mechanisms. The results showed that YPFP repaired the integrity of intestinal epithelium, enhanced the abundance of Muribaculaceae&#95;unclassified, Bacteroide and Muribaculum, downgraded the abundance of Lachnospiraceae&#95;NK4A136&#95;group, improved the excretion of lipids and bile acids especially 3-oxo-LCA, increased the content of SCFAs in feces and inhibited the expression of key proteins of PI3K-AKT and MAPK-JUN pathways. More importantly, Th17 and Treg balance was remodeled after YPFP administration, which might be related to certain differential metabolites and pathways enriched by metabolomics. This study provides a rich understanding of YPFP and lays a foundation for further development of Yupingfeng granules. It was shown for the first time that the immunomodulatory effect of YPFP might be involved in multiple mechanisms of intestinal homeostasis. YPFP could be regarded as an immunomodulator to alleviate immune damage caused by cyclophosphamide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The incidence of obesity is increasing annually worldwide. A high-fat diet (HFD) causes intestinal barrier damage, but effective interventions are currently unavailable. Our previous work demonstrated the therapeutic effect of nobiletin on obese mice; thus, we hypothesized that nobiletin could reverse HFD-induced damage to the intestinal barrier. Male C57BL/6 J mice were orally administered nobiletin for 14 d. After identification, the obese mice were equally divided into three groups: the HFD group, the low-dose (NOL, 100 mg/kg/d) group and the high-dose nobiletin (NOH, 200 mg/kg/d) group. A normal control group (CON) was also included. Hematoxylin and eosin (HE) staining and immunofluorescence were used to observe the intestinal barrier. RT-qPCR was used to determine the transcriptomic levels of genes involved in intestinal barrier integrity and lipid metabolism. The results revealed that intestinal tight proteins, including ZO-1 and Occludin, were significantly reduced in HFD-fed mice but markedly restored after nobiletin intervention, particularly in NOH mice. Improvements in the intestinal barrier and lipid metabolism associated with major histocompatibility complex class II (MHC-II) and relevant elements were revealed after nobiletin intervention. Enrichment analysis revealed that MHC-II plays an important role in the restoration of the intestinal barrier. Taken together, nobiletin restored intestinal barrier integrity and lipid metabolism by regulating MHC-II expression., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were performed according to the protocol approved by the Ethics Committee of Chengdu University of Traditional Chinese Medicine (License: 2021-05). Consent for publication: Not applicable. Competing interests: The authors declare that they have no potential competing interests., (© 2025. The Author(s).)

There are limited studies on the improvement of leaky gut with minor inflammation associated with various diseases. To explore the therapeutic potential of Lactiplantibacillus plantarum 22 A-3, a member of the Lactobacillus species, in addressing a leaky gut. Lactiplantibacillus plantarum 22 A-3 was administered to a leaky gut mice model with low dextran sulfate sodium concentrations. The Lactiplantibacillus plantarum 22 A-3-treated group exhibited amelioration of increased intestinal permeability, as indicated by lower blood fluorescein isothiocyanate-dextran levels compared with that of the control group. Furthermore, the messenger RNA expression of interleukin-10, an anti-inflammatory cytokine, was upregulated in the small intestine of Lactiplantibacillus plantarum 22 A-3-treated mice. Moreover, forkhead box P3 was upregulated in the small intestine and colon following Lactiplantibacillus plantarum 22 A-3 administration. Flow cytometry showed that forkhead box P3-positive regulatory T cells tended to increase in the small intestine and colon; however, this was not significant. Messenger RNA levels for the pro-inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha showed no significant changes in the small intestine; however, their expressions significantly decreased in the colon. Blood fluorescein isothiocyanate-dextran levels showed that intestinal permeability also decreased in Lactiplantibacillus plantarum 22 A-3-dead bacteria. The bacterial component of Lactiplantibacillus plantarum 22 A-3 ameliorates increased intestinal permeability through its anti-inflammatory effect in the intestinal tract and may be a novel treatment for leaky gut., Competing Interests: Declarations. Competing interests: T.Ko., M.I., A.No., T.Ke., M.Y., S.S., and A.Na. declare no competing interests. Y.Y., Y.N., and H.K. are employees of Maruzen Pharmaceutical Co., Ltd. The funders had no role in study design, data collection, and analysis, the decision to publish, or preparation of the manuscript. Ethics approval: The experiment was approved by the Yokohama City University Animal Experiment Committee (approval no.: F-A-19-022) and was conducted in accordance with the guidelines of the Yokohama City University School of Medicine Ethics Committee. All procedures involving animals were approved and conducted in compliance with the guidelines of the Yokohama City University Ethics Committee for Animal Experiments (permit no. F-A-19-022)., (© 2025. The Author(s).)

Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the P app of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [ 14 C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [ 3 H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hanne Morck Nielsen reports financial support was provided by Novo Nordisk Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Inflammatory Bowel Diseases (IDB) are chronic disorders characterized by gut inflammation, mucosal damage, increased epithelial permeability and altered mucus layer. No accurate in vitro model exists to simulate these characteristics. In this context, drug development for IBD or intestinal inflammation requires in vivo evaluations to verify treatments efficacy. A new model with altered mucus layer composition; altered epithelial permeability and pro-inflammatory crosstalk between immune and epithelial cells will be developed to enhance in vitro models for studying IBD treatments. The effects of dextran sulfate sodium and/or lipopolysaccharides on intestinal permeability, cytokines synthesis (IL-6, IL-8, TNF-α and IL-1β), mucins (MUC2, MUC5AC) and tight junction proteins expression (Claudin-1, ZO-1 and Occludin) were investigated in a tri-coculture model combining differentiated Caco-2/HT29-MTX cells and THP-1 cells. Two anti-inflammatory agents were evaluated to assess the model's therapeutic strategy applicability (corticoids and pro-resolving factors). Two in vitro models have been developed. The first model, characterized by increased permeability of the epithelial layer and subsequent secretion of inflammatory cytokines, can reproduce the different phases of inflammation, and enables the evaluation of preventive treatments. The second model simulates the acute phase of inflammation and allows for the assessment of curative treatments. Both models demonstrated reversibility when treated with betamethasone and pro-resolving factors. These in vitro models are valuable for selecting therapeutic agents prior to their application in in vivo models. They enable the assessment of agents' anti-inflammatory effects and their ability to permeate the inflamed epithelial layer and interact with immune cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francis Bonnefoy and Sylvain Perruche are shareholders and employed by MED’INN’Pharma SAS, which develops the SuperMApo biologic drug candidate. The remaining authors declare that the research was conducted in the absence of any potential conflicts (financial, professional or personal) that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Expanding devices designed to physically facilitate the permeation of drugs across the gastrointestinal mucosa are gaining attention for the oral delivery of therapeutic macromolecules. The ideal system should be biodegradable with latex-like properties, allowing it to withstand gut movement without breaking prematurely and preventing intestinal obstruction or damage. A highly foldable and elastic device is desirable because it can fit into commercial capsules by being compressed into confined spaces. However, this compression has limits due to the device's tendency to spring back to its original shape driven by stored elastic energy after deformation. This challenge can be addressed by using shape-memory polymers. In this work, we report a photo-crosslinkable resin suitable for 3D printing by digital light processing that yields an elastomer with latex-like properties, shape-recovery at body temperature, and degradation within 6 h under simulated intestinal conditions. Thermal shape-memory was conferred by adding stearyl(acrylate) to poly(β-aminoester)-based inks, achieving high elasticity (>700 %) and strength (>7.5 MPa), along with strain-hardening properties., Competing Interests: Declaration of competing interest JCL is a co-inventor on a patent application describing the expandable intestinal device., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Obesity is a significant risk factor for severe acute pancreatitis (SAP) and is typically associated with increased intestinal permeability. Understanding the role of specific molecules can help reduce the risk of developing SAP. Claudin 11 (CLDN11), a member of the Claudin family, regulates the permeability of various internal barriers. However, the role and mechanism of CLDN11 in the intestinal permeability of obesity-related SAP remain unclear., Methods: We evaluated intestinal permeability and the expression of CLDN11 in experimental obesity-related SAP. A recombinant adeno-associated virus carrying CLDN11 was used to treat experimental obesity-related SAP. The interaction between CLDN11 mRNA and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) protein was predicted through bioinformatics analysis and validated by RNA immunoprecipitation and RNA pull-down assay. Additionally, tumor necrosis factor-α (TNF-α) treatment in Caco-2 cells was conducted, and the IGF2BP3/CLDN11 axis was detected. Moreover, we conducted anti-TNFα therapy and evaluated intestinal permeability and pancreatic inflammation in experimental obesity-related SAP., Results: Downregulation of CLDN11 was observed in the intestinal epithelial cells of experimental obesity-related SAP. When the expression of CLDN11 in intestinal epithelial cells of experimental obesity-related SAP was increased exogenously, intestinal epithelial permeability and pancreatic inflammation were relieved. Overexpression of CLDN11 reduced the paracellular permeability of Caco-2 monolayer cells, while knockdown of CLDN11 increased it. IGF2BP3 bound to and regulated the stability of CLDN11 mRNA. TNF-α treatment downregulated IGF2BP3 and CLDN11 in vitro. Anti-TNFα therapy reduced intestinal permeability, alleviated pancreatitis, and improved the expression of IGF2BP3 and CLDN11 in intestinal epithelial cells in experimental obesity-related SAP., Conclusion: CLDN11 regulates intestinal permeability in obesity-related SAP. Mechanistically, an increase in TNF-α impaired the stability of IGF2BP3-dependent CLDN11 mRNA in obesity-related SAP., Competing Interests: Declarations. Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. All animal experiments were approved by the Ethical Committee of the Laboratory Animal Center of Sun Yat-sen University (Date June 25, 2023/No. 2023000734). Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Administering medication precisely to the inflamed intestinal sites to treat ulcerative colitis (UC), with minimized side effects, is of urgent need. In UC, the inflammation damaged mucosa contains a large number of amino groups which are positively charged, providing new opportunities for drug delivery system design. Here, we report an oral drug delivery system utilizing the tacrolimus-loaded poly (lactic-co-glycolic acid) (TAC/PLGA) particles with an adhesion coating by in situ UV-triggered polymerization of polyacrylic acid and N-hydroxysuccinimide (PAA-NHS). The negatively charged carboxyl groups effectively interact with the positively charged focal mucosa, and the NHS ester groups form the covalent bonds with the amino groups, thereby synergically enhancing the adhesion of the PLGA particles to the focal mucosa. Our findings reveal that, compared to the naked particles, the PAA-NHS coating increases the adhesion of particles to the inflammatory intestine. In a dextran sulfate sodium-induced acute colitis mouse model, the TAC/PLGA particles with PAA-NHS coating exhibits substantial retention of TAC within the inflammatory intestine, enhancing drug delivery efficiency and therapeutic effects. This approach holds promise for UC management, minimizing systemic side effects and optimizing therapeutic outcomes., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were approved by the Animal Care and Use Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Ref.20241227). Consent for publication: All authors agree for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Transcription factors guide tissue development by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of transcription factors. However, how transcription factors navigate chromatin features to selectively bind a small subset of all the possible genomic target loci remains poorly understood. Here we show that Cdx2-a lineage defining transcription factor that binds distinct targets in developing versus adult intestinal epithelial cells-has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic Cdx2 targets and methylated state of the CpG during development enables selective Cdx2 binding and activation of developmental enhancers and genes. In adult cells, demethylation at these enhancers prevents ectopic Cdx2 binding, instead directing Cdx2 to its canonical motif without a CpG. This shift in Cdx2 binding facilitates Ctcf and Hnf4 recruitment, establishing super-enhancers during development and homeostatic enhancers in adult cells, respectively. Induced DNA methylation in adult mouse epithelium or cultured cells recruits Cdx2 to developmental targets, promoting corecruitment of partner transcription factors. Thus, Cdx2's differential CpG motif preferences enable it to navigate distinct DNA methylation profiles, activating genes specific to appropriate developmental stages., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Food allergens are the key triggers of allergic diarrhea, causing damage to the immune-rich ileum. This weakens the mucosal barrier and tight junctions, increases intestinal permeability, and exacerbates allergen exposure, thereby worsening the condition. Sesamin, a natural lignan isolated from sesame seed, has shown potential in regulating immune responses, but its effects on intestinal health remain unclear. In this study, we constructed an ovalbumin (OVA)-induced allergic diarrhea mouse model, which demonstrated increased mast cell degranulation, reduced tight junction integrity, and impaired intestinal barrier function. Pro-inflammatory cytokines were significantly increased in the ileum, along with unbalanced cluster of differentiation 4 (CD4 + ) T-cell immunity, altered gut microbiota composition, and disrupted bacterial metabolism. Sesamin treatment significantly alleviated intestinal damage by modulating gut microbiota abundance, enhancing short-chain fatty acid (SCFA) production, and increasing SCFA receptor expression. This study suggests that sesamin may be a promising therapeutic candidate for allergic diarrhea and intestinal injury.

This article discusses the recent study written by Koizumi et al . Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, which is driven by complex mechanisms, including lipid accumulation, apoptosis, and inflammatory responses exacerbated by gut barrier dysfunction. The study explored the therapeutic potential of elafibranor, a dual peroxisome proliferator-activated receptor alpha/delta agonist. In clinical trials, elafibranor has shown promise for the treatment of other liver conditions; however, its effects on ALD remain unclear. The authors' findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD. These positive effects of elafibranor are mediated through multiple pathways. Elafibranor promotes lipid metabolism, reduces oxidative stress, and inhibits inflammatory responses by restoring gut barrier function. Specifically, it improves hepatocyte function by enhancing autophagic and antioxidant capacity, and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway. These findings indicate that elafibranor has promising clinical applications. In addition, the study highlights elafibranor's potential as a therapeutic agent for liver diseases, particularly ALD. This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Crohn's disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: This study was approved by the Ethics Committee (approval no. 2022-089) of Zhongshan Hospital of Xiamen University, Fujian Province, China. Written informed consent was obtained from all the participants in the study. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the Supplementary Table 1., (© 2025. The Author(s).)

Background: Inflammatory bowel disease (IBD) is a chronic condition influenced by diet, which affects gut microbiota and immune functions. The rising prevalence of IBD, linked to Western diets in developing countries, highlights the need for dietary interventions. This study aimed to assess the impact of white kidney beans (WKB) on gut inflammation and microbiota changes, focusing on their effects on enteric glial cells (EGCs) and immune activity in colitis., Methods: Male C57BL/6 mice were divided into four groups: normal diet (ND), ND with 2.5% dextran sulfate sodium (DSS) for colitis induction, ND with 20% WKB, and WKB with 2.5% DSS. The dietary intervention lasted 17 weeks, with DSS given in the final week. Colonic inflammation was assessed by body weight, disease activity index, and histopathology. Epithelial barrier integrity was evaluated using immunofluorescence, transmission electron microscopy, and permeability assays. EGCs activity was analyzed via immunofluorescence and quantitative real-time PCR. Immune responses were measured using flow cytometry and cytokine profiling, while gut microbiota changes were examined through metagenomic sequencing., Results: WKB supplementation significantly alleviated DSS-induced colitis in mice, evidenced by reduced weight loss, disease activity, and improved colonic histology. This effect was linked to enhanced mucosal barrier integrity, seen through increased tight junction protein and Muc2 expression, accompanied by favorable ultrastructural changes. WKB modulated EGCs activity via TNF-like cytokine 1 A inhibition, resulting in reduced glial fibrillary acidic protein expression. Immunologically, it downregulated Th1 and Th17 pro-inflammatory cells, increased Treg cells, and altered cytokine profiles (reduced TNF-α, IFN-γ, IL-17; increased IL-10). Metagenomic analysis showed that WKB restored gut microbiota balance, particularly enhancing beneficial bacteria like Akkermansia. KEGG pathway analysis further indicated that WKB supplementation improved key metabolic pathways, notably those related to phenylalanine, tyrosine, and tryptophan biosynthesis, thereby countering DSS-induced metabolic disruptions., Conclusions: WKB shows promise for treating IBD by enhancing mucosal barriers, inhibiting EGCs activity, balancing Th1/Th17/Treg cells, and restoring gut microbiota and metabolic homeostasis, thereby alleviating colitis symptoms., Competing Interests: Declarations. Ethics approval and consent to participate: This animal experiment was supported by Air Force Medical Center according to Laboratory Animal Welfare and Ethical review. Consent for publication: All authors agree to this submission. Competing interests: The authors declare no competing interests. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Qi Sun and Bai-Rong Li have contributed equally to this work., (© 2025. The Author(s).)

Intestinal barrier damage causes an imbalance in the intestinal flora and microbial environment, promoting a variety of gastrointestinal diseases. This study aimed to explore the mechanism by which adipose-derived stem cells (ADSCs) repair intestinal barrier damage. The human colon adenocarcinoma cell line Caco-2 and rats were treated with lipopolysaccharide (LPS) to establish in vitro and in vivo models, respectively, of intestinal barrier damage. The expression of inflammatory cytokines (TNF-α, HMGB1, IL-1β and IL-6), antioxidant enzymes (iNOS, SOD and CAT), and oxidative products (MDA and 8-iso-PGF2α) was detected using ELISA kits and related reagent kits. Apoptosis-related proteins (Bcl-2, Bax, Caspase-3 and Caspase-9), tight junction proteins (ZO-1, Occludin, E-cadherin, and Claudin-1) and p38 MAPK pathway-associated protein were detected by Western blotting. In addition, cell viability and apoptosis was determined by a CCK-8 kit and flow cytometry, respectively. Cell permeability was assayed by the transepithelial electrical resistance value and FITC-dextran concentration. The homing effect of ADSCs was detected by fluorescence labeling, and intestinal barrier tissue was observed by HE staining. After ADSC treatment, the level of phosphorylated p38 MAPK protein decreased, the expression of inflammatory factors, oxidative stress and cell apoptosis decreased, the expression of tight junction proteins increased, and cell permeability decreased in Caco-2 cells stimulated with LPS. In rats, ADSCs are directionally recruited to damaged intestinal tissue. ADSCs significantly decreased the levels of D-lactate, diamine oxidase (DAO) and FITC-dextran induced by LPS. ADSCs promoted tight junction proteins and inhibited oxidative stress in intestinal tissue. These effects were reversed after the use of a p38 MAPK activator. ADSCs can be directionally recruited to intestinal tissue, upregulate tight junction proteins, and reduce apoptosis and oxidative stress by inhibiting the p38MAPK signaling pathway. This study provides novel insights into the treatment of intestinal injury.

The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria., Competing Interests: Declarations. Ethics approval: No human and animal experiment data were generated for this review article. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)