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Highsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD-mediated gut barrier dysfunction. Specifically, 16-week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)-epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD-mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal-specific knockout of the sEH gene significantly attenuated HSD-caused intestinal injuries by reducing HSD-mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6-dihydroxyeicosatrienoic acid (5,6-DiHET), significantly ablated high sucrose-caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti-inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD., Competing Interests: Competing interests statement:The authors declare no competing interest.

d-amino acids have been actively examined since improved analytical techniques revealed their presence in animal bodies. Although D-Asp was identified in mammals earlier than D-Ser, research on D-Asp has lagged behind that on D-Ser, mainly because the target protein of D-Asp remains unknown. To date, the only reported functions of D-Asp are its roles in reproduction and suggested neuromodulatory functions. Since d-amino acids are also present in food, it is important to clarify their effects on gastrointestinal epithelial cells, which are always contacted after ingestion. Therefore, the present study examined the effects of d-amino acids on gastrointestinal tract basal cells. The effects of 11 types of amino acids (Ala, Arg, Asn, Asp, Gln, Glu, Leu, Lys, Pro, Ser, and Val) on the proliferation of three types of gastrointestinal epithelial cells (HGC-27, IEC-6, and Caco-2) were assessed. Although the proliferation of HGC-27 and Caco-2 was not affected by any of the 11 types of L- and d-amino acids, D-Asp inhibited the proliferation of IEC-6, derived from small intestinal epithelial cells, in concentration- and exposure time-dependent manners. The present study also examined uptake transporters, metabolic enzymes, and insulin signaling pathways; however, the mechanisms underlying the inhibitory effects of D-Asp on the proliferation of IEC-6 were not elucidated. A more detailed understanding of these mechanisms may lead to the development of pharmaceuticals as main drugs or formulation materials. Further studies are warranted on the physiological effects of d-amino acids, including D-Asp., Competing Interests: Declaration of competing interest The authors state that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dihydroquercetin (DHQ), also known as Taxifolin (TA), is a flavanonol with various biological activities, such as anticancer, anti-inflammatory, and antioxidative properties. It has been found to effectively increase the viability of porcine intestinal epithelial cells (IPEC-J2). However, the precise mechanism by which DHQ increases the proliferation of IPEC-J2 cells is not entirely understood. This study aimed to explore the potential pathways through which DHQ encourages the proliferation of IPEC-J2 cells. The findings indicated that DHQ significantly improved the protein expression of tight junction proteins (ZO-1, Occludin, and Claudin1) and a molecular biomarker of proliferation (PCNA) in IPEC-J2 cells. Furthermore, DHQ was found to increase the Wnt/β-catenin pathway-associated β-catenin, c-Myc, and cyclin D1 mRNA expression, and promote the protein expression of β-catenin and TCF4. To confirm the involvement of the Wnt/β-catenin signaling pathway in the DHQ-promoted proliferation of IPEC-J2 cells, the inhibitor LF3, which targets β-catenin/TCF4 interaction, was used. It was found that LF3 inhibited the protein expressions upregulated by DHQ and blocked the promotion of cell proliferation. These results indicate that DHQ positively regulates IPEC-J2 cell proliferation through the Wnt/β-catenin pathway, providing constructive insights into the role of DHQ in regulating intestine development., 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.)

Purpose: Threonine (Thr) can be involved in the synthesis of immunoglobulins, which play the role of immune regulation, Thr also has to improve intestinal morphology, adjust the sticky protein synthesis, maintain the intestinal barrier function, etc. The experiment aimed to investigate the effects of diets supplemented with different levels of Thr on growth performance and intestinal health of rabbits under lipopolysaccharide (LPS) stress conditions., Methods: A total of 180 healthy 35-day-old weaned New Zealand White rabbits were randomly assigned in a 2 × 3 factorial design to receive an intraperitoneal injection of 100 µg/kg BW LPS or saline and three diets with different levels of digestible threonine (0.43%, 0.54%, and 0.64%)., Results: The LPS challenge resulted in a reduction in body weight in rabbits at day 22, as well as a decrease in the serum d-lactic acid (D-LA) content and the number of goblet cells (GCs) in the jejunum. Additionally, the duodenum JAM2 and JAM3 were down-regulated. The expression of OCLN, ZO-1, and IL-2 in the jejunum, and CLDN, nuclear factor-κB (NF-κB) and ZO-1 mRNA in the ileum were also down-regulated. Furthermore, the duodenum TLR4 and IL-1β mRNA expression, while the jejunum exhibited an elevation in CLDN, TNF-α, and ileum TNF-α mRNA expression (P < 0.05). In the context of LPS challenge condition, dietary Thr addition was found to down-regulate the duodenum ZO-1 and jejunum CLDN mRNA expression of rabbits (P < 0.05). This was accompanied by an increase in ileum sIgA content and GCs number (P < 0.05). Additionally, dietary Thr addition resulted in a downregulation of duodenum TLR4, MyD88, NF-κB, TNF-α and IL-1β, jejunum MyD88, and IL-1β mRNA expression, as well as an up-regulation of ileum IL-10 mRNA expression in rabbits (P < 0.05)., Conclusion: In conclusion, the LPS challenge can result in intestinal inflammation and damage the integrity of the intestinal barrier in rabbits. Nevertheless, dietary Thr supplementation can alleviate the intestinal inflammatory response in rabbits challenged with LPS., Competing Interests: Declarations Ethical approval All animal protocols were approved by the Animal Care and Use Committee of Sichuan Agricultural University (Approval number: SICAU20211121). Conflict of interest The authors declare no competing financial interest., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Aging is a process that accompanies a decline in the function of various tissues and organs, especially affecting intestinal health. Agarose oligosaccharide (AOS) can prolong the lifespan of organisms and protect the intestine in the previous study. It was examined to evaluate the effects of AOS on intestinal health, and the potential associations between intestinal homeostasis and health status were further validated., Methods: D-galactose-induced aging mice were used to investigate the role of AOS in promoting intestinal health by determining intestinal physiology, microbiota and stem cells., Results: AOS supplementation decreased the clinical frailty index of aging mice with increasing intestinal length and crypt depth; moreover, it decreased the average flatulence index and PCNA protein content in the intestine. Besides, AOS contributed to the diversity of the gut microbiota by increasing the relative abundance of Bacteroidetes and other bacteria that could produce short-chain fatty acids. Furthermore, AOS affected the expression of proinflammatory factors in aging mice, promoting the proliferative equilibrium of intestinal stem cells., Conclusion: These findings confirmed that AOS could improve intestinal health in aging mice by maintaining intestinal homeostasis, which provides new insights into the potential application of AOS as a prebiotic., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interest. Ethical approval All experimental protocols involving animals were approved by the Animal Care and Welfare Committee of Life Science College and the Scientific Ethical Committee of China Jiliang University (No. CJLU2023004; Hangzhou, China)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Due to the increasing global incidence rate of nonalcoholic steatohepatitis (NASH) combined with the lack of effective treatment methods for this disease, there is an urgent need to find new treatment strategies. The aim of this study was to investigate the efficacy of rifaximin in preventing and treating NASH and the related mechanism., Materials and Methods: A NASH model was constructed by feeding male C57BL/6 mice a methionine-choline-deficient (MCD) diet for 4 weeks. Rifaximin was administered for 1 week before MCD diet feeding or during the last week of MCD diet feeding to investigate its preventive or therapeutic effects. Liver pathology, hepatic enzyme levels and metabolic indices were measured to evaluate the effects of rifaximin on NASH. Intestinal barrier integrity was measured via the Ussing chamber system and western blotting. 16S rDNA sequencing was conducted to investigate the fecal microbiota composition. Western blotting was performed to evaluate peroxisome proliferator activated receptor (PPAR)α and PPARγ protein levels., Key Findings: Rifaximin effectively alleviated MCD diet-induced NASH. The microbiota composition in MCD diet-fed mice was significantly altered, and intestinal barrier integrity was disrupted. Dysbiosis and intestinal barrier dysfunction were reversed by rifaximin. In addition, rifaximin modulated PPARα and PPARγ expression in the liver., Significance: Rifaximin effectively alleviated MCD diet-induced NASH by restoring the gut microbiota and reversing intestinal barrier dysfunction, suggesting that rifaximin treatment is a new approach for preventing and treating NASH., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. Figure of Graphical Abstract was created by Figdraw (www.figdraw.com)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis., 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.)

Grifola frondosa polysaccharide (GFP) is a consumable fungus recognized for its potential health advantages. The present study aimed to investigate the development and potential etiologies of ulcerative colitis (UC) utilizing oxazolone (OXZ) as an inducer in mice, along with assessing the therapeutic effects of GFP at varying doses in UC mice, with sulfasalazine (SASP) serving as the positive control. The obtained results indicated that OXZ intervention in mice induced numerous physical manifestations of UC, including increased disease activity index (DAI), decreased goblet cell division, enhanced fibrosis, reduced expression of Claudin1 and Zona encludens protein1 (ZO-1), decreased proliferative activity of colonic mucosal epithelial cells, disturbed oxidation balance, and alterations in intestinal flora. Nonetheless, GFP intervention significantly ameliorated or even resolved these abnormal indicators to a considerable extent. Consequently, this study suggests that GFP might serve as a prebiotic to regulate intestinal flora, mitigate enterotoxin production, restore oxidative balance, thereby reducing the generation of inflammatory mediators, restoring the intestinal barrier, and ultimately improving OXZ-induced UC in mice. GFP demonstrates promising potential as a candidate drug for colitis treatment and as a dietary supplement for alleviating intestinal inflammatory issues., 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.)

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD). There is a growing prevalence of UC, but current conventional drugs lack efficacy. Carthamin yellow (CY) is a flavonoid compound extracted from safflower that is widely used and has various pharmacological effects. In the present study, we established colitis models in mice via DSS and in Caco-2 cells via lipopolysaccharide (LPS). Our results showed that CY treatment attenuated the symptoms of colitis by decreasing colonic pathological damage and improving disease activity index (DAI) scores. Notably, we observed that CY treatment decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) by inhibiting the NLRP3/Caspase-1/IL-1β and MAPK/NF-κB signaling pathways. Moreover, we verified that treatment with CY obviously improved intestinal barrier function in both DSS-induced mice and LPS-stimulated Caco-2 cells. Ferroptosis-related markers were assessed. CY attenuated DSS-induced colitis by inhibiting ferroptosis, as assessed by Fe 2+ accumulation, total antioxidant capacity (T-AOC), and reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and glutathione (GSH) levels. Additionally, there was an increase in superoxide dismutase (SOD) and catalase (CAT) activity, as well as alterations in ferroptosis-related protein and gene expression (ACSL4, GPX4, SLC7A11, TfR1, and FTH1). Further analyses revealed that CY could inhibit ferroptosis via the Nrf2/GPX4 axis in both in vivo and RSL3-induced Caco-2 cell models. Importantly, the antiferroptotic and protective effects of CY were nullified by Nrf2 knockout in vivo and by the use of ML385 in vitro. In conclusion, the effects of CY on UC are strongly associated with the Nrf2 pathway. CY might be a potential candidate for the treatment of UC. Therefore, our results provide an important reference for investigating the mechanisms of flavonoid compounds involved in preventing inflammatory diseases., 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.)

Ectodermal mesenchymal stem cells-derived conditioned medium (EMSCs-CM) has been reported to protect against ulcerative colitis (UC) in mice, but its underlying mechanism in alleviating UC need to be further elucidated. Here, it is reported that EMSCs-CM could attenuate pro-inflammatory response of LPS-induced IEC-6 cells and regulate the polarization of macrophages towards anti-inflammatory type in vitro. Furthermore, PLGA microspheres prepared by the double emulsion method were constructed for oral delivery of EMSCs-CM (EMSCs-CM-PLGA), which are beneficial for colon-targeted adhesion of EMSCs-CM to the damaged colon mucosa. The results showed that orally-administered of EMSCs-CM-PLGA microspheres reduced inflammatory cells infiltration and maintained the intestinal mucosal barrier. Further investigation found that EMSCs-CM-PLGA microspheres treatment gradually inhibited the activation of NF-κB pathway to regulate M1/M2 polarization balance in colon tissue macrophages, thereby alleviating DSS-induced UC. These results of this study will provide a theoretical basis for clinical application of EMSCs-CM in UC repair., 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.)

Ulcerative colitis (UC) is a chronic inflammatory disease that is increasing in prevalence globally. Senescence is characterized by a specific chronic, low-grade, "sterile" inflammatory state known as inflammaging, suggesting that senescence may exacerbate the severity of UC. However, the link between UC and senescence remains unclear. Valnemulin (VAL) is a semi-synthetic derivative of a naturally occurring diterpenoid antibiotic (pleuromutilin), which can inhibit peptidyl transferase. Studies investigating the potential of valnemulin to inhibit senescence and alleviate colitis are currently limited. In this study, we revealed that dextran sulfate sodium (DSS), an inducer of UC, induces senescence in both colon epithelial NCM460 cells and colon tissues. Additionally, VAL, identified from a compound library, exhibited robust anti-senescence activity in DSS-treated NCM460 cells. Identified in our study as an anti-senescence agent, VAL effectively mitigated DSS-induced UC and colonic senescence in mice. Through network pharmacology analysis and experimental validation, the potential signaling pathway (AMPK/NF-κB) for VAL in treating UC was identified. We discovered that DSS significantly inhibited the AMPK signaling pathway and activated the NF-κB signaling pathway. However, supplementation with VAL remarkably restored AMPK activity and inhibited the NF-κB signaling pathway, which led to the inhibition of senescence. In summary, our study demonstrated that DSS-induced UC stimulates the senescence of colonic tissues, and VAL can effectively alleviate DSS-induced colonic damage and reduce colonic senescence. Our research findings provide a new perspective for targeting anti-senescence in the treatment of UC., 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/aims: : The effect of proton pump inhibitors (PPIs) on the lower gastrointestinal (GI) tract is uncertain, with potential to worsen damage. This study aimed to find the best method for protecting the entire GI tract from mucosal damage., Methods: : A retrospective cohort study at Samsung Medical Center (2002-2019) included 195,817 patients prescribed GI mucosa-damaging agents. The primary goal was to assess the effectiveness of GI protective agents in preventing significant hemoglobin drops (>2 g/dL), indicating overall GI mucosal damage. Self-controlled case series and landmark analysis were used to address biases in real-world data., Results: : The incidence rate ratios for rebamipide, PPI, and histamine-2 receptor antagonist (H2RA) were 0.34, 0.33, and 0.52, respectively. Rebamipide showed a significantly lower incidence rate than H2RA and was comparable to PPIs. Landmark analysis revealed significant reductions in hemoglobin drop risk with rebamipide and H2RA, but not with PPI., Conclusions: : Rebamipide, like PPIs, was highly effective in preventing blood hemoglobin level decreases, as shown in real-world data. Rebamipide could be a comprehensive strategy for protecting the entire GI tract, especially when considering PPIs' potential side effects on the lower GI tract.

Ethnopharmacological Relevance: WenTongGanPi Decoction (WTGPD) is a representative medical practice of the Fuyang School of Traditional Chinese Medicine (TCM), which originated from the classical Lu's Guizhi method. WTGPD places emphasis on the balance and functionality of yang qi, and is effective in treating TCM symptoms related to liver qi stagnation and spleen yang deficiency. In TCM, diarrhea-predominant irritable bowel syndrome (IBS-D) is often diagnosed as liver depression and spleen deficiency, and the use of WTGPD has shown significant therapeutic effect. However, the underlying mechanism of WTGPD treating IBS-D remains unclear., Aim of the Study: To explore the effect and mechanism of WTGPD in the treatment of IBS-D., Materials and Methods: An IBS-D model with liver depression and spleen deficiency was constructed by chronic immobilization stress stimulation and sennae folium aqueous gavage. The impact of WTGPD on IBS-D rats was evaluated through measurements of body weight, fecal water content, and abdominal withdrawal reflex (AWR). Intestinal permeability was assessed using hematoxylin-eosin (HE), alcian blue-periodic acid schiff (AB-PAS), immunofluorescence (IF) staining, and quantitative real-time PCR (qRT-PCR). The components of WTGPD were analyzed using UPLC-Q-TOF-MS. The underlying mechanisms were investigated through network pharmacology, transcriptomics sequencing, western blot (WB), molecular docking, and 16S rRNA sequencing., Results: WTGPD treatment effectively alleviated diarrhea and abnormal pain in IBS-D rats (P < 0.05). It enhanced the intestinal barrier function by improving colonic structure and increasing the expression of tight junction proteins (P < 0.05). A total of 155 components were identified in WTGPD. Both network pharmacology and transcriptomics sequencing analysis highlighted MAPK as the key signaling pathway in WTGPD's anti-IBS-D effect. The WB results showed a significant decrease in p-p38, p-ERK and p-JNK expression after WTGPD treatment (P < 0.0001). Guanosine, adenosine and hesperetin in WTGPD may be involved in regulating the phosphorylation of p38, ERK and JNK. Additionally, WTGPD significantly enhanced microbial diversity and increased the production of colonic valeric acid in IBS-D rats (P < 0.01)., Conclusion: In conclusion, our findings suggest that WTGPD can effectively alleviate IBS-D and improve intestinal barrier likely via inhibiting MAPK signal pathway and improving micobial dysbiosis., 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: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis., Methods: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103., Results: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation., Conclusion: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC., Competing Interests: Declaration of competing interest The authors declare that they have no 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.)

Probiotics are increasingly being used as an adjunctive therapy for ulcerative colitis. However, some safety issues have been found in the clinical use of probiotics. Postbiotics have attracted much attention due to their storage stability, safety, and potential functions, but the dose required to exert a significant protective effect is unknown. Therefore, this study evaluated the potential mechanisms of different doses (200, 400, 600 mg/kg) of Lactobacillus rhamnosus 1.0320 postbiotics (1.0320P) in alleviating dextran sodium sulfate (DSS)-induced colitis. The study revealed that 1.0320P could mitigate DSS-induced colitis with signs of reductions in the disease activity index, amelioration of colon tissue damage, decreased secretion of proinflammatory cytokines, reduced oxidative stress levels, and lower bone marrow peroxidase activity. Furthermore, high dose of 1.0320P could upregulated the expression of key proteins in the Nrf2/ARE pathway (NQO1, Nrf2, and HO-1) and downregulated the expression of key proteins in the TLR4/NF-κB signaling pathway (TLR4, MyD88, and NF-κB p65). In addition, high dose of 1.0320P could upregulate the expression of tight junction (TJ) proteins including ZO-1, Occludin, and Claudin-1, contributing to the restoration of the intestinal mucosal barrier function. Additionally, 1.0320P was found to effectively correct imbalances in the intestinal microbiota and enhance the synthesis of short-chain fatty acids (SCFAs), thereby regulating homeostasis in the intestinal internal environment. Overall, our findings suggest that postbiotics could ameliorate colonic inflammation while being somewhat dose-dependent. This study provides new insights into postbiotics as a next-generation biotherapeutic agent for the treatment of ulcerative colitis and even other diseases.

We determined the in vivo counteracting effect of fiber and probiotic supplementation on colonic mucosal damage and alterations in gut microbiota caused by 2-amino-1-methyl-6-phenylimidazo [4,5- b ] pyridine (PhIP) and sodium dextran sulfate (DSS). Male Fischer-344 rats were randomly divided into 4 groups: control (standard diet), PhIP + DSS group (standard diet + PhIP + DSS), fiber (fiber diet + PhIP + DSS), and probiotic (probiotic diet + PhIP + DSS). The intake of PhIP + DSS for 3 weeks induced colonic mucosal erosion, crypt loss, and inflammation, and the distal colon was more severely damaged. Fiber alleviated colonic mucosal damage by reducing crypt loss and inflammation, while the probiotic increased colon length. The intake of PhIP + DSS increased the fecal relative abundance of Clostridia UCG014 along the intervention, in contrast to the lower abundances of these taxa found after PhIP + DSS administration in the rats supplemented with probiotics or fiber. Fiber supplementation mitigated the histological damage caused by PhIP + DSS shifting the gut microbiota toward a reduction of pro-inflammatory taxa.

Fibroblast growth factor (FGF)-21 is a salient liver-derived endocrine regulator for metabolism of glucose and triglyceride as well as bone remodeling. Previously, certain peptides in the FGF family have been shown to modulate calcium absorption across the intestinal epithelia. Since FGF21 receptor, i.e., FGF receptor-1, is abundantly expressed in the enterocytes, there was a possibility that FGF21 might exert direct actions on the intestine. Herein, a large-scale production of recombinant FGF21 at the multi-gram level was developed in order to minimize variations among various batches. In the oral glucose tolerance test, recombinant FGF21 was found to reduce plasma glucose levels in mice fed high-fat diet. A series of experiments applying radioactive tracer 45 Ca in Ussing chamber showed that FGF21 potentiated the stimulatory effect of low-dose 1,25-dihydroxyvitamin D 3 [10 nM 1,25(OH) 2 D 3 ] on the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer. FGF21 + 1,25(OH) 2 D 3 also decreased transepithelial resistance, but had no effect on epithelial potential difference or short-circuit current. Furthermore, 1,25(OH) 2 D 3 alone upregulated the Caco-2 mRNA expression of the major apical calcium channels, i.e., transient receptor potential vanilloid subfamily member 6 (TRPV6), which was further elevated by a combination of FGF21 and 1,25(OH) 2 D 3 , consistent with the upregulated TRPV6 protein expression in enterocytes of FGF21-treated mice. However, FGF21 was without effects on the mRNA expression of voltage-gated calcium channel 1.3, calbindin-D 9k , plasma membrane Ca 2+ -ATPase 1b, claudin-12 or claudin-15. In conclusion, FGF21 did exert a direct action on the intestinal epithelial cells by potentiating the 1,25(OH) 2 D 3 -enhanced calcium transport, presumably through the upregulation of TRPV6 expression., 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 Inc. All rights reserved.)

Background: Aflatoxin B1 (AFB1) is a mycotoxin that widely found in the environment and mouldy foods. AFB1 initially targets the intestine, and AFB1-induced intestinal injury cannot be ignored. Lactobacillus amylovorus (LA), a predominant species of Lactobacillus, plays a role in carbohydrate metabolism. Extracellular vesicles (EVs), small lipid membrane vesicles, are widely involved in diverse cellular processes. However, the mechanism by which Lactobacillus amylovorus-QC1H-derived EVs (LA.EVs) protect against AFB1-induced intestinal injury remains unclear., Results: In our study, a new strain named Lactobacillus amylovorus-QC1H (LA-QC1H) was isolated from pig faeces. Then, EVs derived from LA-QC1H were extracted via ultracentrifugation. Our results showed that LA.EVs significantly alleviated AFB1-induced intestinal injury by inhibiting the production of proinflammatory cytokines, decreasing intestinal permeability and increasing the expression of tight junction proteins. Moreover, 16 S rRNA analysis revealed that LA.EVs modulated AFB1-induced gut dysbiosis in mice. However, LA.EVs did not exert beneficial effects in antibiotic-treated mice. LA.EVs treatment increased intestinal levels of indole-3-acetic acid (IAA) and activated intestinal aryl hydrocarbon receptor (AHR)/interleukin-22 (IL-22) signalling in AFB1-exposed mice. Inhibition of intestinal AHR signalling markedly weakened the protective effect of LA.EVs in AFB1-exposed mice., Conclusions: LA.EVs alleviated AFB1-induced intestinal injury by modulating the gut microbiota, activating the intestinal AHR/IL-22 signalling, reducing the inflammatory response and promoting intestinal barrier repair in mice., Competing Interests: Declarations Ethics approval and consent to participate Protocols of animal experiments included in this study were approved by Nanjing Agricultural University under the Laboratory Animal Care Ethics Committee for animal experiments (NJAU. No 20210624093). Informed consent was obtained from all individual participants. Consent for publication All authors consent to the publication of the article. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

As the non-steroidal anti-inflammatory drugs (NSAIDs) are typically used in the treatment of chronic conditions, the incidence of NSAID-induced enteropathy is increasing. Given the challenges associated with discontinuing NSAIDs, effective preventive and treatment strategies are crucial. We assessed the effect of tegoprazan on NSAID-induced enteropathy. Human epithelial cells (HIEC-6, HT-29, and Caco-2) were treated with indomethacin and tegoprazan. Cell viability, expression levels of tight-junction proteins, levels of proinflammatory cytokines, and apoptosis were assessed by conducting MTT assays, RT-PCR, western blotting, and immunofluorescence staining, respectively. Tegoprazan significantly ameliorated the inhibition of cell proliferation induced by indomethacin. Tegoprazan also mitigated the suppression of occludin and ZO-1 expression by indomethacin, thereby restoring intestinal permeability. Additionally, tegoprazan reversed the indomethacin-induced elevation of the levels of proinflammatory cytokines and the rate of apoptosis of small intestinal epithelial cells. Our findings indicate that tegoprazan exerts a protective effect against NSAID-induced injury to small intestinal epithelial cells. The effect involves enhancement of the expression levels of tight junction proteins and the suppression of inflammation and apoptosis., (© 2024. The Author(s).)

Postbiotic lactate modulates the immune system in inflammatory bowel diseases. However, its role in experimental intestinal mucositis (IM) has not been elucidated. This study aimed to evaluate the effects of lactate supplementation (1 and 2 × 10-1 mol/l) in a 5-fluorouracil (5-FU)-induced IM model. Male BALB/c mice (6-8 weeks old) were randomly divided into four groups: control (CTL), mucositis (MUC), mucositis with 1 × 10-1 mol/l lactate solution (MUC10), and mucositis with 2 × 10-1 mol/l lactate solution (MUC200). Lactate was administered via oral gavage for 10 days. Following the treatment period, the animals were subjected to an intraperitoneal injection of 300 mg/kg 5-FU to induce IM and were euthanized 72 h later for analysis. The MUC group presented intestinal damage with a poor histological score and decreased morphometric parameters as well as decreased mucus production and increased inflammatory infiltration and intestinal permeability compared to those of the CTL group (P < .05). However, the MUC200 group exhibited better results for the evaluated parameters than the MUC group (P < .05). Notably, the results in the MUC10 group were similar to those in the MUC group (P > .05). In conclusion, lactate supplementation attenuates mucositis-induced damage in a dose-dependent manner., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Dietary fiber is known to promote the production of short-chain fatty acids (SCFAs) by gut bacteria, which can enhance intestinal epithelial barrier function and ameliorate intestinal inflammation in patients with inflammatory bowel disease (IBD). Interestingly, some IBD patients show reduced expression of solute carrier family member 3 (Slc26a3) in intestinal epithelial cells. The objective of this research was to investigate the interaction between SCFAs and Slc26a3 during colitis and assess how this interaction affects intestinal epithelial barrier function. We showed that butyrate alleviated colonic inflammation in a dose-dependent manner in a dextran sulfate sodium salt (DSS)-induced colitis model. Consistent with this, butyrate increased Slc26a3 and tight junction protein levels. In addition, butyrate inhibited histone deacetylase (HDAC) levels and significantly increased the expression of Slc26a3 by the acetylation of histones in Caco-2BBe cells. The utilization of a pan-HDAC inhibitor or inhibitors specific to certain classes of HDACs revealed that butyrate primarily suppressed HDAC8 to blunt the NF-κB pathways and enhance the expression of Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted the beneficial effect of butyrate in DSS-induced colitis. Therefore, we concluded that butyrate improves the expression of Slc26a3 via inhibition of the HDAC8/NF-κB pathway, leading to increased intestinal epithelial barrier function.

Alcoholic liver disease (ALD) is one of the causes of hepatocellular carcinoma, accompanied by intestinal leakage and microbial changes. Pueraria has protective effects on liver injury. The aim of this study was to investigate the mechanism of pueraria in the treatment of ALD. UPLC-Q/TOF-MS was used to analyze the composition of the pueraria extract (PUE). Acute and chronic ALD models were established to evaluate the antialcoholic and hepatoprotective effects of PUE. As a result, PUE treatment reduced the serum levels of ALT, AST, TC, and TG and inflammatory factors and alleviated liver inflammation and drunk state. PUE decreased the gene expression of ADH1 and the serum level of acetaldehyde (ACH) to inhibit the generation of ACH from ethanol metabolism, increased the gene level of ALDH2 to accelerate the decomposition of ACH, and thereby alleviated liver inflammation and intestinal barrier damage. Meanwhile, 16 S rDNA revealed that PUE altered the microbiota composition, reduced the amount of Proteobacteria and Desulfobacterota , and thus inhibited the generation of lipopolysaccharide and its downstream-like TLR4/MyD88/NF-κB pathway. PUE also increased the abundance of Bacteroides , Ruminococcus , and Prevotella and producted short-chain fatty acids to protect the intestinal wall. Treatment with fecal microbiota transplantation further confirmed that PUE gut microbiota dependently alleviated ALD. Therefore, PUE regulated gut microbiota and inhibited ethanol metabolism to alleviate ALD through the liver-gut-brain axis. It has good prospects in the future.

Intestinal stem cells (ISCs) are necessary to maintain intestinal renewal. Here, we found that the highland barley β-glucan (HBG) alleviated pathological symptoms and promoted the proliferation of intestinal stem cells in colitis mice. Notably, metabolomics studies showed that docosahexaenoic acid (DHA) was significantly increased by the HBG treatment. DHA is a ligand for peroxisome proliferator-activated receptor α (PPARα), which can promote ISC proliferation. Expectedly, HBG facilitated the expression of intestinal PPARα and the proliferation of ISCs in colitis mice. Further experiments verified that DHA significantly facilitated the expression of PPARα and the proliferation of ISCs in intestinal organoids. Intriguingly, the effect of DHA on ISC proliferation was reversed by the PPARα inhibitor. Together, our data indicate that HBG might accelerate PPARα-mediated ISC proliferation through DHA. This provides new insights into the effective application of polysaccharides in maintaining intestinal homeostasis.

Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological disorganization of colon epithelial barrier proteins in HIV-1 transgenic (Tg) rats. The current study evaluated mechanisms that may underlie gut barrier pathology induced by toxic HIV-1 proteins. Methamphetamine (meth) use is prevalent among HIV-infected individuals, and meth can exaggerate morbidity of HIV infection. Thus, we determined whether meth exposure worsened HIV-associated gut pathology using colon samples from HIV-1 Tg and non-Tg rats that self-administered meth 2 h/day for 21 days. Immunoblotting was conducted for occludin (a gut barrier protein) and matrix metalloproteinase-9 (MMP-9; a proteinase regulator of occludin). Colon levels of occludin were decreased, and MMP-9 levels and activity were increased in HIV-1 Tg rats. A Pearson correlation revealed an inverse relationship between occludin levels and MMP-9 activity. Doses of meth that were self-administered by Tg rats were lower than other rat models. Meth-induced trends in non-Tg rats were not significant, and meth did not exaggerate effects seen in Tg rats. Accordingly, only the HIV-effects on epithelial function were explored further. Transepithelial resistance (TER) across a monolayer of human colon epithelial cells (Caco-2) was used to examine treatments with the HIV-1 toxic protein, Tat, and the ability of pioglitazone, a PPARγ agonist that inhibits MMP-9, to mitigate Tat-induced changes. Exposure to Tat for 24 h decreased TER, which co-occurred with decreases in levels of barrier tight junction proteins (occludin, claudin-1, and zonula occludens-1) and with increases in the level and activity of MMP-9. Pretreatment or post-treatment with pioglitazone respectively prevented and restored Tat-induced impairments of Caco-2 barrier. Thus, while low doses of meth did not alter barrier proteins in the current study, exposure to HIV-1 proteins disrupted the gut barrier, and this action involved a dysregulation of MMP-9., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

BACKGROUND The gastrointestinal (GI) barrier can be damaged by chemotherapy or radiation therapy, causing fatigue, malnutrition, sepsis, dose-limiting toxicity, and, occasionally, death. Glucagon-like peptide-2 (GLP-2) promotes mucosal epithelium growth and repair in the GI tract. Here, we examined the GI-protective effects of apraglutide, a long-acting peptide GLP-2 analog, in murine models of chemotherapy, and total body irradiation followed by allogeneic transplantation. MATERIAL AND METHODS The impact of apraglutide on cytarabine or melphalan chemotherapy-induced intestinal damage was assessed in BALB/c mice, and the effect on allogeneic transplantation in BALB/cJ and C57BL/6J mice. Outcomes included survival, and changes in body weight, intestinal function and morphology, including colon length and bacterial composition of the intestinal microbiota. RESULTS Adding apraglutide to chemotherapy significantly improved survival rates and reduced weight loss, with no impact on leukocyte counts (and, therefore, no effect on chemotherapy-induced immunosuppression), compared with chemotherapy alone in mice. These benefits were associated with preservation of the morphological integrity of the GI mucosa, attenuation of the negative impact of cytarabine on the intestinal microbiota, and significant improvement in plasma levels of citrulline. In addition, in a model of irradiation followed by allogeneic transplantation, mice in groups receiving apraglutide had improved survival, reduced weight loss, and increased colon length compared with those that did not. CONCLUSIONS Apraglutide protects intestinal function and improves survival in mice following allogeneic transplantation or chemotherapy with cytarabine or melphalan. The potential effect of apraglutide on chemotherapy efficacy and on engraftment following allogeneic transplantation has been investigated in a parallel manuscript.

Intestinal epithelium has the largest surface of human body, contributes dramatically to defense of toxicant-associated intestinal injury. Triclosan (TCS) and triclocarban (TCC), extensively employed as antibacterial agents in personal care products (PCPs) and healthcare facilities, caused serious damage to human intestine. However, the role of the intestinal epithelium in TCS/TCC-induced intestinal toxicity and its underlying toxic mechanisms remain incompletely understood. In this study, a novel 3D intestinal organoid model was utilized to investigate that exposure to TCS/TCC led to a compromised self-renewal and differentiation of intestinal stem cells (ISCs). Consequently, this disrupted intestinal epithelial homeostasis ultimately caused a reduction in nutrient absorption and deficient of epithelial defense to exogenous and endogenous pathogens stimulation. The inhibition of the Wnt signaling pathway in intestinal stem cell was contributed to the intestinal toxicity of TCS/TCC. These results were further confirmed in vivo with mice exposed to TCS/TCC. The findings of this study provide evidence that TCS/TCC possess the capacity to disturb the homeostasis of the intestinal epithelium, and emphasize the credibility of organoids as a valuable model for toxicological studies, as they could faithfully recapitulate in vivo phenomena., 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.)

ATP, released e.g. after cell damage or during inflammation, can alter ion transport across the intestinal mucosa via stimulation of purinergic receptors in the basolateral as well as in the apical membrane of epithelial cells. When ATP acts from the serosal side, it induces an increase in short-circuit current (I sc ) via Cl - secretion across the colonic epithelium. In contrast, mucosal ATP or its derivative, BzATP, predominantly stimulating ionotropic P2X 4 and P2X 7 receptors, evoke an increase in I sc , which could not be explained by Cl - secretion. The underlying ion currents after stimulation of apical purinergic receptors in rat distal colon are still unclear and were investigated in the present study. Ussing chamber experiments revealed that the I sc induced by mucosal ATP was dependent on the presence of mucosal Ca 2+ and inhibited by the K + channel blocker, Ba 2+ , indicating the involvement of Ca 2+ -dependent K + channels. Blockade of the transepithelial I sc by lanthanides (La 3+ , Gd 3+ ) suggests that Ca 2+ enters the epithelium via nonselective cation channels. Experiments with basolaterally depolarized epithelia confirmed the activation of apical lanthanide-sensitive Na + - and Ca 2+ -permeable cation channels by ATP. Putative candidates might be TRP channels, from which several subtypes were detected in colonic tissue in RT-PCR experiments. In addition, the activation of an apical Cl - conductance was observed when suitable Cl - concentration gradients were applied. Consequently, mucosal ATP, acting as 'danger signal', stimulates cation and anion channels in the apical membrane to induce a secretory response as part of the local defence mechanism in the intestinal epithelium., Competing Interests: Declaration of competing interest Purinergic control of apical ion conductance by luminal ATP in rat colonic epitheliumJasmin Ballout, Martin Diener. The authors declare that there are no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To investigate intestinal health and its potential disruptors in vitro, representative models are required. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) more closely resemble the in vivo intestinal tissue than conventional in vitro models like human colonic adenocarcinoma Caco-2 cells. However, the potential of IECs to study immune-related responses upon external stimuli has not been investigated in detail yet. The aim of the current study was to evaluate immune-related effects of IECs by challenging them with a pro-inflammatory cytokine cocktail. Subsequently, the effects of Lactiplantibacillus plantarum WCFS1 were investigated in unchallenged and challenged IECs. All exposures were compared to Caco-2 cells and in vivo data where possible. Upon the inflammatory challenge, IECs and Caco-2 cells induced a pro-inflammatory response which was strongest in IECs. Heat-killed L. plantarum exerted the strongest effect on immune parameters in the IEC model, while L. plantarum in the stationary growth phase had most pronounced effects on immune-related gene expression in Caco-2 cells. Unfortunately, comparison to in vivo transcriptomics data showed limited similarities, which could be explained by essential differences in the study setups. Altogether, hiPSC-derived IECs show a high potential as a model to study immune-related responses in the intestinal epithelium in vitro., (© 2024. The Author(s).)

The disorder of group 3 innate lymphoid cells (ILC3) subgroup, such as the predominance of NCR - ILC3 but the depletion of NCR + ILC3, is unfavorable to damaged intestinal barrier repair, which leads to the prolongations and obstinacy of ulcerative colitis (UC). Our previous studies had shown that luteolin promoted NCR - ILC3 differentitating into NCR + ILC3 to improving the depletion of NCR + ILC3 in UC mice, while the mechanism is unclear. This article aimed to explore the underlying mechanism of luteolin enhancing the proportion NCR + ILC3. UC mice model was established with 2% DSS and Notch signaling was blocked, then luteolin was used to intervene. The results showed that the effect of luteolin on ameliorating disease symptoms in UC mice, including inhibiting the weight loss, reducing the pathological damage of colon mucosa, etc., was diminished with blocking Notch signaling pathway. In addition, luteolin increased the proportion of NCR + ILC3, NCR + MNK3 and IL-22 + ILC3, decreased intestinal permeability, promoted mucin secretion, and promoted ZO-1 and Occludin expression, the above effect of luteolin was neutralized by Notch inhibitor LY-411575. Luteolin activated the abnormally blocked Notch signaling pathway in UC mice. And molecular docking predicted the affinity of luteolin for RBPJ to be -7.5 kcal·mol -1 in mouse, respectively; the affinity of luteolin for Notch1 and RBPJ was respectively scored to be -6.4 kcal·mol -1 and -7.7 kcal·mol -1 homo sapiens. These results proved that luteolin is positive for enhancing the proportion of NCR + ILC3 via Notch signaling, and it provides a basis for targeting NCR + ILC3 for restoring intestinal barrier function to alleviating ulcerative colitis., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Curcumin (Cur) exerts many benefits on the host, but its application is limited by its poor bioavailability. In this study, composite polysaccharide microparticles loading Cur (Cur-CPM) was prepared by food-grade materials and gel technology. Its properties were analyzed via the in vitro and in vivo models, and then its benefit on gut health was assessed in DSS-treated mice. Compared to free Cur, CPM extended the residence time and absorption efficiency of Cur in the intestine, effectively ameliorating the symptoms of colitis. Cur-CPM alleviated colonic inflammation by inhibiting the activation of the MAPK and NF-κB pathways and suppressing NLRP3 inflammasome activity, affecting the expression of inflammation-related cytokines and mediators. In addition, Cur-CPM regulated the levels of antioxidants and oxidants in the colon tissues via Nrf2 activation, alleviating oxidative stress. Cur-CPM protected gut barrier function by maintaining the integrity of colonic mucosal layer and tight junction. The underlying mechanism can be attributed not only to the anti-inflammatory and antioxidant activities of Cur but also to modulation of Cur and CPM on the gut microbiota and metabolites. It suggests that Cur-CPM holds the potential to be developed as a functional component to enhance gut health., Competing Interests: Declaration of competing interest All authors have no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals., 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. SILVINA VILLANUEVA reports financial support was provided by National Agency for the Promotion of Research Technological Development and Innovation. 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. Fabiana Garcia reports equipment, drugs, or supplies was provided by National Council for Scientific and Technological Research. Silvina Stella Maris Villanueva reports equipment, drugs, or supplies was provided by National Agency for the Promotion of Research Technological Development and Innovation. There are no additional relationships or activities to declare. Fabiana Garcia 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 Elsevier Inc. All rights reserved.)

Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions. Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model. Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches. In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D., 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 B.V. All rights reserved.)

Ulcerative colitis (UC), an incurable and recurrent inflammatory bowel disease, presents a significant threat to health and highlights the need for novel therapeutic strategies. Oleanolic acid 28-O-β-D-glucopyranoside (OAG) is a naturally occurring pentacyclic triterpenoid found in ginseng. In this study, we demonstrated that OAG exhibited remarkable anti-UC activity in LPS-induced Caco-2 cells and DSS-induced model mice. First, OAG alleviated the symptoms of UC by mitigating weight loss, reducing the DAI score, and increasing colon length. Second, the inflammatory response was inhibited after OAG intervention, evidenced decreases in the spleen coefficient, cytokine levels, and inflammatory cell infiltration in colon tissue. Thirdly, OAG also enhanced intestinal epithelial barrier function, as evidenced by elevated TEER values, increased expression of tight junction proteins, diminished bacterial translocation, and maintained intact ultrastructure of colonic mucosal cells. Notably, compared with 5-aminosalicylic acid, OAG demonstrated superior efficacy in enhancing mucosal barrier function. Fourth, OAG increased microbial diversity, promoted the abundance of beneficial bacteria, reduced the abundance of harmful bacteria, and rebalanced the gut microbiome. Finally, the PI3K-AKT and MAPK signaling pathways were identified as crucial mechanisms underlying the therapeutic effects of OAG against UC through multi-omics. In summary, we identified OAG as a novel therapeutic agent against UC, demonstrating anti-inflammatory, barrier-preserving, and gut microbiota-modulating effects, highlighting its promising potential as a candidate UC drug., Competing Interests: Declaration of Competing Interest All the authors declare that there are no conflicts of interest associated with this publication and there is no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Intestinal health is closely linked to intestinal stem cells (ISCs), which are highly sensitive to the harmful substances in the lumen. However, there is limited knowledge regarding the effects of food additives on ISCs. This study aims to investigate the impact of dietary titanium dioxide nanoparticles (TiO 2 NPs) compared with titanium dioxide microparticles (TiO 2 MPs) on intestinal health associated with ISCs in response to dextran sodium sulfate (DSS)-induced enteritis in mice, as well as the related mechanism. We found that exposure to 1% (w/w) TiO 2 NPs aggravated DSS-induced enteritis in mice, while this effect could not be observed under exposure to TiO 2 MPs. Additionally, 1% (w/w) TiO 2 NPs exposure under DSS-induced enteritis worsened the ISC-mediated regeneration of intestinal epithelium by decreasing the epithelial cell proliferation and epithelial turnover rate while increasing epithelial cell death. Meanwhile, using a 3D intestinal organoid model, we discovered that 20 μg/mL TiO 2 NPs impaired ISC function and disrupted ISC fate specification both ex vivo and in vitro. Furthermore, TiO 2 NPs hindered the nuclear translocation of β-catenin, reducing the overall output of Wnt signaling. Together, TiO 2 NPs deteriorated the intestinal epithelial regeneration of mice with DSS-induced enteritis by perturbating ISC function and fate specification through a mechanism involving Wnt signaling. These findings highlight the adverse effect of dietary TiO 2 NPs on ISCs and shed light on the particle size optimization of TiO 2 food additive., 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.)

The incidence of inflammatory bowel disease (IBD) is rising globally, increasing interest in food ingredients for its prevention and control. This study evaluated the effect of farnesol (FAR), a key component of pomelo flower volatile oil, on dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice. FAR significantly alleviated DSS-induced colitis and secondary liver injury, as shown by improved body weight, DAI, colon length, and pathology, as well as liver function and blood lipid indices. The mechanism involves FAR-mediated regulation of inflammatory cytokines, increased expression of tight junction protein genes, and decreased expression of lipid metabolism-related proteins. FAR also enhanced gut microbiota diversity, balancing harmful and probiotic bacteria. Fecal metabolome analysis indicated FAR's role in reversing metabolic disturbances related to inflammation and liver lipid metabolism. These findings support developing functional foods for IBD treatment using pomelo flower volatile oil., 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 Masson SAS.. All rights reserved.)

Engineered nanoparticles (NPs) are extensively used in the food industry, yet safety concerns remain. The lack of validated methodologies is a bottleneck towards resolving this uncertainty. Hence, the current study aims to compare two cell models by examining the toxicological impacts of two food-relevant NPs (SiO 2 and Ag) on intestinal epithelia using monolayer Caco-2 cells and full-thickness 3D tissue models of human small intestines (EpiIntestinal™). Comprehensive characterization and dosimetric analysis of the NPs were performed to determine effective doses and model realistic exposures. Neither genotoxicity nor cytotoxicity were detected in the 3D tissues after NP treatment, while the 2D cultures exhibited cytotoxic response from Ag NP treatment for 24 h at 1 μg/ml. Hyperspectral imaging and transmission electron microscopy confirmed uptake of both NPs by cells in both 2D and 3D culture models. Ag NPs caused an increase in autophagy, whereas SiO 2 NPs induced increased cytoplasmic vacuolization. Based on realistic exposure levels studied, the 3D small intestinal tissue model was found to be more resilient to NP treatment compared to 2D cell monolayers. This comparative approach towards toxicological assessment of food relevant NPs could be used as a framework for future analysis of NP behavior and nanotoxicity in the gut., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In recent years, natural polysaccharides (PSs) have attracted increasing interest because of their remarkable biological properties and potential in various areas, such as medicine, and food. This study aimed to present a detailed review of the evidence on the therapeutic potential of PSs for the treatment of gastrointestinal diseases. The main evidence was correlated with their chemical composition, mechanism of action and therapeutic effect. The main results showed that the action can be attributed to their ability to suppress excessive inflammatory responses, regulating the expression of cytokines and interleukins, reducing intestinal inflammation and promoting wound healing. Furthermore, we discussed how PSs help in the repair of the intestinal mucosa and related these effects with the composition of monosaccharides. A detailed analysis was performed on the ability of PSs to modulate the intestinal microbiota, promoting the growth of beneficial bacteria and suppressing inflammatory bacteria, in addition to its probiotic action with production of short-chain fatty acids. All this evidence was also taken into a broader context, in which the main challenges in processing PSs were considered and strategies to circumvent them were pointed out. Therefore, this review sought to demonstrate the great potential and viability of PSs as innovative and effective therapeutic agents., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Radiation-induced intestinal injury (RIII) constitutes a challenge in radiotherapy. Ionizing radiation (IR) induces DNA and mitochondrial damage by increasing reactive oxygen species (ROS). Sodium-glucose cotransporter 1 (SGLT1) is abundant in the gastrointestinal tract and the protective effects of inhibited SGLT1 in kidney and cardiovascular disease have been widely reported. However, the function of SGLT1 in RIII remains unclear. Herein, we reported that IR induced intestinal epithelial cell damage along with upregulation of SGLT1 in vivo and in vitro, which was alleviated by inhibition of SGLT1. Specifically, maintaining intestinal cell homeostasis was detected through cellular proliferation, apoptosis, and DNA damage assays, promoting epithelial regeneration and lifespan extension. Considering the importance of mitochondrial function in cell fate, we next confirmed that SGLT inhibition maintains mitochondrial homeostasis through enhanced mitophagy in intestinal epithelial cells. Finally, based on the bioinformatics analysis and cell validation, we demonstrated that inhibition of SGLT1 suppresses the PI3K/AKT/mTOR pathway to enhance mitophagy activation post-irradiation. In addition, we preliminarily demonstrate that SGLT inhibitors do not affect the radiosensitivity of tumors. Hence, our findings suggest that inhibition of SGLT is a promising therapeutic strategy to protect against RIII. To the best of our knowledge, this is the first report on the potential effect of SGLT1 inhibition in RIII., 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. This study was supported by the National Natural Science Foundation of China (82304082)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To study the therapeutic effect and mechanism of Shaoyao Gancao Decoction (SGD) on ulcerative colitis (UC) mice based on the perspective of intestinal barrier, and this study provides a new consultation for the clinical application of SGD., Methods: The chemical composition of SGD was characterized by HPLC. The UC mouse model was constructed by 3 % dextran sodium sulfate (DSS), which were randomly divided into the model group (DSS), the positive drug group (5-ASA), the Shaoyao group (SYD), Gancao group (GCD), and the Shaoyao Gancao Decoction group (SGD) at low, medium, and high dosages, respectively. The effects of each drug treatment group on UC were evaluated by the rate of body weight loss, disease activity index (DAI), colon length, spleen index, histopathological evaluations, and the levels of serum inflammatory factors (IL-1β, IL-6, IL-10, IL-21, and TNF-α). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining, ELISA was used to detect the content of LPS in serum, and Western blot was used to detect the changes in the expression of tight junction proteins ZO-1, occludin, and the pathway proteins TLR4 and NF-κBp65 in the colonic tissues, to explore the protective effect of SGD on the intestinal barrier of UC mice. The vivo absorption process of the main active ingredients in the SG, SY and GC groups was determined by LC-MS., Results: The contents of albiflorin, paeoniflorin, liquiritin apioside, liquiritin and glycyrrhetinic acid were 6.1227 mg/g, 20.8993 mg/g, 4.0054 mg/g, 3.6140 mg/g and 8.2515 mg/g, respectively. Compared with DSS group, SGD reduced weight loss(P<0.01) and DAI scores(P<0.05), prevented colon shortening(P<0.01), and ameliorated histopathological damage of the colon in UC mice(P<0.01). SGD also protected the intestinal barrier to alleviate UC by significantly reducing serum LPS and inflammatory factor levels, altering the number of goblet cells, promoting tight junction proteins (ZO-1 and occludin) and decreasing the expression of TLR4 and NF-κB in colonic tissues. Pharmacokinetic results showed that there was no significant difference in C max , AUC 0-t (μg/L . h) and T max of albiflorin and paeoniflorin between the SY and SG groups, the T max was within 1 h; the AUC 0-t (μg/L . h) of liquiritin and glycyrrhizic acid were about 1.6 and 1.9 times higher in the SG group compared to the GC group, respectively. The C max , T max and AUC 0-t (μg/L . h) of glycyrrhizinic acid were significantly reduced to 0.73, 0.68 and 0.68 times of that of the GC group., Conclusion: SGD may have a therapeutic effect on DSS-induced UC mice by repairing the damaged intestinal barrier through the TLR4/NF-κB pathway. The combination of Shaoyao and Gancao increased the absorption of liquiritin and glycyrrhizic acid in vivo. The combination of Shaoyao and Gancao could promote the absorption of Gancao, and that the pairing of the two herbs could have a synergistic effect., 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.)

Intestinal development has a crucial role in the absorption of nutrients and the ability to resist infections in the early stages of life. This study utilized a 3-week-old C57BL/6 mice model to evaluate the beneficial impacts of sulfated fucans from Saccharina japonica (SJ-FUC) on the growth and development of the intestines. SJ-FUC enhanced the dimensions of the intestine, specifically the length, height of villi, and depth of the crypts. Additionally, it raised the mRNA expression of ZO-1 and Occludin, hence enhancing the structural integrity of the intestinal epithelium. SJ-FUC significantly increased mRNA expression of Lyz1, Muc2, and Math1, which resulted in the promotion of intestinal epithelial development. Furthermore, SJ-FUC augmented the mRNA levels of the ISC markers (Lgr5, Olfm4, and Ascl2). Our further research uncovered that SJ-FUC has a positive impact on the growth of beneficial bacteria, such as Akkermansia, Dubosiella, and Lactobacillus, which in turn promotes epithelial development of the intestine. In summary, our research indicates that SJ-FUC has a beneficial impact on the growth of the intestines in young mice. This is achieved by enhancing the stemness of intestinal stem cells (ISCs) and promoting the formation of the intestinal epithelium through the regulation of gut bacteria., 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.)

Vitamin K2 (VK2) has been shown to have potential benefits in improving intestinal integrity, but its potential and mechanisms for alleviating intestinal inflammation are still unclear. The present results showed that VK2 supplementation significantly alleviated the symptoms of colitis and maintained the intestinal barrier integrity. In addition, VK2 significantly down-regulated the mRNA expression levels of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, while up-regulated the mRNA expression level of anti-inflammatory cytokines such as IL-10. Moreover, VK2 significantly alleviated DSS-induced intestinal epithelial barrier dysfunction by maintaining the tight junction function. Furthermore, VK2 also regulated DSS-induced gut microbiota dysbiosis by reshaping the structure of gut microbiota, such as increasing the relative abundance of Firmicutes, Euryarchaeota, Prevotellaceae, and Prevotella and reducing the relative abundance of Proteobacteria, Rikenellaceae, Enterobacteriaceae, Acetatifactor, and Alistioes. In conclusion, these results indicated that VK2 effectively alleviates DSS-induced colitis in mice by modulating the gut microbiota., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alginate oligosaccharides (AOS) exhibits notable effects in terms of anti-inflammatory, antibacterial, and antioxidant properties. Deoxynivalenol (DON) has the potential to trigger intestinal inflammation by upregulating pro-inflammatory cytokines and apoptosis, thereby compromising the integrity of the intestinal barrier function and perturbing the balance of the gut microbiota., Objectives: We assessed the impact of AOS on mitigating DON-induced intestinal damage and systemic inflammation in mice., Methods: After a 1-wk acclimatization period, the mice were divided into 4 groups. For 3 wk, the AOS and AOS + DON groups were gavaged daily with 200 μL of AOS [200 mg/kg body weight (BW)], whereas the CON and DON groups received an equivalent volume of sterile Phosphate-Buffered Saline (PBS). Subsequently, for 1 wk, the DON and AOS + DON groups received 100 μL of DON (4.8 mg/kg BW) daily, whereas the control (CON) and AOS groups continued receiving PBS., Results: After administering DON via gavage to mice, there was a significant decrease (P < 0.05) in body weights compared with the CON group. Interestingly, AOS exhibited a tendency to mitigate this weight loss in the AOS + DON group. In the feces of mice treated with both AOS and DON, the concentration of DON significantly increased (P < 0.05) compared with the DON group alone. Histological analysis revealed that DON exposure caused increased intestinal damage, including shortened villi and eroded epithelial cells, which was ameliorated by presupplementation with AOS, alleviating harm to the intestinal barrier function. In both jejunum and colon tissues, DON exposure significantly reduced (P < 0.05) the expression of tight junction proteins (claudin and occludin in the colon) and the mucin protein mucin 2, compared with the CON group. Prophylactic administration of AOS alleviated these reductions, thereby improving the expression levels of these key proteins. Additionally, AOS supplementation protected DON-exposed mice by increasing the abundance of probiotics such as Bifidobacterium, Faecalibaculum, and Romboutsia. These gut microbes are known to enhance (P < 0.05) anti-inflammatory responses and the production of short-chain fatty acids (SCFAs), including total SCFAs, acetate, and valerate, compared with the DON group., Conclusions: This study unveils that AOS not only enhances gut microbiota and intestinal barrier function but also significantly mitigates DON-induced intestinal damage., Competing Interests: Conflict of 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 © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI 2 ), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI 2 improves intestinal microcirculation and barrier function via endothelial protective effects., Methods: ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI 2 effects. Beraprost served as PGI 2 . PGI 2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions., Results: We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration., Conclusions: Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure., (© 2024 The Author(s). Microcirculation published by John Wiley & Sons Ltd.)

C-type lectin (CTL) plays a vital role in parasite adhesion, invading host's cells and immune escape. The objective of this research was to explore whether recombinant T. spiralis CTL (rTsCTL) binding with syndecan-1 damages intestine epithelial integrity and mediates T. spiralis intrusion in mice. The results showed that rTsCTL interacted with syndecan-1 and activated STAT3 pathway in gut epithelium, decreased tight junctions (TJs) expressions and damaged gut epithelium integrity, promoted T. spiralis intrusion, and increased expression level of inflammatory cytokine and mucin. The syndecan-1 inhibitor (β-xyloside) and STAT3 phosphorylation inhibitor (Stattic) significantly suppressed syndecan-1 expression and STAT3 pathway activation, reduced the expression levels of TJs, pro-inflammatory cytokines (TNF-α and IL-1β), Muc2 and Muc5ac, and declined intestinal permeability in T. spiralis-infected mice. These results revealed that the inhibitors suppressed T. spiralis invasion and development in gut mucosa, decreased intestinal adult burdens and relieved gut inflammation. These findings further testified that the in vivo binding of TsCTL with syndecan-1 destroyed enteral mucosal epithelial integrity and promoted T. spiralis intrusion of gut mucosa via activating STAT3 pathway and decreasing TJs expression. TsCTL could be deemed as a promising vaccine target to interrupt T. spiralis infection., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. β diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

We aimed to investigate the effect of a polysaccharide from Tremella aurantialba on ulcerative colitis (UC), which targets ferroptosis in epithelial cells. TA 2-1 (127 kDa) was isolated from T. aurantialba and consisted of Man, Xyl, GlcA, Glc, Fuc and Rha with a molar ratio of 59.2: 23.2: 13.9: 1.6: 1.7: 0.4, exhibited a 1, 3-Man structure with branch chains of T-Xylp, 1,3-Xylp, 1,4-GlcAp, and T-Manp at its O-2 position. TA 2-1 (100 μg/mL) inhibited the cell viability of ferroptosis (19.8 %) in RLS3-induced Caco-2 cells and significantly ameliorated symptoms in the colons of mice with dextran sodium sulfate (DSS)-induced UC. TA 2-1 remarkably repaired the intestinal barrier by upregulating claudin-1 and zonula occludens-1 levels. Further analysis found TA 2-1 significantly suppressed lipid peroxidation by regulating ferroptosis-related proteins in UC mice, suggesting that its protective effects are partially mediated by inhibiting ferroptosis. Further analysis of the gut microbiota and fecal microbiota transplantation revealed TA 2-1 might relieve UC symptoms or inhibit ferroptosis by modulating the gut microbiota's composition or metabolites. Results suggest the protective effects of TA 2-1 on the intestinal barrier by inhibiting ferroptosis of epithelial cells, at least by regulating the gut microbiota, highlighting the potential of TA 2-1 in UC 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Parenteral nutrition (PN) without enteral nutrition (EN) leads to marked atrophy of gut-associated lymphoid tissue (GALT), causing mucosal defense failure in both the gut and the extraintestinal mucosal system. We evaluated the effects of beta-hydroxy-beta-methylbutyrate (HMB) on GALT and gut morphology in PN-fed mice., Methods: Experiment 1: male Institute of Cancer Research mice were assigned to the Chow (n = 12), Control (standard PN: n = 10), or H600 and H2000 (PN containing 600 mg/kg or H2000 mg/kg body weight of Ca-HMB: n = 12 and 10, respectively) groups. After 5 days of dietary manipulation, all mice were killed and the whole small intestine was harvested. GALT lymphocyte cell numbers and phenotypes of Peyer patch (PP), intraepithelial space, and lamina propria lymphocytes were evaluated. Experiment 2: 47 mice (Chow: n = 12; Control: n = 14; H600: n = 11; and H2000: n = 10) were fed for 5 days as in experiment 1. Proliferation and apoptosis of gut immune cells and mucosa, and protein expressions (mammalian target of rapamycin [mTOR], caspase-3, and Bcl2) were evaluated in the small intestine., Results: Compared with the Controls, the Chow and HMB groups showed significantly higher PP cell numbers, prevented gut mucosal atrophy, inhibited apoptosis of gut cells, and increased their proliferation in association with increased mTOR activity and Bcl2 expression., Conclusion: HMB-supplemented PN is a potentially novel method of preserving GALT mass and gut morphology in the absence of EN., (© 2024 American Society for Parenteral and Enteral Nutrition.)

The effect of baicalin methyl ester (BME) on the regulation of mice intestinal barrier in the inflammatory response was studied in vivo and in vitro. Thirty six C57/BL mice were randomly divided into six groups (n = 6): control group; LPS group (LPS 3.5 mg/kg given intraperitoneal [ip] on day 7 of the study only), PBS group, and three BME groups (low: 50 mg/kg; medium: 100 mg/kg; high: 200 mg/kg) orally dosed with BME for 7d and LPS ip on day 7. All mice were sacrificed on day 8, and jejunum tissue collected for histopathology (H&E and PAS staining), protein expression of pro-inflammatory factors (TNF-α, IL-6, IL-8, IFN-γ) by ELISA, and intestinal tight junction proteins (ZO-1, occludin, claudin-1 and claudin-4) by Western Blot. Compared with the control group, LPS significantly increased the serum cytokines DAO (p < 0.01) and DLA (p < 0.01), upregulated the expression of pro-inflammatory factors, MLCK proteins (p <0.05) and increased the MLCK/ZO-1ratio (p <0.001). LPS also decreased the expression of claudin-4 (p < 0.01) in the jejunum and induced an inflammatory response damaging the jejunal mucosal barrier. Pretreatment with BME (100-200 mg/kg) significantly decreased the cytokines DAO (p < 0.05) and DLA (p < 0.01) in the serum, pro-inflammatory factors in the jejunum, significantly down-regulated the expression of MLCK (p <0.05) and the ratio of MLCK/ZO-1(p <0.001) but upregulated the expressions of ZO-1(p < 0.01), occludin (p < 0.05), claudin-1(p < 0.05) and claudin-4 (p < 0.05), and thereby restored the intestinal tissue structure, suggestive of alleviation of LPS-induced intestinal inflammation by BME. In vitro, MODE-K cells (derived from mice intestinal epithelium) were exposed to BME at 0 (control group-No LPS), 10, 20 and 40 μM BME for 24 h prior to LPS addition at 50 μg/mL for 2 h. LPS significantly increased the expression of pro-inflammatory factors, MLCK (p < 0.01) and the ratio of MLCK/ZO-1(p <0.001), decreased the expressions of ZO-1 (p < 0.05), occludin (p < 0.01), claudin-1 (p < 0.01) and claudin-4 (p < 0.01) in MODE-K cells compared with the control group. Compared with the LPS group, BME (10 - 40 μM) significantly decreased the expression of pro-inflammatory factors, MLCK (p < 0.05) and the ratio of MLCK/ZO-1(p <0.01) but increased the expressions of ZO-1(p < 0.01), occludin (p < 0.05) and claudin-4(p < 0.01) indicating an up-regulation of the expression of tight junction proteins by BME. On addition of extrinsic TNF-α plus LPS, the TNF- α level increased (p < 0.001) in MODE-K cells and the protein expression of MLCK (p < 0.01) was markedly up-regulated. Molecular docking predicted BME interacted with P65 by forming hydrogen bonds. IP-WB further confirmed that BME was directly bound to P65 protein in MODE-K cells. In conclusion, BME was able to restore the intestinal barrier through the P65 / TNF-α / MLCK / ZO-1 signaling pathway., 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 Masson SAS.. All rights reserved.)

This study examined the effect of exposure of small and large intestinal epithelial cells to the bacterial lipopolysaccharide (LPS) on uptake of free form of vitamin B1, i.e., thiamin. The intestinal tract encounters two sources of thiamin: diet and the gut microbiota. Absorption of thiamin in both the small and large intestine occurs via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and -2). Complementary in vitro (human duodenal epithelial HuTu-80 cells and human colonic epithelial NCM460 cells), in vivo (mice), and ex vivo (human primary differentiated enteroid and colonoid monolayers) models were used. The results showed that exposure to LPS causes a significant inhibition in carrier-mediated [ 3 H]-thiamin uptake by small and large intestinal epithelia, with no change in the levels of expression of THTR-1 and -2 mRNAs and their total cellular proteins. However, a significant decrease in the fractions of the THTR-1 and -2 proteins that are expressed at the cell membranes of these epithelial cells was observed. These effects of LPS appeared to involve a protein kinase A (PKA) signaling pathway as activating this pathway caused a reversal in the inhibition of thiamin uptake and level of expression of its transporters at the cell membrane. These findings demonstrate that exposure of gut epithelia to LPS (a situation that occurs under different pathological conditions) leads to inhibition in thiamin uptake due to a decrease in level of expression of its transporters at the cell membrane that is likely mediated via a PKA signaling pathway. NEW & NOTEWORTHY This study shows that the exposure of gut epithelial cells to bacterial LPS negatively impact the uptake process of the free form of vitamin B1 (i.e., thiamin). This appears to be mediated via suppression in the level of thiamin transporters 1 and 2 (THTR-1 and -2) expression at the cell membrane and involves a protein kinase A (PKA) signaling pathway.

The unknown mechanism that controls intestinal barrier dysfunction in individuals with Crohn's disease (CD) plays a crucial role in the onset of intestinal inflammation. Testin, an intercellular linker protein, has the potential to protect epithelial barrier function. This study aimed to analyse the effects of Testin on CD-like colitis and explore the possible underlying mechanism. Colon samples from CD patients and trinitrobenzene-sulfonic acid (TNBS)-treated mice were collected to examine changes in Testin expression. To assess the therapeutic effects of Testin on CD-like colitis in mice, we examined the symptoms of enteritis, performed histological analysis, and evaluated intestinal barrier permeability. The ability of Testin to stabilize tight junction (TJ) proteins was investigated via immunofluorescence and western blotting. We conducted in vivo and in vitro experiments using colonic organoids and blocking techniques to explore how Testin safeguards the integrity of the intestinal barrier. Testin expression was downregulated in the colons of CD patients and TNBS-treated mice. Increasing Testin expression led to amelioration of colitis symptoms and reduced the production of inflammatory cytokines in the colons of TNBS-induced colitis model mice. Furthermore, increased Testin expression resulted in decreased depletion of TJ proteins (ZO-1 and Claudin-1) and promoted the effectiveness of the intestinal barrier in mice with TNBS-induced colon damage and in lipopolysaccharide (LPS)-stimulated colonic organoids. Elevated Testin levels inactivated the JNK/P38 signalling pathway, potentially contributing to the beneficial impact of Testin on the intestinal barrier. Testin can inhibit the loss of TJ proteins in CD mice by inactivating the JNK/P38 pathway. These findings help to clarify how Testin alleviates CD-like colitis in mice by protecting intestinal barrier function. These findings could lead to the use of a new treatment approach for CD in clinical practice., 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 B.V. All rights reserved.)