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As a medicinal and edible homologous Chinese herb, Polygonatum sibiricum has been used as a primary ingredient in various functional and medicinal products. Damage to the intestinal mucosal barrier can lead to or worsen conditions such as type 2 diabetes and Alzheimer's disease. Traditional Chinese medicine and its bioactive components can help prevent and manage these conditions by restoring the integrity of the intestinal mucosal barrier. This review delves into the mode of action of P. sibiricum polysaccharide in disease prevention and management through the restoration of the intestinal barrier. Polysaccharide from P. sibiricum effectively treats conditions by repairing the intestinal mucosal barrier, offering insights for treating complex diseases and supporting the application of P. sibiricum in clinical settings. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of Shaoyao-Gancao decoction (SGD) on inflammation and mucosal barrier damage in rats with 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced inflammatory bowel disease (IBD). METHODS: Forty-eight male SD rats were randomly divided into normal group, model group, high-dose (500 mg/kg), medium-dose (250 mg/kg) and low-dose (125 mg/kg) SGD groups, and balsalazide sodium (1 g/kg) group. All rats were pre-administered for 3 d, and on the 4th day of the experiment, they were fasted for 24 h. Except for the normal group, the rats in the other 5 groups were given enema mixed with TNBS (100 mg/kg) and 50% ethanol, and continued to be administered for 5 d after modeling. After modeling, the disease activity index (DAI) was evaluated. After the experiment, the levels of nitric oxide (NO) and myeloper oxidase (MPO) in serum and colonic tissues of rats were determined. RT-qPCR and Western blot were used to determine tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) in the colon of rats. The expression of tight junction proteins zonula occludens-1 (ZO-1) and claudin 2 in rat colon tissues was determined by immunofluorescence staining. RESULTS: Compared with normal group, the weight of rats in model group was decreased, the colon was shortened, DAI and colon tissue macroscopic scores were significantly increased (P<0. 05), colon pathological injury was serious, and NO and MPO levels in serum and colon tissues of the rats in model group were significantly increased (P<0. 05). The mRNA and protein expression levels of TNF-α, COX-2, iNOS and NF-κB in colon tissues were significantly increased (P<0. 01), while the expression levels of ZO-1 and claudin 2 were significantly decreased (P<0. 01). Compared with model group, the body weight and colon shortening of rats in SGD groups were alleviated, DAI and macroscopic scores of colon tissues were significantly decreased (P<0. 05), the pathological damage of colon was improved, and the levels of NO and MPO in serum and colon tissues of rats were significantly decreased (P<0. 05). The mRNA and protein expression levels of TNF-α, COX-2, iNOS and NF-κB in colon tissues were significantly decreased (P<0. 05), while the expression levels of ZO-1 and claudin 2 were significantly increased (P<0. 05). CONCLUSION: Treatment with SGD effectively attenuates the inflammatory response and intestinal mucosal barrier damage caused by TNBS-induced IBD in rats. [ABSTRACT FROM AUTHOR]

Abstract The Apple polysaccharides (AP), extracted from the fruit of apple, has been used to treat multiple pathological diseases. In this study, we evaluated the effects of AP on cognitive impairment and intestinal aging in naturally aging mice. As a result, it was found that AP could improve spatial learning and memory impairment in aging mice through the Morris water maze experiment. Additionally, AP intervention can upregulate the expression of nerve growth factor (BDNF), postsynaptic marker (PSD95), and presynaptic marker (SYP) proteins. Moreover, AP can enhance total antioxidant capacity, reduce the level of pro-inflammatory cytokine, and inhibit the activation of the NF-κB signaling pathway, exerting anti-inflammatory and antioxidant functions. And the administration of AP restored intestinal mucosal barrier function, reduced the expression of aging and apoptosis related proteins. The administration of AP also altered the gut microbiota of mice. At the genus level, AP decreased the abundance of Helicobacter and Bilophila, while increased the abundance of Lactobacillus and Bacteroides. In summary, these data demonstrate that AP treatment can alleviate cognitive impairment, oxidative stress, and inflammatory reactions, repair the intestinal mucosal barrier, reduce intestinal aging, and alter specific microbial characteristics, ultimately improving the health of the elderly.

Backgrounds: Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease, and UC diagnosis rates continue to rise throughout the globe. The research and development of new drugs for the treatment of UC are urgent, and natural compounds are an important source. However, there is a lack of systematic summarization of natural compounds and their mechanisms for the treatment of UC. Methods: We reviewed the literature in the databases below from their inception until July 2023: Web of Science, PubMed, China National Knowledge Infrastructure, and Wanfang Data, to obtain information on the relationship between natural compounds and UC. Results: The results showed that 279 natural compounds treat UC through four main mechanisms, including regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as regulating other mechanisms (Mechanism IV) such as cellular autophagy modulation and ferroptosis inhibition. Of these, Mechanism III is regulated by all natural compounds. The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC. Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. It is noteworthy to highlight that a total of 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III. Conclusion: This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC. Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) refers to long-term medical conditions that involve inflammation of the digestive tract, and the global incidence and prevalence of IBD are on the rise. Gut microbes play an important role in maintaining the intestinal health of the host, and the occurrence, development, and therapeutic effects of IBD are closely related to the structural and functional changes of gut microbes. Published studies have shown that the natural products from traditional Chinese medicine have direct or indirect regulatory impacts on the composition and metabolism of the gut microbes. In this review, we summarize the research progress of several groups of natural products, i.e., flavonoids, alkaloids, saponins, polysaccharides, polyphenols, and terpenoids, for the therapeutic activities in relieving IBD symptoms. The role of gut microbes and their intestinal metabolites in managing the IBD is presented, with focusing on the mechanism of action of those natural products. Traditional Chinese medicine alleviated IBD symptoms by regulating gut microbes, providing important theoretical and practical basis for the treatment of variable inflammatory intestinal diseases. [ABSTRACT FROM AUTHOR]

Chemotherapy is a common and effective treatment for cancer, but these drugs are also associated with significant side effects affecting patients' well‐being. One such debilitating side effect is mucositis, characterized by inflammation, ulcerations, and altered physiological functions of the gastrointestinal (GI) tract's mucosal lining. Understanding the mechanisms of chemotherapy‐induced intestinal mucositis (CIM) is crucial for developing effective preventive measures and supportive care. Chemotherapeutics not only target cancer cells but also rapidly dividing cells in the GI tract. These drugs disrupt endoplasmic reticulum (ER) homeostasis, leading to ER‐stress and activation of the unfolded protein response (UPR) in various intestinal epithelial cell types. The UPR triggers signaling pathways that exacerbate tissue inflammation and damage, influence the differentiation and fate of intestinal epithelial cells, and compromise the integrity of the intestinal mucosal barrier. These factors contribute significantly to mucositis development and progression. In this review, we aim to give an in‐depth overview of the role of ER‐stress in mucositis and its impact on GI function. This will provide valuable insights into the underlying mechanisms and highlighting potential therapeutic interventions that could improve treatment‐outcomes and the quality of life of cancer patients. [ABSTRACT FROM AUTHOR]

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The Apple polysaccharides (AP), extracted from the fruit of apple, has been used to treat multiple pathological diseases. In this study, we evaluated the effects of AP on cognitive impairment and intestinal aging in naturally aging mice. As a result, it was found that AP could improve spatial learning and memory impairment in aging mice through the Morris water maze experiment. Additionally, AP intervention can upregulate the expression of nerve growth factor (BDNF), postsynaptic marker (PSD95), and presynaptic marker (SYP) proteins. Moreover, AP can enhance total antioxidant capacity, reduce the level of pro-inflammatory cytokine, and inhibit the activation of the NF-κB signaling pathway, exerting anti-inflammatory and antioxidant functions. And the administration of AP restored intestinal mucosal barrier function, reduced the expression of aging and apoptosis related proteins. The administration of AP also altered the gut microbiota of mice. At the genus level, AP decreased the abundance of Helicobacter and Bilophila, while increased the abundance of Lactobacillus and Bacteroides. In summary, these data demonstrate that AP treatment can alleviate cognitive impairment, oxidative stress, and inflammatory reactions, repair the intestinal mucosal barrier, reduce intestinal aging, and alter specific microbial characteristics, ultimately improving the health of the elderly. [ABSTRACT FROM AUTHOR]

Background and Aim: Circular RNA (circRNA) has been found to mediate ulcerative colitis (UC) progression by regulating intestinal mucosal barrier function. However, the role of circSOD2 in UC process and its underlying molecular mechanism still need to be further elucidated. Methods: Lipopolysaccharide (LPS)‐induced Caco2 cells were used to mimic UC cell models. CircSOD2, miR‐378g, and Snail1 levels were determined by quantitative real‐time PCR. Cell viability was detected using MTT assay, and inflammatory cytokine levels were measured using ELISA. The intestinal mucosal barrier function was evaluated by testing transepithelial electrical resistance and fluorescein isothiocyanate (FITC)‐dextran permeability. Snail1 and tight junction‐related markers (Zo‐1 and Claudin2) protein levels were examined using western blot. The interaction between miR‐378g and circSOD2 or Snail1 was confirmed by dual‐luciferase reporter assay. Dextran sulfate sodium (DSS) was used to induce UC rat models in vivo. Results: CircSOD2 was overexpressed in UC patients, and its knockdown significantly increased cell viability, transepithelial electrical resistance, and tight junction‐related protein expression, while reduced inflammation cytokine levels and the permeability of FITC‐dextran in LPS‐induced Caco2 cells. In terms of mechanism, circSOD2 sponged miR‐378g to positively regulate Snail1 expression. MiR‐378g inhibitor reversed the effect of circSOD2 knockdown on intestinal mucosal barrier injury and Snail1 expression in LPS‐induced Caco2 cells. In DSS‐induced UC rat models, circSOD2 knockdown also could repair the intestinal mucosal barrier injury through regulating miR‐378g/Snail1 axis. Conclusion: CircSOD2 could destroy intestinal mucosal barrier function in LPS‐induced Caco2 cells and DSS‐induced UC rats by miR‐378g/Snail1 axis. [ABSTRACT FROM AUTHOR]

Intestinal tract is one of the largest organs in human body that is continuously exposed to the external environment, and it plays an important role as a physical and chemical barrier to protect the human body from pathogens. As an important part of the intestinal tract, the integrity of the intestinal mucosal barrier plays a key role in maintaining the intestinal microecological balance. The destruction of the intestinal mucosal barrier can lead to the imbalance and translocation of intestinal flora, which is related to the occurrence and development of various diseases. Intestinal fatty acid binding protein (I-FABP) is one of the fatty acid-binding protein family, which exhibits specificity towards intestinal injury and will be released into the blood circulation rapidly when intestinal injury, ischemia, intestinal mucosal barrier damage and permeability increase occur. The elevated level of I-FABP is an important marker of intestinal injury, and intestinal dysfunction is often associated with many clinical diseases. This article mainly reviews the structural characteristics and function of I-FABP and its relationship with intestinal mucosal barrier related diseases [ABSTRACT FROM AUTHOR]

Objective: The aim of the study is to investigate the function and mechanism of Zinc Gluconate (ZG) on intestinal mucosal barrier damage in antibiotics and Lipopolysaccharide (LPS)-induced mice. Methods: We established a composite mouse model by inducing intestinal mucosal barrier damage using antibiotics and LPS. The animals were divided into five groups: Control (normal and model) and experimental (low, medium, and high-dose ZG treatments). We evaluated the intestinal mucosal barrier using various methods, including monitoring body weight and fecal changes, assessing pathological damage and ultrastructure of the mouse ileum, analyzing expression levels of tight junction (TJ)-related proteins and genes, confirming the TLR4/NF-B signaling pathway, and examining the structure of the intestinal flora. Results: In mice, the dual induction of antibiotics and LPS led to weight loss, fecal abnormalities, disruption of ileocecal mucosal structure, increased intestinal barrier permeability, and disorganization of the microbiota structure. ZG restored body weight, alleviated diarrheal symptoms and pathological damage, and maintained the structural integrity of intestinal epithelial cells (IECs). Additionally, ZG reduced intestinal mucosal permeability by upregulating TJassociated proteins (ZO-1, Occludin, Claudin-1, and JAM-A) and downregulating MLCK, thereby repairing intestinal mucosal barrier damage induced by dual induction of antibiotics and LPS. Moreover, ZG suppressed the TLR4/NF-B signaling pathway, demonstrating anti-inflammatory properties and preserving barrier integrity. Furthermore, ZG restored gut microbiota diversity and richness, evidenced by increased Shannon and Observed features indices, and decreased Simpson's index. ZG also modulated the relative abundance of beneficial human gut bacteria (Bacteroidetes, Firmicutes, Verrucomicrobia, Parabacteroides, Lactobacillus, and Akkermansia) and harmful bacteria (Proteobacteria and Enterobacter), repairing the damage induced by dual administration of antibiotics and LPS. Conclusion: ZG attenuates the dual induction of antibiotics and LPS-induced intestinal barrier damage and also protects the intestinal barrier function in mice. [ABSTRACT FROM AUTHOR]

Porcine astrovirus (PAstV) has a potential zoonotic risk, with a high proportion of co-infection occurring with porcine epidemic diarrhea virus (PEDV) and other diarrheal pathogens. Despite its high prevalence, the cellular mechanism of PAstV pathogenesis is ill–defined. Previous proteomics analyses have revealed that the differentially expressed protein NOD–like receptor X1 (NLRX1) located in the mitochondria participates in several important antiviral signaling pathways in PAstV–4 infection, which are closely related to mitophagy. In this study, we confirmed that PAstV–4 infection significantly up-regulated NLRX1 and mitophagy in Caco–2 cells, while the silencing of NLRX1 or the treatment of mitophagy inhibitor 3–MA inhibited PAstV–4 replication. Additionally, PAstV–4 infection triggered the activation of the extracellular regulated protein kinases/ myosin light-chain kinase (ERK/MLCK) pathway, followed by the down-regulation of tight–junction proteins (occludin and ZO–1) as well as MUC–2 expression. The silencing of NLRX1 or the treatment of 3–MA inhibited myosin light-chain (MLC) phosphorylation and up-regulated occludin and ZO–1 proteins. Treatment of the ERK inhibitor PD98059 also inhibited MLC phosphorylation, while MLCK inhibitor ML-7 mitigated the down-regulation of mucosa-related protein expression induced by PAstV–4 infection. Yet, adding PD98059 or ML–7 did not affect NLRX1 expression. In summary, this study preliminarily explains that NLRX1 plays an important role in the disruption of intestinal mucosal function triggered by PAstV–4 infection via the ERK/MLC pathway. It will be helpful for further antiviral drug target screening and disease therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT The gut microbiota, a pivotal component of the intestinal mucosal barrier, is critical for host resistance to enteric pathogen infection. Here, we report a novel function of the potentially probiotic Lactococcus garvieae strain LG1 (L. garvieae strain LG1) in maintaining intestinal mucosal barrier integrity and protecting against foodborne Clostridium perfringens (C. perfringens) infection. L. garvieae was isolated from the intestinal contents of Chinese Mongolian sheep (MS) and exhibited potential probiotic properties. In a C. perfringens enterocolitis model, L. garvieae-pretreated mice were less susceptible to C. perfringens infection compared with Phosphate buffered solution (PBS)-pretreated mice, which manifested as higher survival rates, lower pathogen loads, less weight loss, mild clinical symptoms and intestinal damage, and minor inflammation. Further mechanistic analysis showed that L. garvieae could ameliorate the disruption of intestinal permeability and maintain the integrity of the intestinal mucosal barrier by promoting the expression of tight junction proteins and mucoproteins. Moreover, L. garvieae was also able to facilitate antimicrobial peptide expression and ameliorate dysbiosis of the gut microbiota caused by C. perfringens. Together, these findings highlight the prospect of immunomodulatory potentially probiotic L. garvieae and might offer valuable strategies for prophylaxis and/or treatment of pathogenic C. perfringens mucosal infection.IMPORTANCEC. perfringens necrotic enteritis leads to losses of about US $2 billion to the poultry industry worldwide every year. Worse, US Centers for Disease Control and Prevention (CDC) has estimated that C. perfringens causes nearly 1 million foodborne illnesses in the United States annually. Nowadays, the treatment recommendation is a combination of a broad-spectrum synergistic penicillin with clindamycin or a carbapenem, despite growing scientific concern over antibiotic resistance. The global understanding of the gut microbiome for C. perfringens infection may provide important insights into the intervention. L. garvieae originated from Mongolian sheep intestine, exhibited potentially probiotic properties, and was able to limit C. perfringens enterocolitis and pathogenic colonization. Importantly, we found that L. garvieae limits C. perfringens invasion via improving intestinal mucosal barrier function. Also, L. garvieae alleviates C. perfringens-induced gut microbiota dysbiosis. It allowed us to convince that utilization of probiotics to promote protective immunity against pathogens infection is of pivotal importance.

ABSTRACT: The aim of this study was to investigate the effects of cardamonin (CDN) on the growth performance, intestinal mucosal barrier function and intestinal microbiota of Danzhou chickens under heat stress. A total of 200 one-day-old female Danzhou chickens were randomly divided into 5 groups. The daytime temperature of heat stress (HS) was set at 36 ± 2°C, and the nighttime temperature was kept the same as in the control (CON) group at 25 ± 2°C. The formal experiment lasted for 21 d. The CON and HS groups were fed a basal diet, whereas the L-CDN, M-CDN, and H-CDN groups received a basal diet supplemented with 50, 100, and 200 mg/kg CDN, respectively. Compared with the HS group, the CDN group presented a significantly greater average daily gain (ADG) (P < 0.001) but a significantly lower feed-to-gain ratio (F/G) (P = 0.007). CDN supplementation also increased the villus height (VH) and the ratio of the villus height to crypt depth (V/C) (P < 0.001) and reduced intestinal permeability by increasing expression of the ZO-1 (P < 0.001), Occludin (P < 0.001), and Claudin-1 (P = 0.034) proteins and decreasing the content of D-lactic acid (D-LA) and the activity of diamine oxidase (DAO) in serum (P < 0.001). Additionally, CDN reduced the levels of the intestinal mucosal inflammatory factors (IL-1β (P = 0.031), IL-6 (P = 0.003), and TNF-α (P = 0.014)) while upregulating IL-10 (P < 0.001). Furthermore, it increased the total antioxidant capacity (T-AOC) (P = 0.004) and catalase (CAT) activity (P < 0.001) and reduced the malondialdehyde (MDA) content (P = 0.017), effectively reducing intestinal oxidative stress and inflammatory reactions. Expression of the Nrf2 pathway-related proteins Nrf2 (P = 0.012), HO-1 (P = 0.008), and NQO1 (P = 0.003) was also increased by CDN. Moreover, feeding CDN increased the proportion of beneficial bacteria such as Firmicutes and Bacteroidetes but decreased the proportion of harmful bacteria such as Proteobacteria, thus protecting the intestinal barrier. In summary, 200 mg/kg CDN in the diet improved growth performance, enhanced intestinal barrier function and improved intestinal flora disorders in heat stress-induced Danzhou chickens, which may be related to the Nrf2/NQO1 signaling pathway.

The intestinal tract is one of the important immune organs of the animal body, the intestinal mucosa is the main place of direct contact and communication between the internal environment and the outside world, and is the first line of defense against intestinal antigens. The integrity of the intestinal mucosal barrier is a prerequisite for the maintenance of normal intestinal function and health. Fucoidan is a macromolecular polysaccharide rich in sulfate groups, which has antiinflammatory, antioxidant, and antiviral functions, and can maintain the homeostasis of the intestinal environment by regulating the intestinal epithelial barrier function, bile secretion, intestinal epithelial cell tight junction, intestinal microbiota structure, and immune cell function. This article mainly reviews the effect of fucoidan on the intestinal mucosal barrier of animals and its application in animal production, aiming to provide a reference for the development of new feed additives. [ABSTRACT FROM AUTHOR]

To observe the improvement effect of the intragastric administration of curcumin on intestinal mucosal barrier injury rats with fatty liver, and to explore its mechanism of action. Methods Non-alcoholic fatty liver disease rat models were established by high-fat diet, and then were randomly divided into the high fat group, low-dose curcumin group, and high-dose curcumin group, with 10 mice in each group. Anther 10 normal rats were used as the control group. Rats in low-dose curcumin group were given curcumin 200 mg/ (kg · d) by gavage, while rats in the high-dose group were given curcumin 400 mg/ (kg · d) by gavage. Rats in the control and model groups were given sodium carboxymethyl cellulose by gavage, and rats in each group were sacrificed after 8 weeks of gavage. We took the liver and small intestine tissues from rats of each group, and observed pathological changes under light microscopy by HE staining. We took the portal vein blood from rats and measured LPS, diamine oxidase (DAO）, ALT and AST. The small intestine tissues were taken to measure the content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) . Western blotting was used to detect nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins in the small intestine tissues. Results Hepatocyte architecture was normal in the control group. Lipid droplets of varying sizes were seen in hepatocytes of the model group. Hepatocellular steatosis was attenuated in the low-dose group and high-dose group. The villi of rats in the control group showed no congestion and edema, while the villi of rats in the model group showed structural damage. The villi of rats in the low-dose and high-dose curcumin groups showed loss and reduction. Compared with the control group, the blood levels of DAO, LPS, AST, and ALT in the model group, low-dose curcumin group, and high-dose curcumin group increased (all P<0. 05) . However, those in the low-dose and high-dose curcumin groups were lower than those of the model group (all P<0. 05）, with a dose-dependent manner (all P<0. 05) . Compared with the control group, MDA content of intestine in the model group, low-dose curcumin group, and high-dose curcumin group increased (P<0. 05）, but that in the low-dose and high-dose curcumin groups was lower than that of the model group, with a dose-dependent manner (P<0. 05) . Compared with the control group, SOD activity of intestine in the model group, low-dose curcumin group, and high-dose curcumin group decreased (P<0. 05）, but that in low-dose curcumin group and high-dose curcumin group was higher than model group, with a dose-dependent manner (P<0. 05) . Compared with the control group, the SOD activity of small intestine tissues in the model group, low-dose curcumin group, and highdose curcumin group decreased (all P<0. 05）, but that in the low-dose curcumin group and high-dose curcumin group was higher than that in the model group (all P<0. 05）, with a dose-dependent manner (all P<0. 05) . Compared with the control group, the relative expression levels of Nrf2 and HO-1 proteins in the small intestine tissues of the model group, lowdose curcumin group, and high-dose curcumin group increased (all P<0. 05）, and those were higher in the low-dose curcumin group and high-dose curcumin group than in the model group (all P<0. 05）, and there was in a dose-dependent manner (all P<0. 05) . Conclusion Intragastric administration of curcumin can alleviate intestinal mucosal barrier damage in rats with fatty liver, and its mechanism of action may be related to activating the Nrf2/HO-1 pathway to improve intestinal oxidative stress status [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the immunomodulatory effect of Polygonatum sibiricum saponin (PS) in a cyclophosphamide-induced (Cy) immunosuppression mice model. Oral administration of PS by gavage effectively alleviated weight loss caused by Cy and increased the index of immune organs. PS promoted the proliferation of splenic lymphocytes and T cell subsets (CD3+, CD355+, CD4+/CD8+) and relieved the xylene-induced inflammatory response and Cy-induced increase of serum hemolysin. Moreover, PS increased serum levels of lactate dehydrogenase and acid phosphatase. PS elevated serum level of cytokines and immunoglobulins (TNF-α, IFN-γ, IL-4, IL-6, IL-β, SIgA, and IgG) and the expression of mRNA of IL-10, TNF-α, and IL-6 in the spleen. Increased mRNA expression of tight junction protein (ZO-1, Mucin2, Occludin) expression and protein expression of IL-6/MyD88/TLR4 in the small intestine showed that PS exhibited a restorative effect on intestinal mucosal injury caused by cyclophosphamide. Oral PS prevented Cy-induced decline in leukocytes, red blood cells, lymphocytes, hemoglobin concentrations, and neutrophils, providing evidence for alleviating hematopoietic disorders. In addition, PS increased SOD and NO levels, reduced MDA levels, and improved oxidative damage in the liver. These findings demonstrate that PS has the potential to be developed as a supplemental agent for alleviating immunosuppression caused by chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a serious public health problem, and among noncommunicable diseases, CVD is now the leading cause of mortality and morbidity worldwide. CVD involves multiple organs throughout the body, especially the intestinal tract is the first to be involved. The impairment of the intestinal mucosal barrier is considered a significant pathological alteration in CVD and also contributes to the accelerated progression of the disease, thereby offering novel insights for CVD prevention and treatment. The treatment of Chinese medicine is characterized by multi-metabolites, multi-pathways, and multitargets. In recent years, the studies of Traditional Chinese Medicine (TCM) in treating CVD by repairing the intestinal mucosal barrier have gradually increased, showing great therapeutic potential. This review summarizes the studies related to the treatment of CVD by TCM (metabolites of Chinese botanical drugs, TCM formulas, and Chinese patent medicine) targeting the repair of the intestinal mucosal barrier, as well as the potential mechanisms. We have observed that TCM exerts regulatory effects on the structure and metabolites of gut microbiota, enhances intestinal tight junctions, improves intestinal dyskinesia, repairs intestinal tissue morphology, and preserves the integrity of the intestinal vascular barrier through its anti-inflammatory, antioxidant, and anti-apoptotic properties. These multifaceted attributes position TCM as a pivotal modulator of inhibiting myocardial fibrosis, and hypertrophy, and promoting vascular repairment. Moreover, there exists a close association between cardiovascular risk factors such as hyperlipidemia, obesity, and diabetes mellitus with CVD. We also explore the mechanisms through which Chinese botanical drugs impact the intestinal mucosal barrier and regulate glucose and lipid metabolism. Consequently, these findings present novel insights and methodologies for treating CVD. [ABSTRACT FROM AUTHOR]

Pyroptosis is an innate immune response triggered by the activation of inflammasomes by various influencing factors, characterized by cell destruction. It impacts the immune system and cancer immunotherapy. In recent years, the roles of pyroptosis and inflammasomes in intestinal inflammation and cancer have been continuously confirmed. This article reviews the latest progress in pyroptosis mechanisms, new discoveries of inflammasomes, mutual regulation between inflammasomes, and their applications in intestinal diseases. Additionally, potential synergistic treatment mechanisms of intestinal diseases with pyroptosis are summarized, and challenges and future directions are discussed, providing new ideas for pyroptosis therapy. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease whose pathogenesis remains unclear. Dysfunction of the intestinal mucosal barrier is closely related to the pathogenesis of UC, which is characterised by damage to the colon epithelial barrier, disruption of immune homeostasis, and persistent inflammatory cell infiltration. MicroRNAs (miRNAs) exhibit specific or differential expression in both UC animal models and patients, implicating their involvement in the pathogenesis of UC. In recent years there has been progress in using Traditional Chinese medicine (TCM) to regulate miRNA expression for repairing the intestinal mucosal barrier in UC, as demonstrated in animal and cell experiments. However, it has not been applied in a clinical setting and its underlying molecular mechanisms require further investigation. Therefore, this study systematically described the role of miRNAs in UC-induced intestinal barrier damage and the application of TCM to repair this intestinal barrier by regulating miRNA expression, offering new therapeutic targets for UC treatment.

Inhibiting the death receptor 3 (DR3) signaling pathway in group 3 innate lymphoid cells (ILC3s) presents a promising approach for promoting mucosal repair in individuals with ulcerative colitis (UC). Paeoniflorin, a prominent component of Paeonia lactiflora Pall., has demonstrated the ability to restore barrier function in UC mice, but the precise mechanism remains unclear. In this study, we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s. C57BL/6 mice were subjected to random allocation into 7 distinct groups, namely the control group, the 2 % dextran sodium sulfate (DSS) group, the paeoniflorin groups (25, 50, and 100 mg/kg), the anti-tumor necrosis factor-like ligand 1A (anti-TL1A) antibody group, and the IgG group. We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using Western blot and flow cytometry, respectively. Meanwhile, DR3-overexpressing MNK-3 cells and 2 % DSS-induced Rag1−/− mice were used for verification. The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier. Simultaneously, paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines (Interleukin-17A, Granulocyte-macrophage colony stimulating factor, and Interleukin-22). Alternatively, paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage independently of the adaptive immune system. We additionally confirmed that paeoniflorin-conditioned medium (CM) restored the expression of tight junctions in Caco-2 cells via coculture. In conclusion, paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner, and its mechanism is associated with the inhibition of the DR3 signaling pathway.

ABSTRACT: Long-term feeding of a high-concentrate diet can induce subacute ruminal acidosis (SARA) in ruminants, which further leads to systemic inflammatory response. However, few studies have examined the effects of feeding a high-concentrate diet on the hindgut of ruminants. The purpose of this study was to investigate the effects of a high-concentrate diet on the composition of gut microbiota in colonic contents, inflammatory response, and barrier damage in the colon tissue of ruminants. A total of 12 healthy multiparous lactating Hu sheep were randomly allotted into the following 2 groups: a high-concentrate (HC) group (concentrate:forage = 7:3) and a low-concentrate (LC) group (concentrate:forage = 3:7). All sheep were fitted with ruminal fistulas. The formal feeding experiment lasted for 8 wk. After the feeding experiment, rumen fluid, portal vein blood, hepatic vein blood, colonic contents, and colon tissue samples were collected. The results showed that feeding the HC diet induced SARA in Hu sheep and significantly reduced pH in the colonic contents. The abundances of Firmicutes, Verrucomicrobiota, and Actinobacteriota decreased significantly, whereas those of Bacteroidota, Spirochaetota, and Fibrobacterota significantly increased in colonic contents. At the genus level, the relative abundances of 29 genera were significantly altered depending on the different type of diets. Analysis of the 10 bacterial genera with high relative abundance revealed that feeding the HC diet significantly reduced the abundance of UCG-005, Christensenellaceae R-7 group, UCG-010-norank, Monoglobus, [Eubacterium] coprostanoligenes group_norank, and Alistipes, whereas the abundances of Rikenellaceae RC9 gut group, Treponema, Bacteroides, and Prevotella increased. Compared with the LC group, feeding the HC diet significantly increased the concentration of LPS in rumen fluid, portal vein blood, hepatic vein blood, and colonic contents, and significantly upregulated the mRNA expression levels of proinflammatory cytokines in colon tissue, including TNF-α, IL-1β, IL-6, and IL-8, indicating the occurrence of inflammatory response in the colon tissue. In addition, the structure of colonic epithelial cells was loose, the intercellular space became larger, epithelial cells were exfoliated, and the mRNA and protein abundances of ZO-1, occludin, claudin-1, claudin-3, and claudin-4 were significantly decreased in the HC group, which was consistent with the results of immunohistochemistry. Furthermore, feeding the HC diet increased the ratios of DNA methylation and chromatin compaction in the promoter regions of occludin and claudin-1, which in turn inhibited their transcriptional expression. Therefore, the present study demonstrated that feeding an HC diet induced SARA in Hu sheep, altered the composition and structure of the microbial community in the colonic contents, induced an inflammatory response, and disrupted the intestinal mucosal barrier in the colonic tissue.

Introduction: Colorectal cancer (CRC) is the third most common malignant tumor, and neoadjuvant chemo-radiotherapy is usually recommended for advanced stage colorectal cancer. Radiotherapy can cause damage to intestinal mucosal barrier, which may be related to perioperative complications. Intestinal microbiota is one of the constituents of the intestinal mucosal biological barrier, and literature reports that patients with CRC have changes in corresponding oral microbiota. This study aims to analyze the levels of immunoglobulin SIgA, inflammatory factors, lymphocyte subsets quantity, and proportion in surgical specimens of intestinal mucosa at different time intervals after radiotherapy, in order to seek investigation for the optimal surgical time after radiotherapy and to provide evidence for finding probiotics or immunomodulators through high-throughput sequencing of bacterial 16s rRNA in patients' saliva microbiota. Ultimately, this may provide new ideas for reducing perioperative complications caused by radiotherapy-induced intestinal damage. Methods: We selected intestinal mucosal tissue and saliva samples from over 40 patients in our center who did not undergo radiotherapy and underwent surgery at different time intervals after radiotherapy. Detection of SIgA was performed using ELISA assay. Western Blotting was used to detect IL-1b, IL-6, and IL-17 in the intestinal mucosal tissue. Flow cytometry was used to detect CD4 and CD8. And the microbial community changes in saliva samples were detected through 16s rRNA sequencing. Results: After radiotherapy, changes in SIgA, various cytokines, CD4CD8 lymphocyte subsets, and oral microbiota in the intestinal mucosal tissue of rectal cancer patients may occur. Over time, this change may gradually recover. Discussion: In colorectal cancer, oncological aspects often receive more attention, while studies focusing on the intestinal mucosal barrier are less common. This study aims to understand the repair mechanisms of the intestinal mucosal barrier and reduce complications arising from radiotherapy-induced damage. The relationship between oral microbiota and systemic diseases has gained interest in recent years. However, the literature on the oral microbiota after radiotherapy for rectal cancer remains scarce. This study addresses this gap by analysing changes in the salivary microbiota of rectal cancer patients before and after radiotherapy, shedding light on microbiota changes. It aims to lay the groundwork for identifying suitable probiotics or immunomodulators to alleviate perioperative complications and improve the prognosis of CRC. [ABSTRACT FROM AUTHOR]

Background: Ionizing radiation can cause intestinal microecological dysbiosis, resulting in changes in the composition and function of gut microbiota. Altered gut microbiota is closely related to the development and progression of radiation-induced intestinal damage. Although microbiota-oriented therapeutic options such as fecal microbiota transplantation (FMT) have shown some efficacy in treating radiation toxicity, safety concerns endure. Therefore, fecal bacteriafree filtrate transplantation (FFT), which has the potential to become a possible alternative therapy, is well worth investigating. Herein, we performed FFT in a mouse model of radiation exposure and monitored its effects on radiation damage phenotypes, gut microbiota, and metabolomic profiles to assess the effectiveness of FFT as an alternative therapy to FMT safety concerns. Results: FFT treatment conferred radioprotection against radiation-induced toxicity, representing as better intestinal integrity, robust proinflammatory and anti-inflammatory cytokines homeostasis, and accompanied by significant shifts in gut microbiome. The bacterial compartment of recipients following FFT was characterized by an enrichment of radioprotective microorganisms (members of family Lachnospiraceae). Furthermore, metabolome data revealed increased levels of microbially generated short-chain fatty acids (SCFAs) in the feces of FFT mice. Conclusions: FFT improves radiation-induced intestinal microecological dysbiosis by reshaping intestinal mucosal barrier function, gut microbiota configurations, and host metabolic profiles, highlighting FFT regimen as a promising safe alternative therapy for FMT is effective in the treatment of radiation intestinal injury. [ABSTRACT FROM AUTHOR]

Background: With societal and economic development, the annual incidence of chronic kidney disease (CKD) is increasing. Current treatments for CKD are limited, and once patients progress to the uraemic stage, it places a significant economic burden on families and society. Based on the "gut-kidney axis" theory and real-world research, this study aims to evaluate the clinical efficacy, safety, and potential mechanism of high-position colon dialysis combined with traditional Chinese medicine (TCM) retention enema in treating stage 3-5 chronic kidney disease (non-dialysis). Additionally, it seeks to identify new therapeutic targets and approaches for CKD treatment. Methods: The TCM decoction was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Orbitrap-High Resolution Mass Spectrometry (UPLC-Q-Orbitrap-HRMS). Participants meeting the inclusion criteria were divided into a control group (n = 153) and a treatment group (n = 159) based on their preferences and physicians' recommendations. Both groups adhered to a high-quality low-protein, low-salt, low-phosphorus, and low-fat diet supplemented with essential amino acids, and were monitored for blood pressure, blood glucose, and blood lipids. The treatment group received high-position colon dialysis combined with TCM retention enemas (administered at least 12 times every other day). Results: Thirteen compounds were identified from the herbs by UPLC-QOrbitrap-HRMS. The CKD3-5 treatment group exhibited improvements in blood biochemistry and other laboratory indices, with significant enhancements in renal function-related indices for CKD4 and CKD5 stages (p < 0.05). Following treatment, indoxyl sulfate (IS), endotoxin, and D-lactic acid levels decreased to a certain extent in both groups, with a statistically significant difference observed within the treatment group (p < 0.05). The treatment group displayed a significant reduction in aerobic bacterial colonies, an increase in anaerobic bacterial colonies, a decrease in Escherichia coli colonies, and an increase in Bifidobacterium and Lactobacillus colonies (p < 0.05). No significant changes in colony numbers were observed in the control group. Conclusion: High-position colon dialysis combined with TCM retention enema may serve as an adjuvant treatment for CKD4-5 (non-dialysis), and its mechanism may be related to the reduction of uraemic toxins, improvement of intestinal mucosal barrier function, and regulation of intestinal microecology. [ABSTRACT FROM AUTHOR]

Objective: To evaluate if berberine can act on vitamin D receptors (VDR) and thereby regulate the expression of tight junction proteins (TJPs) in irritable bowel syndrame-diarrhea-predominant (IBS-D) rats. Methods: The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation. After modeling, the model was evaluated and rats were divided into the control group and berberine treatment groups (0.85, 1.7 and 3.4 mg/kg, once a day for 2 weeks). The distal colon was obtained and colonic epithelial cells (CECs) were isolated and cultured after IBS-D model evaluation. The vitamin D receptor response element (VDRE) reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter. VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair, and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs. Results: The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner (P<0.05). The activity of VDRE promoter was also effectively promoted by berberine (P<0.05). Berberine increased the expression of TJPs in IBS-D CECs (P<0.05). VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups (all P<0.05). RT-qPCR and Western blot results showed that compared with the blank group, expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups (all P<0.05). Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1 (P<0.05). Conclusion: Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity, and the main site of action is the N-terminal region of VDR. [ABSTRACT FROM AUTHOR]

Background: To investigate the expression of high mobility group box B-1 (HMGB-1) in patients with colorectal cancer (CRC) and its association with clinicopathological features and prognosis in colorectal carcinoma by combining bioinformatics and clinical data analysis, and to clarify the role of HMGB-1. To examine whether HMGB-1 expression is related to the damage of the intestinal mucosal barrier, and then explore the potential HMGB-1-dependent mechanisms affecting the progression of CRC. Methods: CRC datasets of GSE12945, GSE17536, and GSE17537 from the public gene chip database were screened and downloaded. Clinical information and CRC tissue samples from patients with stage I-III CRC from the hospital were collected. Serum samples of patients were applied by enzyme-linked immunosorbent assay on HMGB-1, and were divided into high and low HMGB-1 expression, which was examined by 16S rDNA sequencing. Immunohistochemistry was performed to examine the relationship between the expression of HMGB-1 and tight junction protein, occludin, tumor necrosis factor-α, and interferon-γ. Results: Based on the Cutoff value of 10.24 ng/mL, the CRC patients were divided into high and low expression groups. In the HMGB-1H patient group, the TNM staging, overall survival, disease-free survival, recurrence, and metastasis were inferior to the HMGB-1L group. The results of 16S rDNA sequencing demonstrated that the Providencia genus was found to be enriched in the HMGB-1L group. Immunohistochemical results showed that HMGB-1 expression was negatively correlated with the expression of ZO-1 and occludin (R = 0.035, R = 0.003, P <.05), but was positively correlated with the expression of TNF-α and IFN-γ (R = 0.016, R = 0.001, P <.05). Conclusion: The survival of CRC patients with positive HMGB-1 expression was significantly shortened, which may be related to the decrease of Rovitensis content, the decreased expression of ZO-1 and occludin, and the increased levels of TNF-α and IFN-γ, which in turn damage the intestinal mucosal barrier, leading to the development of CRC. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of berberine hydrochloride tablets combined with compound glutamine in treating ulcerative colitis (UC). Methods One hundred and two patients with UC admitted to our hospital were collected and grouped into two groups according to the random number table. Fifty-one patients in the control group were given conventional treatment+compound glutamine, and 51 patients in the experimental group were given berberine hydrochloride tablets based on the control group. Both groups were treated for 8 weeks. The efficacy, modified Mayo score, intestinal mucosal barrier function, soluble late glycation end product receptor (sRAGE), interleukin-17 (IL-17), IL-6 and incidence of untoward reactions were compared between the two groups. Results The total effective rate of the experimental group was higher than that of the control group (92.2% vs. 76.5%, P＜0.05). After treatment, scores of defecation frequency, blood in stool, endoscopic findings, physician's overall evaluation, diamine oxidase (DAO), D-lactic acid, endotoxin, sRAGE, IL-17 and IL-6 were lower in both groups than those before treatment (P＜0.05), and the research group was lower than the control group (P＜0.05). There was no significant difference in the total incidence of untoward reactions between the experimental group and the control group (P＞0.05). Conclusion Berberine hydrochloride tablets combined with compound glutamine are effective in treating UC, which can reduce the activity of UC, improve the intestinal mucosal barrier function, regulate serum sRAGE, IL-17 and IL-6 levels, without increasing adverse reactions. [ABSTRACT FROM AUTHOR]

Despite Bacillus species having been extensively utilized in the food industry and biocontrol as part of probiotic preparations, limited knowledge exists regarding their impact on intestinal disorders. In this study, we investigated the effect of Bacillus licheniformis ZW3 (ZW3), a potential probiotic isolated from camel feces, on dextran sulfate sodium (DSS)-induced colitis. The results showed ZW3 partially mitigated body weight loss, disease activity index (DAI), colon shortening, and suppressed immune response in colitis mice, as evidenced by the reduction in the levels of the inflammatory markers IL-1β, TNF-α, and IL-6 (p < 0.05). ZW3 was found to ameliorate DSS-induced dysfunction of the colonic barrier by enhancing mucin 2 (MUC2), zonula occluden-1 (ZO-1), and occludin. Furthermore, enriched beneficial bacteria Lachnospiraceae_NK4A136_group and decreased harmful bacteria Escherichia-Shigella revealed that ZW3 improved the imbalanced gut microbiota. Abnormally elevated uric acid levels in colitis were further normalized upon ZW3 supplementation. Overall, this study emphasized the protective effects of ZW3 in colitis mice as well as some potential applications in the management of inflammation-related diseases. [ABSTRACT FROM AUTHOR]

The symbiotic community of microorganisms in the gut plays an important role in the health of the host. While many previous studies have been performed on the interactions between the gut microbiome and the host in mammals, studies in fish are still lacking. In this study, we investigated changes in the intestinal microbiome and pathogen susceptibility of zebrafish (Danio rerio) following chronic antibiotics exposure. The chronic antibiotics exposure assay was performed on zebrafish for 30 days using oxytetracycline (Otc), sulfamethoxazole/trimethoprim (Smx/Tmp), or erythromycin (Ery), which are antibiotics widely used in the aquaculture industry. The microbiome analysis indicated that Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes were the dominant phyla in the gut microbiome of the zebrafish used in this study. However, in Smx/Tmp-treated zebrafish, the compositions of Fusobacteria and Proteobacteria were changed significantly, and in Ery-treated zebrafish, the compositions of Proteobacteria and Firmicutes were altered significantly. Although alpha diversity analysis showed that there was no significant difference in the richness, beta diversity analysis revealed a community imbalance in the gut microbiome of all chronically antibiotics-exposed zebrafish. Intriguingly, in zebrafish with dysbiosis in the gut microbiome, the pathogen susceptibility to Edwardsiella piscicida, a representative Gram-negative fish pathogen, was reduced. Gut microbiome imbalance resulted in a higher count of goblet cells in intestinal tissue and an upregulation of genes related to the intestinal mucosal barrier. In addition, as innate immunity was enhanced by the increased mucosal barrier, immune and stress-related gene expression in the intestinal tissue was downregulated. In this study, we provide new insight into the effect of gut microbiome dysbiosis on pathogen susceptibility. [ABSTRACT FROM AUTHOR]

Our previous findings confirmed the high enrichment of Bacteroides fragilis (BF) in fecal samples from patients with colorectal cancer (CRC). The intestinal mucosal barrier is the first defense of the organism against commensal flora and intestinal pathogens and is closely associated with the occurrence and development of CRC. Therefore, this study aimed to investigate the molecular mechanisms through which BF mediates intestinal barrier injury and CRC progression. SW480 cells and a Caco2 intestinal barrier model were treated with entero-toxigenic BF (ETBF), its enterotoxin (B. fragilis toxin, BFT), and non-toxigenic BF (NTBF). Cell counting kit-8, flow cytometry, wound healing and transwell assays were performed to analyze the proliferation, apoptosis, migration, and invasion of SW480 cells. Transmission electron microscopy, FITC-dextran, and transepithelial electrical resistance (TEER) were used to analyze damage in the Caco2 intestinal barrier model. The Azoxymethane/Dextran Sulfate Sodium (AOM/DSS) animal model was established to evaluate the effect of ETBF on intestinal barrier injury and CRC progression in vivo. ETBF and BFT enhanced the viability, wound healing ratio, invasion, and EMT of SW480 cells. In addition, ETBF and BFT disrupted the tight junctions and villus structure in the intestinal barrier model, resulting in increased permeability and reduced TEER. Similarly, the expression of intestinal barrier-related proteins (MUC2, Occludin and Zo-1) was restricted by ETBF and BFT. Interestingly, the STAT3/ZEB2 axis was activated by ETBF and BFT, and treatment with Brevilin A (a STAT3 inhibitor) or knockdown of ZEB2 limited the promotional effect of ETBF and BFT on the SW480 malignant phenotype. In vivo experiments also confirmed that ETBF colonization accelerated tumor load, carcinogenesis, and intestinal mucosal barrier damage in the colorectum of the AOM/DSS animal model, and that treatment with Brevilin A alleviated these processes. ETBF-secreted BFT accelerated intestinal barrier damage and CRC by activating the STAT3/ZEB2 axis. Our findings provide new insights and perspectives for the application of ETBF in CRC treatment. [ABSTRACT FROM AUTHOR]

For decades, the therapeutic goal of conventional treatment among inflammatory bowel disease (IBD) patients is alleviating exacerbations in acute phase, maintaining remission, reducing recurrence, preventing complications, and increasing quality of life. However, the persistent mucosal/submucosal inflammation tends to cause irreversible changes in the intestinal structure, which can barely be redressed by conventional treatment. In the late 1990s, monoclonal biologics, mainly anti-TNF (tumor necrosis factor) drugs, were proven significantly helpful in inhibiting mucosal inflammation and improving prognosis in clinical trials. Meanwhile, mucosal healing (MH), as a key endoscopic and histological measurement closely associated with the severity of symptoms, has been proposed as primary outcome measures. With deeper comprehension of the mucosal microenvironment, stem cell niche, and underlying mucosal repair mechanisms, diverse potential strategies apart from monoclonal antibodies have been arising or undergoing clinical trials. Herein, we elucidate key steps or targets during the course of MH and review some promising treatment strategies capable of promoting MH in IBD. [ABSTRACT FROM AUTHOR]

Introduction: "Probiotic therapy" to regulate gut microbiota and intervene in intestinal diseases such as inflammatory bowel disease (IBD) has become a research hotspot. Bacteroides acidifaciens, as a new generation of probiotics, has shown beneficial effects on various diseases. Methods: In this study, we utilized a mouse colitis model induced by dextran sodium sulfate (DSS) to investigate how B. acidifaciens positively affects IBD. We evaluated the effects of B. acidifaciens, fecal microbiota transplantation, and bacterial extracellular vesicles (EVs) on DSS-induced colitis in mice. We monitored the phenotype of mouse colitis, detected serum inflammatory factors using ELISA, evaluated intestinal mucosal barrier function using Western blotting and tissue staining, evaluated gut microbiota using 16S rRNA sequencing, and analyzed differences in EVs protein composition derived from B. acidifaciens using proteomics to explore how B. acidifaciens has a positive impact on mouse colitis. Results: We confirmed that B. acidifaciens has a protective effect on colitis, including alleviating the colitis phenotype, reducing inflammatory response, and improving intestinal barrier function, accompanied by an increase in the relative abundance of B. acidifaciens and Ruminococcus callidus but a decrease in the relative abundance of B. fragilis. Further fecal bacterial transplantation or fecal filtrate transplantation confirmed the protective effect of eosinophil-regulated gut microbiota and metabolites on DSS-induced colitis. Finally, we validated that EVs derived from B. acidifaciens contain rich functional proteins that can contribute to the relief of colitis. Conclusion: Therefore, B. acidifaciens and its derived EVs can alleviate DSS-induced colitis by reducing mucosal damage to colon tissue, reducing inflammatory response, promoting mucosal barrier repair, restoring gut microbiota diversity, and restoring gut microbiota balance in mice. The results of this study provide a theoretical basis for the preclinical application of the new generation of probiotics. [ABSTRACT FROM AUTHOR]

Long-term feeding of a high-concentrate diet can induce subacute ruminal acidosis (SARA) in ruminants, which further leads to systemic inflammatory response. However, few studies have examined the effects of feeding a high-concentrate diet on the hindgut of ruminants. The purpose of this study was to investigate the effects of a high-concentrate diet on the composition of gut microbiota in colonic contents, inflammatory response, and barrier damage in the colon tissue of ruminants. A total of 12 healthy multiparous lactating Hu sheep were randomly allotted into the following 2 groups: a high-concentrate (HC) group (concentrate:forage = 7:3) and a low-concentrate (LC) group (concentrate:forage = 3:7). All sheep were fitted with ruminal fistulas. The formal feeding experiment lasted for 8 wk. After the feeding experiment, rumen fluid, portal vein blood, hepatic vein blood, colonic contents, and colon tissue samples were collected. The results showed that feeding the HC diet induced SARA in Hu sheep and significantly reduced pH in the colonic contents. The abundances of Firmicutes , Verrucomicrobiota , and Actinobacteriota decreased significantly, whereas those of Bacteroidota , Spirochaetota , and Fibrobacterota significantly increased in colonic contents. At the genus level, the relative abundances of 29 genera were significantly altered depending on the different type of diets. Analysis of the 10 bacterial genera with high relative abundance revealed that feeding the HC diet significantly reduced the abundance of UCG-005 , Christensenellaceae R-7 group , UCG-010-norank , Monoglobus , [Eubacterium] coprostanoligenes group_norank , and Alistipes , whereas the abundances of Rikenellaceae RC9 gut group , Treponema , Bacteroides , and Prevotella increased. Compared with the LC group, feeding the HC diet significantly increased the concentration of LPS in rumen fluid, portal vein blood, hepatic vein blood, and colonic contents, and significantly upregulated the mRNA expression levels of proinflammatory cytokines in colon tissue, including TNF-α , IL-1β , IL-6 , and IL-8 , indicating the occurrence of inflammatory response in the colon tissue. In addition, the structure of colonic epithelial cells was loose, the intercellular space became larger, epithelial cells were exfoliated, and the mRNA and protein abundances of ZO-1, occludin, claudin-1, claudin-3, and claudin-4 were significantly decreased in the HC group, which was consistent with the results of immunohistochemistry. Furthermore, feeding the HC diet increased the ratios of DNA methylation and chromatin compaction in the promoter regions of occludin and claudin-1, which in turn inhibited their transcriptional expression. Therefore, the present study demonstrated that feeding an HC diet induced SARA in Hu sheep, altered the composition and structure of the microbial community in the colonic contents, induced an inflammatory response, and disrupted the intestinal mucosal barrier in the colonic tissue. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of wheat peptides on intestinal damage from non-steroidal anti-inflammatory drugs (NSAIDs). Methods: The 4-week-old male KM mice were randomly divided into 6 groups according to body weight, namely blank group (saline gavage), diclofenac sodium group (diclofenac sodium gavage), glutamine group (di-clofenac sodium + glutamine), wheat peptide low, medium and high dose groups (diclofenac sodium + different doses of wheat peptide), 10 mice in each group, and treated continuously for 21 days. Mice were fasted for 12 h after the final gavage and weighed. Mice were subjected to blood sampling for oxidative stress levels and adrenaline E2 (PGE2) assays. Mouse intestine tissue was collected for histopathological testing and western blot was used to detect the expression of intestinal tissue tight junction proteins. Results: Compared with the diclofenac sodium group, mice in the wheat peptides and glutamine groups had higher body weights, lower levels of oxidative stress and restored PGE2 expression to normal levels. The mucosal barrier damage in mouse intestinal tissues was improved and the expression of tight junction protein was increased. Conclusion: Wheat peptides have protective effects against diclofenac sodium-induced intestinal disorders. It is promising to provide an effective method to protect against NSAIDs intestinal barrier function impairment. [ABSTRACT FROM AUTHOR]

Amino acid transporters with different categories are highly expressed in intestinal epithelial cells for maintaining the essential metabolism of body. The zwitterionic property of amino acid with α‐amino and α‐carboxyl also has tremendous potential to conquer the mucus barrier. Therefore, Glu‐derived amphiphilic block polymers [i. e. poly(lactic acid)‐b‐poly(glutamine)25 (PPQ) and poly(lactic acid)‐b‐poly(glutamate)25 (PPD)] were rational designed and Glu‐derived zwitterionic micelles (PPQ‐M and PPD‐M) were further prepared toward oral delivery. In comparison with PEGylated micelles (PEG‐M), PPD‐M and PPQ‐M possessed superior mucus permeability. In addition, enhanced cellular internalization capacity was also detected in both zwitterionic micelles, which was mainly mediated by multiple amino acid transporters. The cellular uptake efficiency of PPQ‐M was obviously higher than that of PPD‐M due to the glutamine constitutional unit of PPQ‐M with higher affinity to amino acid transporters. Furthermore, the retrograde pathway played an important role in the intracellular transport (including transcytosis) of both zwitterionic micelles. Excellent villi absorption of zwitterionic micelles was observed in situ, which gave a convincing evidence for oral delivery application prospect. The results of this research demonstrated that Glu‐derived zwitterionic micelles with distinguished capacity of conquering intestinal mucosal barrier, have promising potential toward oral delivery. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effect and mechanism of fucoidan on intestinal mucosal barrier function in hyperuricemic mice. Methods Forty specific pathogen-free (SPF) C57BL/6J mice were randomly assigned into a control, hyperuricemia model, fucoidan treatment (by gavage administration at the dosage of 200 mg/kg/day continuously for 10 weeks) , and allopurinol positive control group (10 in each group). By the end of the treatments for the mice of the four groups, serum uric acid (UA) was measured with colorimetric method; serum lipopolysaccharides (LPS), diamine oxidase (DAO), tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) were measured with enzyme-linked immunosorbent assay (ELISA). Histopathological changes in ileum mucosa were observed with hematoxylin-eosin (HE) staining; the expressions of tight junction proteins in ileum mucosa and autophagy-related proteins in small intestine were determined with Western blot. ResultsSignificant decreases in serum UA (52.45%), TNF-α (29.18%), IL-1β (25.36%), LPS (27.24%), and DAO (21.78%) were detected in the hyperuricemic mice with fucoidan treatment (P < 0.05 for all); in addition, the fucoidan-treated hyperuricemic mice had significantly improved intestinal cell junctions and permeability, increased expressions of zonula occludens-1 (ZO-l), occludin and autophagy-related proteins (all P < 0.05). Compared to those in model mice, significantly increased ratio of autophagy-related proteins light chain 3B II/I (LC3BII/I), beclin-1, and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) but significantly decreased phosphorylated mammalian target of rapamycin (p-mTOR) were observed in the hyperuricemic mice with fucoidan treatment. Conclusion Oral administration of fucoidan could effectively reduce serum uric acid and improve intestinal mucosal barrier damage by increasing autophagy via p38 MAPK/mTOR pathway in hyperuricemic mice.

Abstract More and more evidence suggests that puerarin, a potential remedy for gut inflammation, may have an ameliorative effect on sleep disturbances. However, the relationship between puerarin and sleep disruption has not been extensively researched. This study aims to explore the role and mechanisms of puerarin in improving sleep disorders. We established a light-induced sleep disorder model in mice and assessed the effects of puerarin on cognitive behavior using open field and water maze tests. Pathological detection demonstrated that sleep disturbances resulted in observable damage to the liver, lung, and kidney. Puerarin reversed multi-organ damage and inflammation. Further, puerarin activated paneth cells, resulting in increased lysozyme and TGF-β production, and stimulating intestinal stem cell proliferation. Puerarin also effectively inhibited the expression of F4/80, iNOS, TNF-α, and IL-1β in the small intestine, while it increased Chil3, CD206, and Arg-1 levels. Moreover, puerarin treatment significantly decreased P-P65, TLR4, Bcl-xl, and cleaved caspase-3 protein levels while increasing barrier protein levels, including ZO-1, Occludin, Claudin 1 and E-cadherin suggesting a reduction in inflammation and apoptosis in the gut. Overall, puerarin diminished systemic inflammation, particularly intestinal inflammation, and enhanced intestinal barrier integrity in mice with sleep disorders. Our findings suggest a potential new therapeutic pathway for sleep disorders. Graphical Abstract

Abstract Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

Abstract Intestinal barrier injury is a common complication of severe acute pancreatitis (SAP), which is often accompanied by intestinal mucosal barrier injury and results in serious consequences. However, the exact mechanism remains unclear. We aimed to investigate whether angiotensin II type 1 receptor (AT1)‐mediated oxidative stress is involved in SAP intestinal barrier injury and assessed the effects of inhibiting this pathway. The SAP model was established by retrograde bile duct injection of sodium taurocholate (5%). The rats were divided into three groups: the control group (SO), the SAP group (SAP), and the azilsartan intervention group (SAP + AZL). Serum amylase, lipase, and other indexes were measured to evaluate SAP severity in each group. Histopathological changes in the pancreas and intestine were evaluated by HE staining. The oxidative stress of intestinal epithelial cells was detected by superoxide dismutase and glutathione. We also detected the expression and distribution of intestinal barrier‐related proteins. The results showed that the serum indexes, the severity of tissue damage, and the level of oxidative stress in the SAP + AZL group were significantly lower than in the SAP group. Our study provided hitherto undocumented evidence of AT1 expression in the intestinal mucosa, confirming that AT1‐mediated oxidative stress is involved in SAP intestinal mucosal injury, and inhibiting this pathway could effectively reduce intestinal mucosal oxidative stress injury, providing a new and effective target for the treatment of SAP intestinal barrier injury.

Antibiotics are one greatest medical discoveries in the 20th century, which are extensively used to treat a variety of pathogenic microbial infections, including irritable bowel syndrome (IBS) . Although antibiotics have proven to be partially effective in improving clinical symptoms of IBS by clinical practice and several clinical studies, and nonabsorbable rifaximin has been also recommended for treating IBS without diarrhea by relevant guidelines and consensuses, the indications for the use of antibiotics in IBS are not clear, and there are concerns about the adverse effects associated with long-term antibiotic use. Meanwhile, making the balance between adverse effects and clinical benefits is difficult. However, several studies have also found that antibiotic use contributes to the development of IBS. This paper reviews recent studies on the effects of antibiotics on IBS, and summarizes that antibiotics may trigger IBS in several ways, including reducing intestinal microbial diversity, impairing epithelial barrier function and affecting cytokine production. This paper also points out the uncertainty of the indications for antibiotic application in IBS from two aspects, and argues that clinicians should pay attention to the effects of antibiotics on the development of IBS, evaluate the pros and cons of antibiotic treatment for IBS, and use antibiotics rationally and cautiously. The purpose of this article is to provide some reference for explaining the pathogenesis of IBS induced by antibiotic treatment, and for clinical application of antibiotics in IBS.

Abstract Ulcerative colitis (UC) is currently the most common inflammatory bowel disease (IBD). Due to its diverse and complex causes, there is no cure at present, and researchers are constantly exploring new therapies. In recent years, nano-selenium particle(SeNP) has attracted wide attention due to excellent biological activities. Therefore, in this study, for the first time, we used a natural polysaccharide, Eucommia ulmoides polysaccharide (EUP), modified SeNP to get EUP-SeNP with a size of about 170 nm, and its effect on 3% dextran sulphate sodium (DSS) induced colitis was explored. Our results showed that colon intestinal histology, intestinal mucosal barrier, inflammatory cytokines and intestinal microbiome composition were changed after EUP-SeNP treatment in colitis mice. Specifically, it was also shown that oral treatment of EUP-SeNP could relieve the degree of DSS-induced colitis in mice by restoring weight loss, reducing disease activity index (DAI), enhancing colon antioxidant capacity and regulating intestinal microbiome composition. In addition, we verified the mechanism in intestinal epithelial cell lines, showing that EUP-SeNP inhibited LPS-induced activation of the TRL-4/NF-κB signaling pathway in intestinal epithelial cell lines. To some extend, our study provides therapeutic reference for the treatment of IBD.

Shuyan Feng,1,&ast; Chi Zhang,1,&ast; Shanshan Chen,2,&ast; Ruonan He,1,&ast; Guanqun Chao,3 Shuo Zhang4 1Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of China; 3Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 310018, People’s Republic of China; 4The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanqun Chao; Shuo Zhang, Email chaoguanqun@zju.edu.cn; zhangshuotcm@126.comAbstract: Toll-like receptor 5 (TLR5) is a pattern recognition receptor that specifically recognizes flagellin and consequently plays a crucial role in the control of intestinal homeostasis by activating innate and adaptive immune responses. TLR5 overexpression, on the other hand, might disrupt the intestinal mucosal barrier, which serves as the first line of defense against harmful microbes. The intestine symbiotic bacteria, mucous layer, intestinal epithelial cells (IECs), adherens junctions (such as tight junctions and peripheral membrane proteins), the intestinal mucosal immune system, and cytokines make up the intestinal mucosal barrier. Impaired barrier function has been linked to intestinal illnesses such as inflammatory bowel disease (IBD). IBD is a persistent non-specific inflammatory illness of the digestive system with an unknown cause. It is now thought to be linked to infection, environment, genes, immune system, and the gut microbiota. The significance of immunological dysfunction in IBD has received more attention in recent years. The purpose of this paper is to explore TLR5’s position in the intestinal mucosal barrier and its relevance to IBD.Keywords: toll-like receptor 5, intestinal mucosal barrier, microbes, intestinal immune, inflammatory bowel disease

Damage to the intestinal mucosal barrier play an important role in the pathogenesis of ulcerative colitis (UC). Discovering the key regulators and repairing the disturbed barrier are crucial for preventing and treating UC. Traditional Chinese medicine (TCM) has been proved to be effective on treating UC and has exhibited its role in repairing the intestinal mucosal barrier. We summarized the evidence of TCM against UC by protecting and repairing the physical barrier, chemical barrier, immune barrier, and biological barrier. Mechanisms of increasing intestinal epithelial cells, tight junction proteins, and mucins, promoting intestinal stem cell proliferation, restoring the abundance of the intestinal microbiota, and modulating the innate and adaptive immunity in gut, were all involved in. Some upstream proteins and signaling pathways have been elucidated. Based on the existing problems, we suggested future studies paying attention to patients' samples and animal models of UC and TCM syndromes, conducting rescue experiments, exploring more upstream regulators, and adopting new technical methods. We hope this review can provide a theoretical basis and novel ideas for clarifying the mechanisms of TCM against UC via repairing the intestinal mucosal barrier. [ABSTRACT FROM AUTHOR]

Background and purpose: Changes in gut microbiota composition, enteric inflammation, impairments of the intestinal epithelial barrier and neuroplastic changes in the enteric nervous system have been reported in Parkinson's disease (PD) patients and could contribute to the onset of both neurological and gastrointestinal symptoms. However, their mutual interplay has rarely been investigated. This study evaluated, in an integrated manner, changes in faecal microbiota composition, morphofunctional alterations of colonic mucosal barrier and changes of inflammatory markers in blood and stools of PD patients. Methods: Nineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin‐1β (IL‐1β) levels, as well as stool IL‐1β and tumour necrosis factor (TNF) levels, were evaluated. Gut microbiota analysis was performed. Epithelial mucins, collagen fibres, claudin‐1 and S100‐positive glial cells as markers of an impairment of the intestinal barrier, mucosal remodelling and enteric glial activation were evaluated on colonic mucosal specimens collected during colonoscopy. Results: Faecal microbiota analysis revealed a significant difference in the α‐diversity in PD patients compared to controls, while no differences were found in the β‐diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL‐1β levels. The histological analysis showed a decrease in epithelial neutral mucins and claudin‐1 expression and an increased expression of acidic mucins, collagen fibres and S100‐positive glial cells. Conclusions: Parkinson's disease patients are characterized by enteric inflammation and increased intestinal epithelial barrier permeability, as well as colonic mucosal barrier remodelling, associated with changes in gut microbiota composition. [ABSTRACT FROM AUTHOR]

Objective: The impact of perioperative immunonutrition on patients undergoing radical gastrectomy remains undetermined. This study aimed to assess the influence of enteral immunonutrition support on postoperative immune function and intestinal mucosal barrier function following radical gastrectomy, contrasting findings with a control group to furnish evidence for perioperative enteral nutrition support. Methods: In this prospective randomized trial, 65 patients who underwent radical gastrectomy between June 2022 and June 2023 were included. Participants were allocated to either the study group (receiving enteral immunonutrition) or the control group (not receiving enteral immunonutrition). We compared postoperative rehabilitation and complications between the groups, analyzed the intestinal mucosal barrier function markers on the 3rd and 7th postoperative days, and delved deeper into peripheral blood cell immunity, inflammation, and nutritional indicators. Results: The cohort consisted of 30 patients in the study group and 35 in the control group, with no significant differences in demographic attributes between the two groups. On the 3rd postoperative day, the diamine oxidase, D-lactic acid, and endotoxin levels in the study group were significantly lower than those in the control group (p = 0.029, p = 0.044, and p = 0.010, respectively). By the 7th postoperative day, these levels continued to be significantly diminished in the study group (p = 0.013, p = 0.033, and p = 0.004, respectively). The times to first flatus (p = 0.012) and first bowel movement (p = 0.012) were significantly shorter in the study group. Moreover, postoperative complications in the study group were fewer than in the control group (p = 0.039). On the 7th postoperative day, the study group had lower peripheral white blood cell (WBC) levels (p = 0.020) and neutrophil–lymphocyte ratios (NLR) (p = 0.031), but displayed elevated albumin levels (p = 0.006). One month post-surgery, the CD4+T and CD8+T counts were significantly greater in the study group (p = 0.003 and p = 0.012, respectively). Correlation analyses indicated that NLR and complications were associated with endotoxin levels. Conclusion: Administering perioperative enteral immunonutrition enhances postoperative immune and intestinal mucosal barrier functions in patients undergoing radical gastrectomy. This effect leads to diminished inflammatory responses, a decreased rate of postoperative complications, and accelerated patient recovery. [ABSTRACT FROM AUTHOR]

The importance of the “gut–liver axis” in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut–liver axis of various liver diseases, reflecting their health benefits in preventing/ alleviating liver diseases. Moreover, some plant-based foods with potential gut–liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease with an unknown pathogenesis and increasing incidence. The objective of this study is to investigate the impact of prophylactic treatment with Cordyceps militaris on UC. The findings demonstrate that prophylactic supplementation of C. militaris powder effectively mitigates disease symptoms in DSS-injured mice, while also reducing the secretion of pro-inflammatory cytokines. Furthermore, C. militaris powder enhances the integrity of the intestinal mucosal barrier by up-regulating MUC2 protein expression and improving tight junction proteins (ZO-1, occludin, and claudin 1) in DSS-injured mice. Multiomics integration analyses revealed that C. militaris powder not only reshaped gut microbiota composition, with an increase in Lactobacillus, Odoribacter, and Mucispirillum, but also exerted regulatory effects on various metabolic pathways including amino acid, glyoxylates, dicarboxylates, glycerophospholipids, and arachidonic acid. Subsequent analysis further elucidated the intricate interplay of gut microbiota, the intestinal mucosal barrier, and metabolites, suggesting that the microbiota–metabolite axis may involve the effect of C. militaris on intestinal mucosal barrier repair in UC. Moreover, in vitro experiments demonstrated that peptides and polysaccharides, derived from C. militaris, exerted an ability to change the gut microbiota structure of UC patients' feces, particularly by promoting the growth of Lactobacillus. These findings suggest that regulatory properties of C. militaris on gut microbiota may underlie the potential mechanism responsible for the protective effect of C. militaris in UC. Consequently, our study will provide support for the utilization of C. militaris as a whole food-based ingredient against the occurrence and development of UC. [ABSTRACT FROM AUTHOR]