• Biomolecules & Therapeutics
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• v.29 no.2
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• pp.175-183
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• 2021

The mitogen-activated protein kinase (MAPK) pathway controls intestinal epithelial barrier permeability by regulating tight junctions (TJs) and epithelial cells damage. Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal epithelial barrier function, but the molecular mechanism is not yet clarified. MAPK activation and barrier permeability were studied using monolayers of Caco-2 cells treated with tissue necrosis factor α (TNF-α) transfected with FUGW-HO-1 or pLKO.1-sh-HO-1 plasmid. Intestinal mucosal barrier permeability and MAPK activation were also investigated using carbon tetrachloride (CCl4) administration with CoPP (a HO-1 inducer), ZnPP (a HO-1 inhibitor), CO releasing molecule 2 (CORM-2), or inactived-CORM-2-treated wild-type mice and mice with HO-1 deficiency in intestinal epithelial cells. TNF-α increased epithelial TJ disruption and cleaved caspase-3 expression, induced ERK, p38, and JNK phosphorylation. In addition, HO-1 blocked TNF-α-induced increase in epithelial TJs disruption, cleaved caspase-3 expression, as well as ERK, p38, and JNK phosphorylation in an HO-1-dependent manner. CoPP and CORM-2 directly ameliorated intestinal mucosal injury, attenuated TJ disruption and cleaved caspase-3 expression, and inhibited epithelial ERK, p38, and JNK phosphorylation after chronic CCl4 injection. Conversely, ZnPP completely reversed these effects. Furthermore, mice with intestinal epithelial HO-1 deficient exhibited a robust increase in mucosal TJs disruption, cleaved caspase-3 expression, and MAPKs activation as compared to the control group mice. These data demonstrated that HO-1-dependent MAPK signaling inhibition preserves the intestinal mucosal barrier integrity by abrogating TJ dysregulation and epithelial cell damage. The differential targeting of gut HO-1-MAPK axis leads to improved intestinal disease therapy.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.1
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• pp.1-7
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• 2015

Our previous study has shown berberine prevents damage to the intestinal mucosal barrier during early phase of sepsis in rat through mechanisms independent of the NOD-like receptors signaling pathway. In this study, we explored the regulatory effects of berberine on Toll-like receptors during the intestinal mucosal damaging process in rats. Male Sprague-Dawlay (SD) rats were treated with berberine for 5 d before undergoing cecal ligation and puncture (CLP) to induce polymicrobial sepsis. The expression of Toll-like receptor 2 (TLR 2), TLR 4, TLR 9, the activity of nuclear factor-kappa B ($NF-{\kappa}B$), the levels of selected cytokines and chemokines, percentage of cell death in intestinal epithelial cells, and mucosal permeability were investigated at 0, 2, 6, 12 and 24 h after CLP. Results showed that the tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interleukin-6 (IL-6) level were significantly lower in berberine-treated rats compared to the control animals. Conversely, the expression level of tight junction proteins, percentage of cell death in intestinal epithelial cells and the mucosal permeability were significantly higher in berberine-treated rats. The mRNA expression of TLR 2, TLR 4, and TLR 9 were significantly affected by berberine treatment. Our results indicate that pretreatment with berberine attenuates tissue injury and protects the intestinal mucosal barrier in early phase of sepsis and this may possibly have been mediated through the TLRs pathway.

• Korean Journal of Veterinary Research
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• v.56 no.2
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• pp.57-66
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• 2016

The gut epithelial barrier, which is composed of the mucosal layer and the intestinal epithelium, has multiple defense mechanisms and interconnected regulatory mechanisms against enteric microbial pathogens. However, many bacterial pathogens have highly evolved infectious stratagems that manipulate mucin production, epithelial cell-cell junctions, cell death, and cell turnover to promote their replication and pathogenicity in the gut epithelial barrier. In this review, we focus on current knowledge about how bacterial pathogens regulate mucin levels to circumvent the epithelial mucus barrier and target cell-cell junctions to invade deeper tissues and increase their colonization. We also describe how bacterial pathogens manipulate various modes of epithelial cell death to facilitate bacterial dissemination and virulence effects. Finally, we discuss recent investigating how bacterial pathogens regulate epithelial cell turnover and intestinal stem cell populations to modulate intestinal epithelium homeostasis.

• Asian-Australasian Journal of Animal Sciences
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• v.29 no.1
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• pp.134-141
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• 2016

To investigate the role of polysaccharide from Acanthopanax senticosus (ASPS) in preventing lipopolysaccharide (LPS)-induced intestinal injury, 18 mice (at 5 wk of age) were assigned to three groups with 6 replicates of one mouse each. Mice were administrated by oral gavage with or without ASPS (300 mg/kg body weight) for 14 days and were injected with saline or LPS at 15 days. Intestinal samples were collected at 4 h post-challenge. The results showed that ASPS ameliorated LPS-induced deterioration of digestive ability of LPS-challenged mice, indicated by an increase in intestinal lactase activity (45%, p<0.05), and the intestinal morphology, as proved by improved villus height (20.84%, p<0.05) and villus height:crypt depth ratio (42%, p<0.05), and lower crypt depth in jejunum (15.55%, p<0.05), as well as enhanced intestinal tight junction proteins expression involving occludin-1 (71.43%, p<0.05). ASPS also prevented intestinal inflammation response, supported by decrease in intestinal inflammatory mediators including tumor necrosis factor ${\alpha}$ (22.28%, p<0.05) and heat shock protein (HSP70) (77.42%, p<0.05). In addition, intestinal mucus layers were also improved by ASPS, as indicated by the increase in number of goblet cells (24.89%, p<0.05) and intestinal trefoil peptide (17.75%, p<0.05). Finally, ASPS facilitated mRNA expression of epidermal growth factor (100%, p<0.05) and its receptor (200%, p<0.05) gene. These results indicate that ASPS can prevent intestinal mucosal barrier injury under inflammatory conditions, which may be associated with up-regulating gene mRNA expression of epidermal growth factor and its receptor.

• Journal of Yeungnam Medical Science
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• v.38 no.1
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• pp.27-33
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• 2021

The gut is a complex organ that has played an important role in digestion, absorption, endocrine functions, and immunity. The gut mucosal barriers consist of the immunologic barrier and nonimmunologic barrier. During critical illnesses, the gut is susceptible to injury due to the induction of intestinal hyperpermeability. Gut hyperpermeability and barrier dysfunction may lead to systemic inflammatory response syndrome. Additionally, gut microbiota are altered during critical illnesses. The etiology of such microbiome alterations in critical illnesses is multifactorial. The interaction or systemic host defense modulation between distant organs and the gut microbiome is increasingly studied in disease research. No treatment modality exists to significantly enhance the gut epithelial integrity, permeability, or mucus layer in critically ill patients. However, multiple helpful approaches including clinical and preclinical strategies exist. Enteral nutrition is associated with an increased mucosal barrier in animal and human studies. The trophic effects of enteral nutrition might help to maintain the intestinal physiology, prevent atrophy of gut villi, reduce intestinal permeability, and protect against ischemia-reperfusion injury. The microbiome approach such as the use of probiotics, fecal microbial transplantation, and selective decontamination of the digestive tract has been suggested. However, its evidence does not have a high quality. To promote rapid hypertrophy of the small bowel, various factors have been reported, including the epidermal growth factor, membrane permeant inhibitor of myosin light chain kinase, mucus surrogate, pharmacologic vagus nerve agonist, immune-enhancing diet, and glucagon-like peptide-2 as preclinical strategies. However, the evidence remains unclear.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.132.2-132.2
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• 2003

Vibrio vulnificus, a Gram-negative estuarine bacterium, is the causative agent of food-borne diseases, such as life-threatening septicemia. V. vulnificus penetrating into the intestinal epithelial barrier stimulates an inflammatory response in the adjacent intestinal mucosa. Therefore, interaction between V. vulnificus and intestinal cells is important for understanding of both the immunology of mucosal surfaces and V. vulnificus. In this study we investigated the effects of V. vulnificus infection on cytokine gene expression of human intestinal epithelial cells, Caco-2 and INT-407 cells. (omitted)

• Journal of Plant Biotechnology
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• v.37 no.3
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• pp.283-291
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• 2010

Vaccine is one of the best known and most successful applications of immunological theory to human health and it protects human life through inducing the immune response in systemic compartment. However, when we consider the fact that mucosal epithelium is exposed to diverse foreign materials including viruses, bacteria, and food antigens and protects body from entry of unwanted materials using layer of tightly joined epithelial cells, establishing the immunological barrier on the lining of mucosal surfaces is believed to be an effective strategy to protect body from unwanted antigens. Unfortunately, however, oral mucosal site, which is considered as the best target to induce mucosal immune response due to application convenience, is prone to induce immune tolerance rather than immune stimulation. Since intestinal epithelium is tightly organized, a prerequisite for successful mucosal vaccination is delivery of antigen to mucosal immune induction site including a complex system of highly specialized cells such as M cells. Consequently, development of efficient mucosal adjuvant capable of introducing antigens to mucosal immune induction site and overcome oral tolerance is an important subject in oral vaccine development. In this review, various approaches on the development of oral mucosal adjuvants being suggested for effective oral mucosal immune induction.

• Journal of Animal Science and Technology
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• v.63 no.2
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• pp.211-247
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• 2021

Livestock species experience several stresses, particularly weaning, transportation, overproduction, crowding, temperature, and diseases in their life. Heat stress (HS) is one of the most stressors, which is encountered in livestock production systems throughout the world, especially in the tropical regions and is likely to be intensified due to global rise in environmental temperature. The gut has emerged as one of the major target organs affected by HS. The alpha- and beta-diversity of gut microbiota composition are altered due to heat exposure to animals with greater colonization of pathogenic microbiota groups. HS also induces several changes in the gut including damages of microstructures of the mucosal epithelia, increased oxidative insults, reduced immunity, and increased permeability of the gut to toxins and pathogens. Vulnerability of the intestinal barrier integrity leads to invasion of pathogenic microbes and translocation of antigens to the blood circulations, which ultimately may cause systematic inflammations and immune responses. Moreover, digestion of nutrients in the guts may be impaired due to reduced enzymatic activity in the digesta, reduced surface areas for absorption and injury to the mucosal structure and altered expressions of the nutrient transport proteins and genes. The systematic hormonal changes due to HS along with alterations in immune and inflammatory responses often cause reduced feed intake and production performance in livestock and poultry. The altered microbiome likely orchestrates to the hosts for various relevant biological phenomena occurring in the body, but the exact mechanisms how functional communications occur between the microbiota and HS responses are yet to be elucidated. This review aims to discuss the effects of HS on microbiota composition, mucosal structure, oxidant-antioxidant balance mechanism, immunity, and barrier integrity in the gut, and production performance of farm animals along with the dietary ameliorations of HS. Also, this review attempts to explain the mechanisms how these biological responses are affected by HS.

• Animal Bioscience
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• v.35 no.8
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• pp.1235-1249
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• 2022

Objective: The purpose of this study was to evaluate the protection of glutamate (GLU) against the impairment in intestinal barrier function induced by lipopolysaccharide (LPS) stress in weaned pigs. Methods: Twenty-four weaned pigs were divided into four treatments containing: i) non-challenged control, ii) LPS-challenged control, iii) LPS+1.0% GLU, and iv) LPS+2.0% GLU. On day 28, pigs were treated with LPS or saline. Blood samples were collected at 0, 2, and 4 h post-injection. After blood samples collection at 4 h, all pigs were slaughtered, and spleen, mesenteric lymph nodes, liver and intestinal samples were obtained. Results: Dietary GLU supplementation inhibited the LPS-induced oxidative stress in pigs, as demonstrated by reduced malondialdehyde level and increased glutathione level in jejunum. Diets supplemented with GLU enhanced villus height, villus height/crypt depth and claudin-1 expression, attenuated intestinal histology and ultrastructure impairment induced by LPS. Moreover, GLU supplementation reversed intestinal intraepithelial lymphocyte number decrease and mast cell number increase induced by LPS stress. GLU reduced serum cortisol concentration at 4 h after LPS stress and downregulated the mRNA expression of intestinal corticotropin-releasing factor signal (corticotrophin-releasing factor [CRF], CRF receptor 1 [CRFR1], glucocorticoid receptor, tryptase, nerve growth factor, tyrosine kinase receptor A), and prevented mast cell activation. GLU upregulated the mRNA expression of intestinal transforming growth factor β. Conclusion: These findings indicate that GLU attenuates LPS-induced intestinal mucosal barrier injury, which is associated with modulating CRF signaling pathway.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.23 no.4
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• pp.388-396
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• 2020

Purpose: Impaired intestinal mucosal integrity may affect the gastrointestinal function, especially in relation to nutrition, absorption, and barrier function. The purpose of this study was to measure the prevalence of impaired intestinal mucosal integrity in presumed healthy children aged 1-3 years and assess the effects of zinc, glutamine, fiber, and prebiotic supplementation in them. Methods: A cross-sectional study was conducted in 200 children aged 1-3 years in Pasar Minggu, South Jakarta, Indonesia. A randomized double-blind parallel group method clinical trial was then performed to assess the effects of zinc, glutamine, fiber, and prebiotic supplementation. Results: Elevated calprotectin was found in 91/200 subjects (45.5%) at the onset of the study. After 10 months, 144 subjects completed the study: 72 subjects received the trial formula, whereas the other 72 received the standard formula. A transitory decrease in fecal calprotectin (FC) was observed after 6 months in the subgroup with normal FC levels, who were fed the test formula (p=0.012). Conclusion: The prevalence of impaired intestinal mucosal integrity in this group of Indonesian children aged 1-3 years was high. Supplementation with zinc, glutamine, fiber, and prebiotics during 6 months reduced FC only in those who had low levels at baseline but not in those with impaired integrity.