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Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options. Int J Mol Sci 2022; 23:ijms23063204. [PMID: 35328624 PMCID: PMC8949204 DOI: 10.3390/ijms23063204] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.
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Maruta K, Takajo T, Akiba Y, Said H, Irie E, Kato I, Kuwahara A, Kaunitz JD. GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats. Dig Dis Sci 2020; 65:2605-2618. [PMID: 32006214 PMCID: PMC7392813 DOI: 10.1007/s10620-020-06097-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/20/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect. METHODS We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability. RESULTS FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors. CONCLUSIONS Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.
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Affiliation(s)
- Koji Maruta
- Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Takeshi Takajo
- Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Yasutada Akiba
- Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA,Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA,Brentwood Biomedical Research Institute, Los Angeles, CA, USA
| | - Hyder Said
- Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Emi Irie
- Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA
| | - Ikuo Kato
- Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Atsukazu Kuwahara
- Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan
| | - Jonathan D. Kaunitz
- Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA,Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA,Department of Surgery, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA,Brentwood Biomedical Research Institute, Los Angeles, CA, USA
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Zhang X, Wu Y, Ye H, Feng C, Han D, Tao S, Pi Y, Zhao J, Chen L, Wang J. Dietary milk fat globule membrane supplementation during late gestation increased the growth of neonatal piglets by improving their plasma parameters, intestinal barriers, and fecal microbiota. RSC Adv 2020; 10:16987-16998. [PMID: 35521473 PMCID: PMC9053443 DOI: 10.1039/d0ra02618b] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022] Open
Abstract
Maternal supplementation of MFGM transgenerationally improves the intestinal microecology and growth performance of their neonatal piglets.
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Nagarajan A, Srivastava H, Jablonsky J, Sun LY. Tissue-Specific GHR Knockout Mice: An Updated Review. Front Endocrinol (Lausanne) 2020; 11:579909. [PMID: 33162937 PMCID: PMC7581730 DOI: 10.3389/fendo.2020.579909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/14/2020] [Indexed: 01/01/2023] Open
Abstract
Growth hormone (GH) signaling plays a key role in mediating growth, development, metabolism, and lifespan regulation. However, the mechanisms of longevity regulation at the cellular and molecular level are still not well-understood. An important area in the field of GH research is in the development of advanced transgenic systems for conditional expression of GH signaling in a cell type- or tissue-specific manner. There have been many recent studies conducted to examine the effects of tissue-specific GHR disruption. This review updates our previous discussions on this topic and summarizes recent data on the newly-made tissue-specific GHR-KO mice including intestinal epithelial cells, bone, hematopoietic stem cells, cardiac myocytes, and specific brain regions. The data from these new genetically-engineered mice have a significant impact on our understanding of the local GH signaling function.
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Comparative Evaluation of Translocation of GFP Producing Escherichia coli Strains in Acute Intestinal Obstruction. Bull Exp Biol Med 2019; 167:660-662. [PMID: 31625067 DOI: 10.1007/s10517-019-04593-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Indexed: 10/25/2022]
Abstract
Comparative evaluation of translocation of E. coli GFP-producing strains in experimental rats with obturation and strangulated intestinal obstruction was carried out. Translocation of infused GFP-producing E. coli strain was studied by bacteriological methods in male rats with experimental obturation and strangulated intestinal obstruction with various ischemia/reperfusion cycles. The maximum incidence of translocation in obturation intestinal obstruction was observed after 24 h. In strangulated intestinal obstruction, the highest incidence was recorded in ischemia/reperfusion cycles of 1 h/2 h and 2 h/6 h. No appreciable differences in the incidence of translocation in animals with two types of intestinal obstruction were detected.
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Salameh E, Morel FB, Zeilani M, Déchelotte P, Marion-Letellier R. Animal Models of Undernutrition and Enteropathy as Tools for Assessment of Nutritional Intervention. Nutrients 2019; 11:nu11092233. [PMID: 31527523 PMCID: PMC6770013 DOI: 10.3390/nu11092233] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/24/2019] [Accepted: 09/08/2019] [Indexed: 02/06/2023] Open
Abstract
: Undernutrition is a major public health problem leading to 1 in 5 of all deaths in children under 5 years. Undernutrition leads to growth stunting and/or wasting and is often associated with environmental enteric dysfunction (EED). EED mechanisms leading to growth failure include intestinal hyperpermeability, villus blunting, malabsorption and gut inflammation. As non-invasive methods for investigating gut function in undernourished children are limited, pre-clinical models are relevant to elucidating the pathophysiological processes involved in undernutrition and EED, and to identifying novel therapeutic strategies. In many published models, undernutrition was induced using protein or micronutrient deficient diets, but these experimental models were not associated with EED. Enteropathy models mainly used gastrointestinal injury triggers. These models are presented in this review. We found only a few studies investigating the combination of undernutrition and enteropathy. This highlights the need for further developments to establish an experimental model reproducing the impact of undernutrition and enteropathy on growth, intestinal hyperpermeability and inflammation, that could be suitable for preclinical evaluation of innovative therapeutic intervention.
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Affiliation(s)
- Emmeline Salameh
- UniRouen, Inserm UMR 1073 Nutrition, Inflammation and Gut-Brain Axis, Normandie University, 76183 Rouen, France.
- Nutriset SAS, 76770 Malaunay, France.
| | | | | | - Pierre Déchelotte
- UniRouen, Inserm UMR 1073 Nutrition, Inflammation and Gut-Brain Axis, Normandie University, 76183 Rouen, France.
- Department of Nutrition, Rouen University Hospital, 76183 Rouen, France.
| | - Rachel Marion-Letellier
- UniRouen, Inserm UMR 1073 Nutrition, Inflammation and Gut-Brain Axis, Normandie University, 76183 Rouen, France.
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Young JA, Jensen EA, Stevens A, Duran-Ortiz S, List EO, Berryman DE, Kopchick JJ. Characterization of an intestine-specific GH receptor knockout (IntGHRKO) mouse. Growth Horm IGF Res 2019; 46-47:5-15. [PMID: 31078722 PMCID: PMC6646076 DOI: 10.1016/j.ghir.2019.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/15/2019] [Accepted: 05/01/2019] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Growth hormone (GH) has been reported to enhance the intestinal barrier; as such, recombinant GH has been administered for several intestinal diseases. However, excess GH action has been implicated in increasing the risk of intestinal dysfunction. The goal of this study was to examine the direct effects of GH on the small and large intestines to clarify the role GH plays in intestinal function through the use of a mouse model. DESIGN An intestinal epithelial-specific GH receptor (GHR) knockout (IntGHRKO) mouse line was generated using Cre-lox with the villin promoter driving Cre expression. The generated mice were characterized with respect to growth and intestinal phenotypes. RESULTS IntGHRKO mice showed no significant changes in body length, weight, or composition compared to floxed controls. Male IntGHRKO mice had significantly shorter large intestines at 4 and 12 months of age. Intestinal barrier function was assessed by measuring the expression of tight junction related genes, as well as levels of serum endotoxin and fecal albumin. Results showed sex differences as males had an increase in occludin levels but normal serum endotoxin and fecal albumin; while, females had changes in fecal albumin levels with normal occludin and serum endotoxin. Evaluation of glucose tolerance and fat absorption also showed sex differences as females were glucose intolerant, while males had impaired fat absorption. Histopathology revealed a trend towards decreased villus height in males, which could explain the sex difference in glucose homeostasis. CONCLUSIONS Overall, the data demonstrate that disruption of GH on the intestinal epithelial cells modestly affects the intestinal gross anatomy, morphology, and function in a sex-specific manner.
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Affiliation(s)
- Jonathan A Young
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Molecular and Cellular Biology Program, Ohio University, Athens, OH, United States of America
| | - Elizabeth A Jensen
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Heritage College of Osteopathic Medicine, Athens, OH, United States of America; Translational Biomedical Sciences Program, Graduate College, Ohio University, Athens, OH, United States of America
| | - Austin Stevens
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America
| | - Silvana Duran-Ortiz
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Molecular and Cellular Biology Program, Ohio University, Athens, OH, United States of America
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States of America
| | - Darlene E Berryman
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States of America; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States of America
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH, United States of America; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States of America.
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Propofol Does Not Reduce Pyroptosis of Enterocytes and Intestinal Epithelial Injury After Lipopolysaccharide Challenge. Dig Dis Sci 2018; 63:81-91. [PMID: 29063417 DOI: 10.1007/s10620-017-4801-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/10/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND To date, mechanisms of sepsis-induced intestinal epithelial injury are not well known. P2X7 receptor (P2X7R) regulates pyroptosis of lymphocytes, and propofol is usually used for sedation in septic patients. AIMS We aimed to determine the occurrence of enterocyte pyroptosis mediated by P2X7R and to explore the effects of propofol on pyroptosis and intestinal epithelial injury after lipopolysaccharide (LPS) challenge. METHODS A novel regimen of LPS challenge was applied in vitro and in vivo. Inhibitors of P2X7R (A438079) and NLRP3 inflammasome (MCC950), and different doses of propofol were administered. The caspase-1 expression, caspase-3 expression, caspase-11 expression, P2X7R expression and NLRP3 expression, extracellular ATP concentration and YO-PRO-1 uptake, and cytotoxicity and HMGB1 concentration were detected to evaluate enterocyte pyroptosis in cultured cells and intestinal epithelial tissues. Chiu's score, diamine oxidase and villus length were used to evaluate intestinal epithelial injury. Moreover, survival analysis was performed. RESULTS LPS challenge activated caspase-11 expression and P2X7R expression, enhanced ATP concentration and YO-PRO-1 uptake, and led to increased cytotoxicity and HMGB1 concentration. Subsequently, LPS resulted in intestinal epithelial damage, as evidenced by increased levels of Chiu's score and diamine oxidase, and shorter villus length and high mortality of animals. A438079, but not MCC950, significantly relieved LPS-induced enterocyte pyroptosis and intestinal epithelial injury. Importantly, propofol did not confer the protective effects on enterocyte pyroptosis and intestinal epithelia although it markedly decreased P2X7R expression. CONCLUSION LPS attack leads to activation of caspase-11/P2X7R and pyroptosis of enterocytes. Propofol does not reduce LPS-induced pyroptosis and intestinal epithelial injury, although it inhibits P2X7R upregulation.
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Growth Hormone Resistance-Special Focus on Inflammatory Bowel Disease. Int J Mol Sci 2017; 18:ijms18051019. [PMID: 28486400 PMCID: PMC5454932 DOI: 10.3390/ijms18051019] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/01/2017] [Accepted: 05/03/2017] [Indexed: 12/25/2022] Open
Abstract
Growth hormone (GH) plays major anabolic and catabolic roles in the body and is important for regulating several aspects of growth. During an inflammatory process, cells may develop a state of GH resistance during which their response to GH stimulation is limited. In this review, we will emphasize specific mechanisms governing the formation of GH resistance in the active phase of inflammatory bowel disease. The specific molecular effects mediated through individual inflammatory mediators and processes will be highlighted to provide an overview of the transcriptional, translational and post-translational inflammation-mediated impacts on the GH receptor (GHR) along with the impacts on GH-induced intracellular signaling. We also will review GH’s effects on mucosal healing and immune cells in the context of experimental colitis, human inflammatory bowel disease and in patients with short bowel syndrome.
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Yu C, Tan S, Zhou C, Zhu C, Kang X, Liu S, Zhao S, Fan S, Yu Z, Peng A, Wang Z. Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage. Biol Pharm Bull 2016; 39:1787-1792. [PMID: 27506986 DOI: 10.1248/bpb.b16-00280] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.
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Affiliation(s)
- Chao Yu
- Department of Nephrology & Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine
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Zhou F, Zhang P, Chen X, Yan J, Yao J, Yu Z, Chen X. Ginsenoside Rb1 protects the intestinal mucosal barrier following peritoneal air exposure. Exp Ther Med 2016; 12:2563-2567. [PMID: 27703510 PMCID: PMC5038908 DOI: 10.3892/etm.2016.3639] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 06/15/2016] [Indexed: 01/02/2023] Open
Abstract
Ginsenoside Rb1 (GRb1), which is one of the main ingredients derived from Panax ginseng, has been widely used to treat various gastrointestinal disorders. The present study aimed to determine whether GRb1 was able to prevent intestinal mucosal barrier damage in rats following peritoneal air exposure for 3 h. GRb1 (5, 10, and 20 mg/kg) was orally administrated via gavage four times prior to and following surgery. Blood and terminal ileum were sampled 24 h following surgery. Levels of serum D-lactate (D-LA) were detected using an enzyme-linked immunosorbent assay kit. Intestinal permeability was assessed by determining the intestinal clearance of fluorescein isothiocyanate-dextran (FD4). Activity of intestinal myeloperoxidase was measured to assess intestinal inflammation, and intestinal histopathology was assessed by light microscopy. The results showed that GRb1 reduced the level of serum D-LA, intestinal clearance of FD4, and the activity of intestinal myeloperoxidase. Intestinal edema and inflammation were also ameliorated by GRb1, and the Chiu's scores employed for assessing intestinal mucosal damage were also reduced in the GRb1-treated peritoneal air exposure group. In addition, GRb1 induced a significant difference at 10 and 20 mg/kg, indicating a dose-dependent effect. The results of the present study suggest that GRb1 may be able to protect the intestinal mucosal barrier against damage induced by peritoneal air exposure, which may be associated with its anti-inflammatory action.
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Affiliation(s)
- Feng Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Peichen Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoxi Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jingyi Yan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiangao Yao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhen Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China; Department of General Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China
| | - Xiaolei Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Deng W, Abliz A, Xu S, Sun R, Guo W, Shi Q, Yu J, Wang W. Severity of pancreatitis‑associated intestinal mucosal barrier injury is reduced following treatment with the NADPH oxidase inhibitor apocynin. Mol Med Rep 2016; 14:3525-34. [PMID: 27573037 PMCID: PMC5042780 DOI: 10.3892/mmr.2016.5678] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 06/17/2016] [Indexed: 02/06/2023] Open
Abstract
Recent studies demonstrated that apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor, significantly decreased acute pancreatitis-associated inflammatory and oxidative stress parameters. In addition, apocynin was able to reduce ischemic reperfusion injury-associated damage; however, the exact effects of apocynin on acute pancreatitis-associated intestinal mucosal injury have yet to be fully clarified. The present study aimed to investigate the protective effects of apocynin on intestinal mucosal injury in a rat model of severe acute pancreatitis (SAP). A total of 60 male Sprague Dawley rats were randomly divided into four groups (n=15/group): Sham operation group (SO), SAP group, apocynin treatment (APO) group and drug control (APO-CON) group. SAP was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Apocynin was administered 30 min prior to SAP induction in the APO group. All rats were sacrificed 12 h after SAP induction. Intestinal integrity was assessed by measuring diamine oxidase (DAO) levels. Morphological alterations to intestinal tissue were determined under light and transmission electron microscopy. NOX2, p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-κB expression levels were detected in the intestine by immunohistochemical staining. Oxidative stress was detected by measuring intestinal malondialdehyde (MDA) and superoxide dismutase content. In addition, blood inflammatory cytokines, and amylase (AMY) and lipase (LIP) levels were evaluated. The results demonstrated that apocynin attenuated the following: i) Serum AMY, LIP and DAO levels; ii) pancreatic and intestinal pathological injury; iii) intestinal MDA content; iv) intestinal ultrastructural alterations; v) serum interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α levels; and vi) NOX2, p38 MAPK and NF-κB expression in intestinal tissues. These results suggested that apocynin may attenuate intestinal barrier dysfunction in sodium taurocholate-induced SAP, presumably via its role in the prevention of reactive oxygen species generation and inhibition of p38 MAPK and NF-κB pathway activation. These findings provide novel insight suggesting that pharmacological inhibition of NOX by apocynin may be considered a novel therapeutic method for the treatment of intestinal injury in SAP.
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Affiliation(s)
- Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ablikim Abliz
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Sheng Xu
- Department of General Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, P.R. China
| | - Rongze Sun
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wenyi Guo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qiao Shi
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jia Yu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. Sci Rep 2016; 6:31203. [PMID: 27491828 PMCID: PMC4974559 DOI: 10.1038/srep31203] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 07/14/2016] [Indexed: 12/13/2022] Open
Abstract
The loss of gut epithelium integrity leads to translocation of microbes and microbial products resulting in immune activation and drives systemic inflammation in acquired immunodeficiency syndrome (AIDS) patients. Although viral loads in HIV patients are significantly reduced in the post-cART era, inflammation and immune activation persist and can lead to morbidity. Here, we determined the interactive effects of the viral protein HIV-1 Tat and lipopolysaccharide (LPS) on enteric neurons and glia. Bacterial translocation was significantly enhanced in Tat-expressing (Tat+) mice. Exposure to HIV-1 Tat in combination with LPS enhanced the expression and release of the pro-inflammatory cytokines IL-6, IL-1β and TNF-α in the ilea of Tat+ mice and by enteric glia. This coincided with enhanced NF-κB activation in enteric glia that was abrogated in glia from TLR4 knockout mice and by knockdown (siRNA) of MyD88 siRNA in wild type glia. The synergistic effects of Tat and LPS resulted in a reduced rate of colonic propulsion in Tat+ mice treated with LPS. These results show that HIV-1 Tat interacts with the TLR4 receptor to enhance the pro-inflammatory effects of LPS leading to gastrointestinal dysmotility and enhanced immune activation.
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Chronic Kidney Disease Induced Intestinal Mucosal Barrier Damage Associated with Intestinal Oxidative Stress Injury. Gastroenterol Res Pract 2016; 2016:6720575. [PMID: 27493661 PMCID: PMC4963601 DOI: 10.1155/2016/6720575] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 06/14/2016] [Indexed: 12/11/2022] Open
Abstract
Background. To investigate whether intestinal mucosal barrier was damaged or not in chronic kidney disease progression and the status of oxidative stress. Methods. Rats were randomized into two groups: a control group and a uremia group. The uremia rat model was induced by 5/6 kidney resection. In postoperative weeks (POW) 4, 6, 8, and 10, eight rats were randomly selected from each group to prepare samples for assessing systemic inflammation, intestinal mucosal barrier changes, and the status of intestinal oxidative stress. Results. The uremia group presented an increase trend over time in the serum tumor necrosis factor-alpha, interleukin-6 (IL-6) and IL-10, serum D-lactate and diamine oxidase, and intestinal permeability, and these biomarkers were significantly higher than those in control group in POW 8 and/or 10. Chiu's scores in uremia group were also increased over time, especially in POW 8 and 10. Furthermore, the intestinal malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were significantly higher in uremia group when compared with those in control group in POW 8 and/or 10. Conclusions. The advanced chronic kidney disease could induce intestinal mucosal barrier damage and further lead to systemic inflammation. The underlying mechanism may be associated with the intestinal oxidative stress injury.
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Gilani S, Howarth GS, Kitessa SM, Forder REA, Tran CD, Hughes RJ. New biomarkers for intestinal permeability induced by lipopolysaccharide in chickens. ANIMAL PRODUCTION SCIENCE 2016; 56:1984. [DOI: 10.1071/an15725] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Intestinal health is influenced by a complex set of variables involving the intestinal microbiota, mucosal immunity, digestion and absorption of nutrients, intestinal permeability (IP) and intestinal integrity. An increase in IP increases bacterial or toxin translocation, activates the immune system and affects health. IP in chickens is reviewed in three sections. First, intestinal structure and permeability are discussed briefly. Second, the use of lipopolysaccharide (LPS) as a tool to increase IP is discussed in detail. LPS, a glycolipid found in the outer coat of mostly Gram-negative bacteria, has been reported to increase IP in rats, mice and pigs. Although LPS has been used in chickens for inducing systemic inflammation, information regarding LPS effects on IP is limited. This review proposes that LPS could be used as a means to increase IP in chickens. The final section focuses on potential biomarkers to measure IP, proposing that the sugar-recovery method may be optimal for application in chickens.
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Tan SJ, Yu C, Yu Z, Lin ZL, Wu GH, Yu WK, Li JS, Li N. High-fat enteral nutrition reduces intestinal mucosal barrier damage after peritoneal air exposure. J Surg Res 2015; 202:77-86. [PMID: 27083951 DOI: 10.1016/j.jss.2015.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 11/05/2015] [Accepted: 12/01/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Peritoneal air exposure is needed in open abdominal surgery, but long-time exposure could induce intestinal mucosal barrier dysfunction followed by many postoperative complications. High-fat enteral nutrition can ameliorate intestinal injury and improve intestinal function in many gastrointestinal diseases. In the present study, we investigated the effect of high-fat enteral nutrition on intestinal mucosal barrier after peritoneal air exposure and the underlying mechanism. METHODS Male adult rats were administrated saline, low-fat or high-fat enteral nutrition via gavage before and after peritoneal air exposure for 3 h. Rats undergoing anesthesia without laparotomy received saline as control. Twenty four hours after surgery, samples were collected to assess intestinal mucosal barrier changes in serum D-lactate levels, intestinal permeability, intestinal tight junction protein ZO-1 and occludin levels, and intestinal histopathology. The levels of malondialdehyde and the activity of superoxide dismutase in the ileum tissue were also measured to assess the status of intestinal oxidative stress. RESULTS High-fat enteral nutrition significantly decreased the serum D-lactate level and increased the intestinal tight junction protein ZO-1 level when compared to the group treated with low-fat enteral nutrition (P < 0.05). Meanwhile, histopathologic findings showed that the intestinal mucosal injury assessed by the Chiu's score and the intestinal epithelial tight junction were also improved much more in the high-fat enteral nutrition-treated group (P < 0.05). In addition, the intestinal malondialdehyde level was lower, and the intestinal superoxide dismutase activity was higher in the high-fat enteral nutrition-treated group than that in the low-fat enteral nutrition-treated group (P < 0.05). CONCLUSIONS These results suggest that high-fat enteral nutrition could reduce intestinal mucosal barrier damage after peritoneal air exposure, and the underlying mechanism may be associated with its antioxidative action. Perioperative administration of high-fat enteral nutrition may be a promising intervention to preserve intestinal mucosal barrier function in open abdominal surgery.
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Affiliation(s)
- Shan-Jun Tan
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chao Yu
- Department of Nephrology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Zhen Yu
- Department of General Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Zhi-Liang Lin
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Guo-Hao Wu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Wen-Kui Yu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Jie-Shou Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ning Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
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Dlugosz A, Nowak P, D'Amato M, Mohammadian Kermani G, Nyström J, Abdurahman S, Lindberg G. Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2015; 27:1747-54. [PMID: 26387872 DOI: 10.1111/nmo.12670] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 08/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial-host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls. METHODS We analyzed serum obtained from 88 patients (74 females) aged 19(43)-73 years and 106 healthy volunteers (77 females) aged 19(38)-62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires. KEY RESULTS We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045). CONCLUSIONS & INFERENCES Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients' self-reported anxiety score.
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Affiliation(s)
- A Dlugosz
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - P Nowak
- Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - M D'Amato
- Karolinska Institutet, Department of Biosciences and Nutrition, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - G Mohammadian Kermani
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - J Nyström
- Karolinska Institutet, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - S Abdurahman
- Department of Science and Technology, Örebro Life Science Center, Örebro University, Örebro, Sweden
| | - G Lindberg
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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18
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Klein BY, Tamir H, Hirschberg DL, Ludwig RJ, Glickstein SB, Myers MM, Welch MG. Oxytocin opposes effects of bacterial endotoxin on ER-stress signaling in Caco2BB gut cells. Biochim Biophys Acta Gen Subj 2015; 1860:402-11. [PMID: 26520666 DOI: 10.1016/j.bbagen.2015.10.025] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 10/02/2015] [Accepted: 10/27/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND The neuropeptide neuromodulator and hormone oxytocin (OT) activates signaling pathways involved in mRNA translation in response to endoplasmic reticulum stress and reduces inflammation associated with experimental colitis in rats. The anti-inflammatory effects of OT may serve a vital role in the development, survival and function of newborn-type enterocytes during microbial gut colonization, which coincides with the milk suckling period when OT receptor expression peaks in the gut. Furthermore, mice deficient in the OT receptor have abnormal gut structure and function, underscoring OT's developmental importance. METHODS We tested the effect of OT upon lipopolysaccharide (LPS)-induced markers of the inflammatory response in Caco2BB gut cells in vitro using automated immunocapillary electrophoresis. RESULTS We demonstrate that OT suppresses NF-κB signaling and presumably inflammatory transcriptional programs, which are unleashed by LPS through the modulation of IκB. We show that OT counteracts LPS-elicited silencing of the unfolded protein response, a pathway limiting endoplasmic reticulum stress by suppressing protein translation. OT selectively activates dsRNA-activated kinase (PKR), X-box binding protein 1 (XBP1), immunoglobulin binding protein (BiP), A20 (TNFα-induced protein 3) and inositol requiring enzyme 1a (IRE1a). OT inactivates eukaryotic translation initiation factor 2a (eIF2a) without significant activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). CONCLUSIONS Mild, preemptive stimulation of endoplasmic reticulum stress sensors by OT may precondition newborn enterocytes to resist apoptosis associated with inflammation and may support their differentiation and development by modulating cellular metabolism. GENERAL SIGNIFICANCE OT may protect enterocytes and other cell types, such as neurons, from stress-related complications during postnatal development.
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Affiliation(s)
- Benjamin Y Klein
- Division of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, USA.
| | - Hadassah Tamir
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA
| | - David L Hirschberg
- Center for Infection and Immunology, Columbia University Medical Center, New York, NY 10032, USA
| | - Robert J Ludwig
- Division of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, USA
| | | | - Michael M Myers
- Division of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA
| | - Martha G Welch
- Division of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
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Zhang HS, Chen Y, Fan L, Xi QL, Wu GH, Li XX, Yuan TL, He SQ, Yu Y, Shao ML, Liu Y, Bai CG, Ling ZQ, Li M, Liu Y, Fang J. The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis. J Biol Chem 2015; 290:15327-36. [PMID: 25925952 DOI: 10.1074/jbc.m114.633560] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Indexed: 12/19/2022] Open
Abstract
Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1α, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1α in IECs leads to spontaneous colitis in mice. Deletion of IRE1α in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1α deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1α deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases.
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Affiliation(s)
- Hai-Sheng Zhang
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Ying Chen
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Li Fan
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Qiu-Lei Xi
- the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030
| | - Guo-Hao Wu
- the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030
| | - Xiu-Xiu Li
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Tang-Long Yuan
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Sheng-Qi He
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Yue Yu
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Meng-Le Shao
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Yang Liu
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031
| | - Chen-Guang Bai
- the Department of Pathology, Changhai Hospital, the Second Military Medical University, Shanghai 200433
| | - Zhi-Qiang Ling
- the Department of Pathology, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital and Zhejiang Cancer Center, Hangzhou 310022
| | - Min Li
- the Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Yong Liu
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031,
| | - Jing Fang
- From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030, the Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, and
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Zhang JW, Zhang GX, Chen HL, Liu GL, Owusu L, Wang YX, Wang GY, Xu CM. Therapeutic effect of Qingyi decoction in severe acute pancreatitis-induced intestinal barrier injury. World J Gastroenterol 2015; 21:3537-3546. [PMID: 25834318 PMCID: PMC4375575 DOI: 10.3748/wjg.v21.i12.3537] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/06/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of Qingyi decoction on the expression of secreted phospholipase A2 (sPLA2) in intestinal barrier injury.
METHODS: Fifty healthy Sprague-Dawley rats were randomly divided into control, severe acute pancreatitis (SAP), Qingyi decoction-treated (QYT), dexamethasone-treated (DEX), and verapamil-treated (VER) groups. The SAP model was induced by retrograde infusion of 1.5% sodium deoxycholate into the biliopancreatic duct of the rats. All rats were sacrificed 24 h post-SAP induction. Arterial blood, intestine, and pancreas from each rat were harvested for investigations. The levels of serum amylase (AMY) and diamine oxidase (DAO) were determined using biochemical methods, and serum tumor necrosis factor (TNF)-α level was measured by an enzyme linked immunosorbent assay. Pathologic changes in the harvested tissues were investigated by microscopic examination of hematoxylin and eosin-stained tissue sections. The expressions of sPLA2 at mRNA and protein levels were detected by reverse transcriptase PCR and Western blot, respectively. A terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was used to investigate apoptosis of epithelial cells in the intestinal tissues.
RESULTS: Compared to the control group, the expression of sPLA2 at both the mRNA and protein levels increased significantly in the SAP group (0.36 ± 0.13 vs 0.90 ± 0.38, and 0.16 ± 0.05 vs 0.64 ± 0.05, respectively; Ps < 0.01). The levels of AMY, TNF-α and DAO in serum were also significantly increased (917 ± 62 U/L vs 6870 ± 810 U/L, 59.7 ± 14.3 ng/L vs 180.5 ± 20.1 ng/L, and 10.37 ± 2.44 U/L vs 37.89 ± 5.86 U/L, respectively; Ps < 0.01). The apoptosis index of intestinal epithelial cells also differed significantly between the SAP and control rats (0.05 ± 0.02 vs 0.26 ± 0.06; P < 0.01). The serum levels of DAO and TNF-α, and the intestinal apoptosis index significantly correlated with sPLA2 expression in the intestine (r = 0.895, 0.893 and 0.926, respectively; Ps < 0.05). The levels of sPLA2, AMY, TNF-α, and DAO in the QYT, VER, and DEX groups were all decreased compared with the SAP group, but not the control group. Qingyi decoction intervention, however, gave the most therapeutic effect against intestinal barrier damage, although the onset of its therapeutic effect was slower.
CONCLUSION: Qingyi decoction ameliorates acute pancreatitis-induced intestinal barrier injury by inhibiting the overexpression of intestinal sPLA2. This mechanism may be similar to that of verapamil.
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Tan S, Yu W, Lin Z, Chen Q, Shi J, Dong Y, Duan K, Bai X, Xu L, Yu Z, Li J, Li N. Berberine Ameliorates Intestinal Mucosal Barrier Damage Induced by Peritoneal Air Exposure. Biol Pharm Bull 2015; 38:122-6. [DOI: 10.1248/bpb.b14-00643] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Shanjun Tan
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Wenkui Yu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Zhiliang Lin
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Qiyi Chen
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Jialiang Shi
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Yi Dong
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Kaipeng Duan
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Xiaowu Bai
- Research Institute of General Surgery, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University
| | - Lin Xu
- Research Institute of General Surgery, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University
| | - Zhen Yu
- Department of General Surgery, Shanghai Tenth People’s Hospital Affiliated to Tongji University
| | - Jieshou Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Ning Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
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Abstract
Intestinal mucosal barrier function is the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. The central element is the epithelial layer, which physically separates the lumen and the internal milieu and is in charge of vectorial transport of ions, nutrients, and other substances. The secretion of mucus-forming mucins, sIgA, and antimicrobial peptides reinforces the mucosal barrier on the extraepithelial side, while a variety of immune cells contributes to mucosal defense in the inner side. Thus, the mucosal barrier is of physical, biochemical, and immune nature. In addition, the microbiota may be viewed as part of this system because of the mutual influence occurring between the host and the luminal microorganisms. Alteration of the mucosal barrier function with accompanying increased permeability and/or bacterial translocation has been linked with a variety of conditions, including inflammatory bowel disease. Genetic and environmental factors may converge to evoke a defective function of the barrier, which in turn may lead to overt inflammation of the intestine as a result of an exacerbated immune reaction toward the microbiota. According to this hypothesis, inflammatory bowel disease may be both precipitated and treated by either stimulation or downregulation of the different elements of the mucosal barrier, with the outcome depending on timing, the cell type affected, and other factors. In this review, we cover briefly the elements of the barrier and their involvement in functional defects and the resulting phenotype.
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The effect of peritoneal air exposure on intestinal mucosal barrier. Gastroenterol Res Pract 2014; 2014:674875. [PMID: 25210511 PMCID: PMC4158158 DOI: 10.1155/2014/674875] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 07/17/2014] [Accepted: 08/04/2014] [Indexed: 11/25/2022] Open
Abstract
Background. Damage of the intestinal mucosa barrier may result in intestinal bacterial and endotoxin translocation, leading to local and systemic inflammation. The present study was designed to investigate whether peritoneal air exposure induces damage of intestinal mucosal barrier. Methods. Sprague-Dawley rats (weighing 210 to 230 g) were randomized into five groups (6/group): a control group, a sham group, and three exposure groups with peritoneal air exposure for 1, 2, and 3 h, respectively. At 24 h after surgery, blood and terminal ileum were sampled. The serum D-lactate levels were determined using an ELISA kit. The intestinal permeability was determined by measuring the intestinal clearance of FITC-dextran (FD4). The histopathological changes in terminal ileum were also assessed. Results. Compared with the controls, peritoneal air exposure caused an increase in both serum D-lactate level and intestinal FD4 clearance, which were proportional to the length of peritoneal air exposure and correlated to Chiu's scores, indices for intestinal mucosal injury. Edema and inflammatory cells were also observed in mucosa and submucosa of ileum in three exposure groups. Conclusions. Peritoneal air exposure could induce damage to the intestinal mucosal barrier, which is proportional to the time length of peritoneal air exposure.
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