ISSN 1001-5256
CN 22-1108/R
Issue 8
Aug.  2017
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Effect of trefoil factor 3 on intestinal mucous barrier in rats with nonalcoholic steatohepatitis

DOI: 10.3969/j.issn.1001-5256.2017.08.029
  • Received Date: 2017-02-22
  • Published Date: 2017-08-20
  • Objective To investigate the change in intestinal mucous barrier in rats with nonalcoholic steatohepatitis ( NASH) , the effect of trefoil factor 3 ( TFF3) on intestinal mucous barrier in NASH rats, and the therapeutic effect of TFF3 on NASH. Methods A total of 60 clean male Sprague-Dawley rats were randomly divided into normal group, model group, and treatment group, with 20 rats in each group.The rats in the normal group were given normal diet, and those in the model group and the treatment group were given high-fat diet to induce NASH. The rats in the treatment group were given intraperitoneal injection of rh TFF3 at a dose of 1 ml·kg-1·d-1 ( a concentration of 0. 1 mg/ml) , and those in the normal group and the model group were given normal saline at a dose of 1 ml·kg-1·d-1; the course of treatment was 3 weeks for all groups. At the end of week 15, fluorescein isothiocyanate-labeled dextran was given by gavage to evaluate intestinal permeability, and after the rats were sacrificed, serum levels of aspartate aminotransferase ( AST) , alanine aminotransferase ( ALT) , total cholesterol ( TC) , triglyceride ( TG) , and endotoxin ( ET) and diamine oxidase ( DAO) activity were measured. HE staining was performed to observe the histopathological changes of the liver and the terminal ileum, PAS staining was performed to observe and count the goblet cells of the terminal ileum, immunohistochemistry was used to measure the expression of the tight junction protein Occludin and TFF3 in the terminal ileum, and quantitative real-time PCR was used to measure the mRNA transcription level of TFF3. A one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between any two groups. Results The model group had significant increases in serum levels of AST, ALT, TC, TG, and ET and DAO activity, and the treatment group had significant reductions compared with the model group ( all P < 0. 01) . The model group had a significant increase in NAFLD activity score compared with the normal group ( P < 0. 01) , and the treatment group had significant improvement in liver inflammation and a significant reduction in NAFLD activity score compared with the model group ( P < 0. 01) . The model group had cell necrosis, damage of the intestinal villi, and a significant reduction in goblet cells in the terminal ileum under a light microscope; in the treatment group, damage of the intestinal villi was repaired and there was an increase in goblet cells. The model group had a significant increase in intestinal permeability compared with the normal group, and the treatment group had a significant reduction compared with the model group ( both P < 0. 01) . The model group had a significant reduction in the expression of Occludin and TFF3, and the treatment group had a significant increase compared with the model group ( all P < 0. 01) . The model group had a downregulated TFF3 mRNA transcription level in the terminal ileum compared with the normal group, and the treatment group had an upregulated level compared with the model group ( both P < 0. 01) . Conclusion NASH rats have damaged goblet cells and mucous barrier dysfunction. TFF3 can repair the damaged terminal ileum, promote the regeneration of goblet cells and mucus secretion, restore intestinal barrier function, reduce intestinal permeability, and thus exert its therapeutic effect on NASH.


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  • [1]LOOMBA R, SANYAL AJ.The global NAFLD epidemic[J].Nat Rev Gastroenterol Hepatol, 2013, 10 (11) :686-690.
    [2]HOFFMANN W, JAGLA W, WIEDE A.Molecular medicine of TFF-peptides:from gut to brain[J].Histol Histopathol, 2001, 16 (1) :319-334.
    [3]GE H, GARDNER J, WU X, et al.Trefoil factor 3 (TFF3) is regulated by food intake, improves glucose tolerance and induces mucinous metaplasia[J].PLo S One, 2015, 10 (6) :e0126924.
    [4]GAO F, PAN S, LIU B, et al.TFF3 knockout in human pituitary adenoma cell HP75 facilitates cell apoptosis via mitochondrial pathway[J].Int J Clin Exp Pathol, 2015, 8 (11) :14568-14573.
    [5]ARNOLD P, RICKERT U, HELMERS AK, et al.Trefoil factor 3shows anti-inflammatory effects on activated microglia[J].Cell Tissue Res, 2016, 365 (1) :3-11.
    [6]LAU WH, PANDEY V, KONG X, et al.Trefoil factor-3 (TFF3) stimulates de novo angiogenesis in mammary carcinoma both directly and indirectly via IL-8/CXCR2[J].PLo S One, 2015, 10 (11) :e0141947.
    [7]XU ZJ, FAN JG, WANG GL, et al.Low dose of endotoxin induced acute liver failure in obese rats with nonalcoholic steatohepfitis[J].Chin J Hepatol, 2004, 12 (4) :57-58. (in Chinese) 徐正婕, 范建高, 王国良, 等.小剂量内毒素导致非酒精性脂肪性肝炎大鼠急性肝功能衰竭[J].中华肝脏病杂志, 2004, 12 (4) :57-58.
    [8]LI J, LUO Y, ZHANG R, et al.Neuropeptide trefoil factor 3 reverses depressive-like behaviors by activation of BDNF-ERKCREB signaling in olfactory bulbectomized rats[J].Int J Mol Sci, 2015, 16 (12) :28386-28400.
    [9]SHI L, ZHOU PH, XI JL, et al.Recombinant human trefoil factor3 ameliorates bowel injury:its anti-inflammatory effect on experimental necrotizing enterocolitis[J].Int J Pept, 2014, 2014:634135.
    [10]KWAK DS, LEE OY, LEE KN, et al.The effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model[J].Gut Liver, 2016, 10 (3) :406-411.
    [11] The Chinese National Workshop on Fatty Liver and Alcoholic Liver disease for the Chinese Liver Disease Association.Guidelines for management of nonalcoholic fatty liver disease:an updated and revised edition[J].J Clin Hepatol, 2010, 26 (2) :120-124. (in Chinese) 中华医学会肝病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南 (2010年修订版) [J].临床肝胆病杂志, 2010, 26 (2) :120-124.
    [12]BERGSTROM KS, GUTTMAN JA, RUMI M, et al.Modulation of intestinal goblet cell function during infection by an attaching and effacing bacterial pathogen[J].Infect Immun, 2008, 76 (2) :796-811.
    [13]PAOLELLA G, MANDATO C, PIERRI L, et al.Gut-liver axis and probiotics:their role in non-alcoholic fatty liver disease[J].World J Gastroenterol, 2014, 20 (42) :15518-15531.
    [14]PAGLIALUNGA S, DEHN CA.Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease[J].Lipids Health Dis, 2016, 15 (1) :159.
    [15]WANG B, SONG HY, YANG JR.The progress on the researches of intestinal barrier function changing in patients with liver diseases[J].J Clin Hepatol, 2011, 27 (8) :893-896. (in Chinese) 王波, 宋怀宇, 杨建荣.肝病患者肠道屏障功能变化的研究进展[J].临床肝胆病杂志, 2011, 27 (8) :893-896.
    [16]LI CM, ZHUANG LW.Research progress in role of myosin light chain kinase in pathogenesis of nonalcoholic fatty liver disease[J].J Clin Hepatol, 2015, 31 (7) :1156-1159. (in Chinese) 李春苗, 庄丽维.肌球蛋白轻链激酶在非酒精性脂肪性肝病发病机制中的作用[J].临床肝胆病杂志, 2015, 31 (7) :1156-1159.
    [17]MIELE L, VALENZA V, LA TORRE G, et al.Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease[J].Hepatology, 2009, 49 (6) :1877-1887.
    [18]FRIEDMAN SL.Liver fibrosis in 2012:convergent pathways that cause hepatic fibrosis in NASH[J].Nat Rev Gastroenterol Hepatol, 2013, 10 (2) :71-72.
    [19]ROH YS, SEKI E.Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis[J].J Gastroenterol Hepatol, 2013, 28 (Suppl 1) :38-42.
    [20]HENSEL KO, BOLAND V, POSTBERG J, et al.Differential expression of mucosal trefoil factors and mucins in pediatric inflammatory bowel diseases[J].Sci Rep, 2014, 4:7343.
    [21]RENES IB, VERBURG M, van NISPEN DJ, et al.Distinct epithelial responses in experimental colitis:implications for ion uptake and mucosal protection[J].Am J Physiol Gastrointest Liver Physiol, 2002, 283 (1) :g169-g179.
    [22]JOHANSSON ME, GUSTAFSSON JK, HOLMEN-LARSSON J, et al.Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis[J].Gut, 2014, 63 (2) :281-291.
    [23]ERMUND A, SCHUTTE A, JOHANSSON ME, et al.Studies of mucus in mouse stomach, small intestine, and colon.I.Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches[J].Am J Physiol Gastrointest Liver Physiol, 2013, 305 (5) :g341-g347.
    [24]VAISHNAVA S, YAMAMOTO M, SEVERSON KM, et al.The antibacterial lectin Reg IIIgamma promotes the spatial segregation of microbiota and host in the intestine[J].Science, 2011, 334 (6053) :255-258.
    [25]JOHANSSON ME, LARSSON JM, HANSSON GC.The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions[J].Proc Natl Acad Sci U S A, 2011, 108 (Suppl 1) :4659-4665.
    [26]PENG X, WANG SL, WANG FJ, et al.Effects of different nutrition support route on changes in intestinal mucus components after burn injury[J].Parenter Enteral Nutr, 2001, 8 (3) :157-160. (in Chinese) 彭曦, 汪仕良, 王凤君, 等.不同营养支持途径对严重烧伤后大鼠肠黏液成分的影响[J].肠外与肠内营养, 2001, 8 (3) :157-160.
    [27]LIDELL ME, MONCADA DM, CHADEE K, et al.Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel[J].Proc Natl Acad Sci U S A, 2006, 103 (24) :9298-9303.
    [28]PODOLSKY DK, GERKEN G, EYKING A, et al.Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency[J].Gastroenterology, 2009, 137 (1) :209-220.
    [29]BECK PL, WONG JF, LI Y, et al.Chemotherapy-and radiotherapy-induced intestinal damage is regulated by intestinal trefoil factor[J].Gastroenterology, 2004, 126 (3) :796-808.
    [30]XU LF, TENG X, GUO J, et al.Protective effect of intestinal trefoil factor on injury of intestinal epithelial tight junction induced by platelet activating factor[J].Inflammation, 2012, 35 (1) :308-315.
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