Skip to content
2000
Volume 32, Issue 30
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

The intestinal barrier, a critical component of the body's defense system, plays a vital role in maintaining homeostasis by preventing the translocation of harmful substances from the gut lumen into the bloodstream. Disruptions in this barrier, often characterized by increased intestinal permeability, are increasingly recognized as contributors to the development and progression of various Chronic Inflammatory Disorders (CIDs). Zonulin, a key regulator of intestinal Tight Junctions (TJs), has emerged as a pivotal player in this process. Dysregulation of zonulin, leading to increased intestinal permeability, has been implicated in the pathogenesis of a wide range of CIDs, including Inflammatory Bowel Disease (IBD), celiac disease, and Multiple Sclerosis (MS). This review examines the intricate relationship between zonulin and intestinal permeability, emphasizing its role in regulating TJ integrity and its association with various CIDs. Recent research has demonstrated the therapeutic potential of targeting zonulin, specifically through the use of larazotide acetate, a zonulin antagonist. Preclinical and clinical studies have shown promising results in improving gut barrier integrity and reducing inflammation in patients with CIDs. These findings underscore the significance of zonulin as a potential biomarker for intestinal barrier function and a promising therapeutic target for managing CIDs. Further research is needed to elucidate the precise mechanisms of action of zonulin antagonists and evaluate their efficacy and safety in clinical trials. A deeper understanding of the complex interplay among zonulin, intestinal permeability, and CIDs is crucial, paving the way for novel therapeutic strategies and personalized approaches to patient care.

Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673335863240829060545
2024-09-06
2025-09-29
Loading full text...

Full text loading...

References

  1. SoderholmA.T. PedicordV.A. Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity.Immunology2019158426728010.1111/imm.1311731509239
    [Google Scholar]
  2. BaumgartD.C. DignassA.U. Intestinal barrier function.Curr. Opin. Clin. Nutr. Metab. Care20025668569410.1097/00075197‑200211000‑0001212394645
    [Google Scholar]
  3. VancamelbekeM. VermeireS. The intestinal barrier: a fundamental role in health and disease.Expert Rev. Gastroenterol. Hepatol.201711982183410.1080/17474124.2017.134314328650209
    [Google Scholar]
  4. CamilleriM. MadsenK. SpillerR. Van MeerveldB.G. VerneG.N. Intestinal barrier function in health and gastrointestinal disease.Neurogastroenterol. Motil.201224650351210.1111/j.1365‑2982.2012.01921.x
    [Google Scholar]
  5. GroschwitzK.R. HoganS.P. Intestinal barrier function: Molecular regulation and disease pathogenesis.J. Allergy Clin. Immunol.2009124132010.1016/j.jaci.2009.05.03819560575
    [Google Scholar]
  6. MatterK. BaldaM.S. Signalling to and from tight junctions.Nat. Rev. Mol. Cell Biol.20034322523710.1038/nrm105512612641
    [Google Scholar]
  7. OtaniT. FuruseM. Tight junction structure and function revisited.Trends Cell Biol.2020301080581710.1016/j.tcb.2020.08.00432891490
    [Google Scholar]
  8. GasbarriniG. MontaltoM. Structure and function of tight junctions. Role in intestinal barrier.Ital. J. Gastroenterol. Hepatol.199931648148810575567
    [Google Scholar]
  9. SturgeonC. FasanoA. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases.Tissue Barriers201644e125138410.1080/21688370.2016.125138428123927
    [Google Scholar]
  10. CapaldoC.T. PowellD.N. KalmanD. Layered defense: how mucus and tight junctions seal the intestinal barrier.J. Mol. Med. (Berl.)201795992793410.1007/s00109‑017‑1557‑x28707083
    [Google Scholar]
  11. FasanoA. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications.Clin. Gastroenterol. Hepatol.201210101096110010.1016/j.cgh.2012.08.01222902773
    [Google Scholar]
  12. WangW. UzzauS. GoldblumS.E. FasanoA. Human zonulin, a potential modulator of intestinal tight junctions.J. Cell Sci.2000113244435444010.1242/jcs.113.24.443511082037
    [Google Scholar]
  13. FasanoA. BaudryB. PumplinD.W. WassermanS.S. TallB.D. KetleyJ.M. KaperJ.B. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions.Proc. Natl. Acad. Sci. USA199188125242524610.1073/pnas.88.12.52422052603
    [Google Scholar]
  14. TripathiA. LammersK.M. GoldblumS. Shea-DonohueT. Netzel-ArnettS. BuzzaM.S. AntalisT.M. VogelS.N. ZhaoA. YangS. ArriettaM.C. MeddingsJ.B. FasanoA. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2.Proc. Natl. Acad. Sci. USA200910639167991680410.1073/pnas.090677310619805376
    [Google Scholar]
  15. DelangheJ.R. DelrueC. SpeeckaertR. SpeeckaertM.M. Unlocking the link between haptoglobin polymorphism and noninfectious human diseases: insights and implications.Crit. Rev. Clin. Lab. Sci.202461427529710.1080/10408363.2023.228592938013410
    [Google Scholar]
  16. LangloisM.R. DelangheJ.R. Biological and clinical significance of haptoglobin polymorphism in humans.Clin. Chem.199642101589160010.1093/clinchem/42.10.15898855140
    [Google Scholar]
  17. GutteridgeJ.M.C. The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation.Biochim. Biophys. Acta Lipids Lipid Metab.1987917221922310.1016/0005‑2760(87)90125‑12879568
    [Google Scholar]
  18. GaliciaG. MaesW. VerbinnenB. KasranA. BullensD. ArredouaniM. CeuppensJ.L. Haptoglobin deficiency facilitates the development of autoimmune inflammation.Eur. J. Immunol.200939123404341210.1002/eji.20093929119795414
    [Google Scholar]
  19. Van VlierbergheH. LangloisM. DelangheJ. Haptoglobin polymorphisms and iron homeostasis in health and in disease.Clin. Chim. Acta20043451-2354210.1016/j.cccn.2004.03.01615193975
    [Google Scholar]
  20. ArredouaniM.S. KasranA. VanoirbeekJ.A. BergerF.G. BaumannH. CeuppensJ.L. Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo.Immunology2005114226327110.1111/j.1365‑2567.2004.02071.x15667571
    [Google Scholar]
  21. Di PierroM. LuR. UzzauS. WangW. MargarettenK. PazzaniC. MaimoneF. FasanoA. Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain.J. Biol. Chem.200127622191601916510.1074/jbc.M00967420011278543
    [Google Scholar]
  22. ValituttiF. FasanoA. Breaking down barriers: how understanding celiac disease pathogenesis informed the development of novel treatments.Dig. Dis. Sci.20196471748175810.1007/s10620‑019‑05646‑y31076989
    [Google Scholar]
  23. Wood HeickmanL.K. DeBoerM.D. FasanoA. Zonulin as a potential putative biomarker of risk for shared type 1 diabetes and celiac disease autoimmunity.Diabetes Metab. Res. Rev.2020365e330910.1002/dmrr.330932162764
    [Google Scholar]
  24. LammersK.M. LuR. BrownleyJ. LuB. GerardC. ThomasK. RallabhandiP. Shea-DonohueT. TamizA. AlkanS. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.Gastroenterology200813519420410.1053/j.gastro.2008.03.023
    [Google Scholar]
  25. ClementeM.G. De VirgiliisS. KangJ.S. MacatagneyR. MusuM.P. Di PierroM.R. DragoS. CongiaM. FasanoA. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function.Gut200352221822310.1136/gut.52.2.21812524403
    [Google Scholar]
  26. FasanoA. Shea-DonohueT. Mechanisms of Disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases.Nat. Clin. Pract. Gastroenterol. Hepatol.20052941642210.1038/ncpgasthep025916265432
    [Google Scholar]
  27. SturgeonC. LanJ. FasanoA. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model.Ann. N. Y. Acad. Sci.20171397113014210.1111/nyas.1334328423466
    [Google Scholar]
  28. AnJ. LiuY. WangY. FanR. HuX. ZhangF. YangJ. ChenJ. The role of intestinal mucosal barrier in autoimmune disease: a potential target.Front. Immunol.20221387171310.3389/fimmu.2022.87171335844539
    [Google Scholar]
  29. CenacN. ChinA.C. Garcia-VillarR. Salvador-CartierC. FerrierL. VergnolleN. BuretA.G. FioramontiJ. BuenoL. PAR2 activation alters colonic paracellular permeability in mice via IFN-γ-dependent and -independent pathways.J. Physiol.2004558391392510.1113/jphysiol.2004.06172115194744
    [Google Scholar]
  30. FasanoA. FiorentiniC. DonelliG. UzzauS. KaperJ.B. MargarettenK. DingX. GuandaliniS. ComstockL. GoldblumS.E. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro.J. Clin. Invest.199596271072010.1172/JCI1181147635964
    [Google Scholar]
  31. SliferZ.M. KrishnanB.R. MadanJ. BlikslagerA.T. Larazotide acetate: a pharmacological peptide approach to tight junction regulation.Am. J. Physiol. Gastrointest. Liver Physiol.20213206G983G98910.1152/ajpgi.00386.202033881350
    [Google Scholar]
  32. CharmotD. Non-systemic drugs: a critical review.Curr. Pharm. Des.201218101434144510.2174/13816121279950485822300258
    [Google Scholar]
  33. KhaleghiS. JuJ.M. LambaA. MurrayJ.A. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate.Therap. Adv. Gastroenterol.201691374910.1177/1756283X1561657626770266
    [Google Scholar]
  34. LefflerD.A. KellyC.P. GreenP.H. FedorakR.N. DiMarinoA. PerrowW. RasmussenH. WangC. BercikP. BachirN.M. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial.Gastroenterology20151481311131910.1053/j.gastro.2015.02.008
    [Google Scholar]
  35. LefflerDA. KellyCP. AbdallahH. ColatrellaA. HarrisL. LeonF. ArterburnL. PatersonB. LanZ. MurrayJ. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.Off. J. Am. Coll. Gastroenterol.20121071554156210.1038/ajg.2012.211
    [Google Scholar]
  36. KellyC.P. GreenP.H.R. MurrayJ.A. DiMarinoA. ColatrellaA. LefflerD.A. AlexanderT. ArsenescuR. LeonF. JiangJ.G. ArterburnL.A. PatersonB.M. FedorakR.N. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo- controlled study.Aliment. Pharmacol. Ther.201337225226210.1111/apt.1214723163616
    [Google Scholar]
  37. SerekP. Oleksy-WawrzyniakM. The effect of bacterial infections, probiotics and zonulin on intestinal barrier integrity.Int. J. Mol. Sci.202122211135910.3390/ijms22211135934768787
    [Google Scholar]
  38. TarkoA. SuchojadA. MichalecM. MajcherczykM. BrzozowskaA. Maruniak-ChudekI. Zonulin: A potential marker of intestine injury in newborns.Disease Mark.20172017241343710.1155/2017/2413437
    [Google Scholar]
  39. MörklS. LacknerS. MeinitzerA. ManggeH. LehoferM. HalwachsB. GorkiewiczG. KashoferK. PainoldA. HollA.K. BengesserS.A. MüllerW. HolzerP. HolasekS.J. Gut microbiota, dietary intakes and intestinal permeability reflected by serum zonulin in women.Eur. J. Nutr.20185782985299710.1007/s00394‑018‑1784‑030043185
    [Google Scholar]
  40. LiuZ. LiN. NeuJ. Tight junctions, leaky intestines, and pediatric diseases.Acta Paediatr.200594438639310.1111/j.1651‑2227.2005.tb01904.x16092447
    [Google Scholar]
  41. ClementeM.G. MusuM. TronconeR. VoltaU. CongiaM. CiacciC. NeriE. NotT. MaggioreG. StrisciuglioP. Enterocyte actin autoantibody detection: a new diagnostic tool in celiac disease diagnosis: results of a multicenter study.Off. J. Am. Coll. Gastroenterol.2004991551155610.1111/j.1572‑0241.2004.30296.x
    [Google Scholar]
  42. FasanoA. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall.Am. J. Pathol.200817351243125210.2353/ajpath.2008.08019218832585
    [Google Scholar]
  43. SmecuolE. SugaiE. NiveloniS. VázquezH. PedreiraS. MazureR. MorenoM.L. LabelM. MauriñoE. FasanoA. MeddingsJ. BaiJ.C. Permeability, zonulin production, and enteropathy in dermatitis herpetiformis.Clin. Gastroenterol. Hepatol.20053433534110.1016/S1542‑3565(04)00778‑515822038
    [Google Scholar]
  44. Moreno-NavarreteJ.M. SabaterM. OrtegaF. RicartW. Fernández-RealJ.M. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance.PLoS One201275e3716010.1371/journal.pone.003716022629362
    [Google Scholar]
  45. Żak-GołąbA. KocełakP. AptekorzM. ZientaraM. JuszczykŁ. MartirosianG. ChudekJ. Olszanecka-GlinianowiczM. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects.Int. J. Endocrinol.20131p. 674106
    [Google Scholar]
  46. Díaz-CoránguezM. SegoviaJ. López-OrnelasA. Puerta-GuardoH. LudertJ. ChávezB. Meraz-CruzN. González-MariscalL. Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.PLoS One201384e6065510.1371/journal.pone.006065523637756
    [Google Scholar]
  47. SkardellyM. ArmbrusterF.P. MeixensbergerJ. HilbigH. Expression of zonulin, c-kit, and glial fibrillary acidic protein in human gliomas.Transl. Oncol.20092311712010.1593/tlo.0911519701495
    [Google Scholar]
  48. Camara-LemarroyC.R. MetzL. MeddingsJ.B. SharkeyK.A. Wee YongV. The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics.Brain201814171900191610.1093/brain/awy13129860380
    [Google Scholar]
  49. LeeA.S. GibsonD.L. ZhangY. ShamH.P. VallanceB.A. DutzJ.P. Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice.Diabetologia201053474174810.1007/s00125‑009‑1626‑y20012858
    [Google Scholar]
  50. SaponeA. de MagistrisL. PietzakM. ClementeM.G. TripathiA. CuccaF. LampisR. KryszakD. CartenìM. GenerosoM. IafuscoD. PriscoF. LaghiF. RieglerG. CarratuR. CountsD. FasanoA. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.Diabetes20065551443144910.2337/db05‑159316644703
    [Google Scholar]
  51. NouriM. BredbergA. WeströmB. LavasaniS. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells.PLoS One201499e10633510.1371/journal.pone.010633525184418
    [Google Scholar]
  52. SecherT. KassemS. BenamarM. BernardI. BouryM. BarreauF. OswaldE. SaoudiA. Oral administration of the probiotic strain Escherichia coli Nissle 1917 reduces susceptibility to neuroinflammation and repairs experimental autoimmune encephalomyelitis-induced intestinal barrier dysfunction.Front. Immunol.20178109610.3389/fimmu.2017.0109628959254
    [Google Scholar]
  53. ParodiB. Kerlero de RosboN. The gut-brain axis in multiple sclerosis. Is its dysfunction a pathological trigger or a consequence of the disease?Front. Immunol.20211271822010.3389/fimmu.2021.71822034621267
    [Google Scholar]
  54. Ramírez-SánchezA.D. TanI.L. Gonera-de JongB.C. VisschedijkM.C. JonkersI. WithoffS. Molecular biomarkers for celiac disease: past, present and future.Int. J. Mol. Sci.20202122852810.3390/ijms2122852833198309
    [Google Scholar]
  55. SchefflerL. CraneA. HeyneH. TönjesA. SchleinitzD. IhlingC.H. StumvollM. FreireR. FiorentinoM. FasanoA. KovacsP. HeikerJ.T. Widely used commercial ELISA does not detect precursor of haptoglobin2, but recognizes properdin as a potential second member of the zonulin family.Front. Endocrinol. (Lausanne)201892210.3389/fendo.2018.0002229459849
    [Google Scholar]
  56. NeurathM.F. Cytokines in inflammatory bowel disease.Nat. Rev. Immunol.201414532934210.1038/nri366124751956
    [Google Scholar]
  57. HattonG.B. MadlaC.M. RabbieS.C. BasitA.W. All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance.Int. J. Pharm.2018548140842210.1016/j.ijpharm.2018.06.05429969711
    [Google Scholar]
  58. BuhnerS. BuningC. GenschelJ. KlingK. HerrmannD. DignassA. KuechlerI. KruegerS. SchmidtH.H. LochsH. Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation?Gut200655334234710.1136/gut.2005.06555716000642
    [Google Scholar]
  59. FasanoA. Pathological and therapeutical implications of macromolecule passage through the tight junction.Tight JunctionsCRC Press2001715740
    [Google Scholar]
  60. TurnerJ.R. Intestinal mucosal barrier function in health and disease.Nat. Rev. Immunol.200991179980910.1038/nri265319855405
    [Google Scholar]
  61. WeberC.R. TurnerJ.R. Inflammatory bowel disease: is it really just another break in the wall?Gut20075616810.1136/gut.2006.10418217172583
    [Google Scholar]
  62. LacombeL.A.C. MatiolloC. RosaJ.S. FelisbertoM. DalmarcoE.M. SchiavonL.L. ROSA J.s.d, Felisberto M, Dalmarco EM, SCHIAVON L.D.L: Factors associated with circulating zonulin in inflammatory bowel disease.Arq. Gastroenterol.202259223824310.1590/s0004‑2803.202202000‑4335830035
    [Google Scholar]
  63. ArrietaM.C. MadsenK. DoyleJ. MeddingsJ. Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse.Gut2009581414810.1136/gut.2008.15088818829978
    [Google Scholar]
  64. WattsT. BertiI. SaponeA. GerarduzziT. NotT. ZielkeR. FasanoA. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.Proc. Natl. Acad. Sci. USA200510282916292110.1073/pnas.050017810215710870
    [Google Scholar]
  65. KhusainovaG. GenkelV. KuznetsovaA. NikushkinaK. SaenkoA. AbramovskikhO. DolgushinaA. The relationship between serum zonulin and innate immunity in patients with inflammatory bowel disease.Gastroenterol. Insights202415117919010.3390/gastroent15010013
    [Google Scholar]
  66. IordacheM.M. TociaC. AschieM. DumitruA. ManeaM. CozaruG.C. PetcuL. VladS.E. DumitruE. ChisoiA. Intestinal permeability and depression in patients with inflammatory bowel disease.J. Clin. Med.20221117512110.3390/jcm1117512136079050
    [Google Scholar]
  67. MalíčkováK. FrancováI. LukášM. KolářM. KrálíkováE. BortlíkM. ĎuricováD. ŠtěpánkováL. ZvolskáK. PánkováA. ZimaT. Fecal zonulin is elevated in Crohn’s disease and in cigarette smokers.Pract. Lab. Med.20179394410.1016/j.plabm.2017.09.00129034305
    [Google Scholar]
  68. RodrigoL. Celiac disease. World. J. gastroenterol.WJG2006126577
    [Google Scholar]
  69. JamesM.W. ScottB.B. Coeliac disease: the cause of the various associated disorders?Eur. J. Gastroenterol. Hepatol.20011391119112110.1097/00042737‑200109000‑0002211564967
    [Google Scholar]
  70. GreenP.H.R. CellierC. Celiac disease.N. Engl. J. Med.2007357171731174310.1056/NEJMra07160017960014
    [Google Scholar]
  71. PlengeR.M. Unlocking the pathogenesis of celiac disease.Nat. Genet.201042428128210.1038/ng0410‑28120348961
    [Google Scholar]
  72. FasanoA. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases.F1000 Res.202096910.12688/f1000research.20510.132051759
    [Google Scholar]
  73. ThomasK.E. SaponeA. FasanoA. VogelS.N. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease.J. Immunol.200617642512252110.4049/jimmunol.176.4.251216456012
    [Google Scholar]
  74. ZuffereyC. ErhartD. SaurerL. MuellerC. Production of interferon-γ by activated T-cell receptor-αβ CD8αβ intestinal intraepithelial lymphocytes is required and sufficient for disruption of the intestinal barrier integrity.Immunology2009128335135910.1111/j.1365‑2567.2009.03110.x20067535
    [Google Scholar]
  75. FasanoA. NotT. WangW. UzzauS. BertiI. TommasiniA. GoldblumS.E. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease.Lancet200035592141518151910.1016/S0140‑6736(00)02169‑310801176
    [Google Scholar]
  76. AsmarR.E. PanigrahiP. BamfordP. BertiI. NotT. CoppaG.V. CatassiC. FasanoA. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure.Gastroenterology200212351607161510.1053/gast.2002.3657812404235
    [Google Scholar]
  77. DragoS. El AsmarR. Di PierroM. Grazia ClementeM. SaponeA.T.A. ThakarM. IaconoG. CarroccioA. D’AgateC. NotT. ZampiniL. CatassiC. FasanoA. FasanoA. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines.Scand. J. Gastroenterol.200641440841910.1080/0036552050023533416635908
    [Google Scholar]
  78. GopalakrishnanS. TripathiA. TamizA.P. AlkanS.S. PandeyN.B. Larazotide acetate promotes tight junction assembly in epithelial cells.Peptides20123519510110.1016/j.peptides.2012.02.01622401910
    [Google Scholar]
  79. GopalakrishnanS. DuraiM. KitchensK. TamizA.P. SomervilleR. GinskiM. PatersonB.M. MurrayJ.A. VerduE.F. AlkanS.S. PandeyN.B. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo.Peptides2012351869410.1016/j.peptides.2012.02.01522401908
    [Google Scholar]
  80. JuJ.M. MariettaE.V. MurrayJ.A. Generating transgenic mouse models for studying celiac disease.Methods Mol Biol.20151326233310.1007/978‑1‑4939‑2839‑2_3
    [Google Scholar]
  81. HoilatG.J. AltowairqiA.K. AyasM.F. AlhaddabN.T. AlnujaidiR.A. AlharbiH.A. AlyahyawiN. KamalA. AlhabeebH. AlbazeeE. AlmustanyirS. Abu-ZaidA. Larazotide acetate for treatment of celiac disease: A systematic review and meta-analysis of randomized controlled trials.Clin. Res. Hepatol. Gastroenterol.202246110178210.1016/j.clinre.2021.10178234339872
    [Google Scholar]
  82. DiMeglioL.A. Evans-MolinaC. OramR.A. Type 1 diabetes.Lancet2018391101382449246210.1016/S0140‑6736(18)31320‑529916386
    [Google Scholar]
  83. Gutierrez-AchuryJ. RomanosJ. BakkerS.F. KumarV. de HaasE.C. TrynkaG. Ricaño-PonceI. SteckA. ChenW.M. Onengut-GumuscuS. SimsekS. RewersM. MulderC.J. LiuE. RichS.S. WijmengaC. Type 1 Diabetes Genetics Consortium Diabeter Contrasting the genetic background of type 1 diabetes and celiac disease autoimmunity.Diabetes Care201538Suppl 2Suppl. 2S37S4410.2337/dcs15‑200726405070
    [Google Scholar]
  84. SavilahtiE. ÖrmäläT. SaukkonenT. Sandini-PohjavuoriU. KanteleJ.M. AratoA. IlonenJ. ÅkerblomH.K. Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation.Clin. Exp. Immunol.20011161707710.1046/j.1365‑2249.1999.00860.x10209507
    [Google Scholar]
  85. SchmidS. KoczwaraK. SchwinghammerS. LampasonaV. ZieglerA.G. BonifacioE. Delayed exposure to wheat and barley proteins reduces diabetes incidence in non-obese diabetic mice.Clin. Immunol.2004111110811810.1016/j.clim.2003.09.01215093559
    [Google Scholar]
  86. De MagistrisL. SecondulfoM. IafuscoD. CarboneA.G. UrioA. PontoniG. CarratuR. Altered mannitol absorption in diabetic children.Ital. J. Gastroenterol.19962863673678891852
    [Google Scholar]
  87. FundaD.P. KaasA. Tlaskalová-HogenováH. BuschardK. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes.Diabetes Metab. Res. Rev.2008241596310.1002/dmrr.74817607660
    [Google Scholar]
  88. VisserJ.T.J. LammersK. HoogendijkA. BoerM.W. BrugmanS. Beijer-LiefersS. ZandvoortA. HarmsenH. WellingG. StellaardF. BosN.A. FasanoA. RozingJ. Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.Diabetologia201053122621262810.1007/s00125‑010‑1903‑920853098
    [Google Scholar]
  89. SimpsonM. MojibianM. BarrigaK. ScottF.W. FasanoA. RewersM. NorrisJ.M. An exploration of Glo-3A antibody levels in children at increased risk for type 1 diabetes mellitus.Pediatr. Diabetes200910856357210.1111/j.1399‑5448.2009.00541.x19622083
    [Google Scholar]
  90. Mohammadi-KordkhayliM. SahraianM.A. GhorbaniS. MansouriF. TalebiF. NoorbakhshF. Saboor- YaraghiA.A. Vitamins A and D enhance the expression of ror-γ-targeting miRNAs in a mouse model of multiple sclerosis.Mol. Neurobiol.202360105853586510.1007/s12035‑023‑03427‑337353624
    [Google Scholar]
  91. Mohammadi KordkhayliM. MansouriF. TalebiF. NoorbakhshF. Saboor-YaraghiA.A. Influence of vitamins A and D on the expression of MicroRNA27-3p isoforms and GATA3 in experimental autoimmune encephalomyelitis.Iran. J. Allergy Asthma Immunol.202221442944010.18502/ijaai.v21i4.1029036243931
    [Google Scholar]
  92. Ahangar-ParvinR. Mohammadi-KordkhayliM. AziziS.V. NematiM. KhorramdelazadH. TaghipourZ. HassanZ. MoazzeniS.M. JafarzadehA. The modulatory effects of vitamin D on the expression of IL-12 and TGF-β in the spinal cord and serum of mice with experimental autoimmune encephalomyelitis.Iran. J. Pathol.2018131102210.30699/ijp.13.1.1029731791
    [Google Scholar]
  93. JafarzadehA. Ahangar-ParvinR. AziziS. AyobiF. TaghipourZ. ShamsizadehA. GoujaniR. NematiM. MoazeniM. Evaluation of the effect of vitamin D3 and ginger extract on the clinical symptoms and the severity of inflammation in EAE.Majallah-i Ilmi-i Danishgah-i Ulum-i Pizishki-i Rafsanjan201513683694
    [Google Scholar]
  94. AlkhawajahM.M. CamineroA.B. FreemanH.J. OgerJ.J.F. Multiple sclerosis and inflammatory bowel diseases: what we know and what we would need to know!Mult. Scler.201319325926510.1177/135245851246139323027881
    [Google Scholar]
  95. ZéphirH. Gower-RousseauC. SalleronJ. SimonO. DebouverieM. Le PageE. BouhnikY. Lebrun-FrenayC. PapeixC. VigneronB. AllezM. PrinL. CosnesJ. VermerschP. ColombelJ.F. Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease.Mult. Scler.20142081135113910.1177/135245851351508124326672
    [Google Scholar]
  96. BuscarinuM.C. RomanoS. MechelliR. Pizzolato UmetonR. FerraldeschiM. FornasieroA. RenièR. CerasoliB. MorenaE. RomanoC. LoizzoN.D. UmetonR. SalvettiM. RistoriG. Intestinal permeability in relapsing-remitting multiple sclerosis.Neurotherapeutics2018151687410.1007/s13311‑017‑0582‑329119385
    [Google Scholar]
  97. FasanoA. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.Physiol. Rev.201191115117510.1152/physrev.00003.200821248165
    [Google Scholar]
  98. FasanoA. Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin.Ann. N. Y. Acad. Sci.2000915121422210.1111/j.1749‑6632.2000.tb05244.x11193578
    [Google Scholar]
  99. MirzaA. Mao-DraayerY. The gut microbiome and microbial translocation in multiple sclerosis.Clin. Immunol.201718321322410.1016/j.clim.2017.03.00128286112
    [Google Scholar]
  100. AntoniniM. Lo ConteM. SoriniC. FalconeM. How the interplay between the commensal microbiota, gut barrier integrity, and mucosal immunity regulates brain autoimmunity.Front. Immunol.201910193710.3389/fimmu.2019.0193731475000
    [Google Scholar]
  101. YacyshynB. MeddingsJ. SadowskiD. Bowen-YacyshynM.B. Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability.Dig. Dis. Sci.199641122493249810.1007/BF021001489011463
    [Google Scholar]
  102. CicciaF. GugginoG. RizzoA. AlessandroR. LuchettiM.M. MillingS. SaievaL. CypersH. StamponeT. Di BenedettoP. GabrielliA. FasanoA. ElewautD. TrioloG. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis.Ann. Rheum. Dis.20177661123113210.1136/annrheumdis‑2016‑21000028069576
    [Google Scholar]
  103. WangC.R. WengC.T. LeeC.T. HuangK.Y. HsuS.M. LiuM.F. Rare occurrence of inflammatory bowel disease in a cohort of Han Chinese ankylosing spondylitis patients- a single institute study.Sci. Rep.2017711316510.1038/s41598‑017‑13573‑z29030592
    [Google Scholar]
  104. McInnesI.B. SchettG. The pathogenesis of rheumatoid arthritis.N. Engl. J. Med.2011365232205221910.1056/NEJMra100496522150039
    [Google Scholar]
  105. FiresteinG.S. Evolving concepts of rheumatoid arthritis.Nature2003423693735636110.1038/nature0166112748655
    [Google Scholar]
  106. FiresteinG.S. Etiology and pathogenesis of rheumatoid arthritis.Textbook. Rheumatol.20011851897
    [Google Scholar]
  107. TajikN. FrechM. SchulzO. SchälterF. LucasS. AzizovV. DürholzK. SteffenF. OmataY. RingsA. BertogM. RizzoA. IljazovicA. BasicM. KleyerA. CulemannS. KrönkeG. LuoY. ÜberlaK. GaiplU.S. FreyB. StrowigT. SarterK. BischoffS.C. WirtzS. CañeteJ.D. CicciaF. SchettG. ZaissM.M. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat. Commun.2020111199510.1038/s41467‑020‑15831‑732332732
    [Google Scholar]
  108. Wölfel, R.; Corman, V.; Guggemos, W.; Seilmaier, M.; Zange, S.; Müller, M. Virological assessment of hospitalized patients with COVID, 2020, 581(7809), 465-469.
  109. HendersonL.A. CannaS.W. SchulertG.S. VolpiS. LeeP.Y. KernanK.F. CaricchioR. MahmudS. HazenM.M. HalyabarO. HoytK.J. HanJ. GromA.A. GattornoM. RavelliA. De BenedettiF. BehrensE.M. CronR.Q. NigrovicP.A. On the alert for cytokine storm: immunopathology in COVID-19.Arthritis Rheumatol.20207271059106310.1002/art.4128532293098
    [Google Scholar]
  110. Ratnikova, A.K.; Grinevich, V.B.; Ratnikov, V.A.; Kozlov, K.V.; Gorelov V.P.; Kravchuk, Y.A. Significance of indicators of intestinal permeability, the state of the microbiota in the development of gastroenterological manifestations in the treatment of patients with a new coronavirus infection (COVID-19)., 2022, 33(1), 80-8.
  111. CrawfordM.S. NordgrenT.M. McColeD.F. Every breath you take: Impacts of environmental dust exposure on intestinal barrier function–from the gut-lung axis to COVID-19.Am. J. Physiol. Gastrointest. Liver Physiol.20213204G586G60010.1152/ajpgi.00423.202033501887
    [Google Scholar]
  112. LiuT. ZhangJ. YangY. MaH. LiZ. ZhangJ. ChengJ. ZhangX. ZhaoY. XiaZ. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019.MedRxiv 20029769202010.1101/2020.03.01.20029769
    [Google Scholar]
  113. YonkerL.M. GilboaT. OgataA.F. SenussiY. LazarovitsR. BoribongB.P. BartschY.C. LoiselleM. RivasM.N. PorrittR.A. LimaR. DavisJ.P. FarkasE.J. BurnsM.D. YoungN. MahajanV.S. HajizadehS. LopezX.I.H. KreuzerJ. MorrisR. MartinezE.E. HanI. GriswoldK.Jr BarryN.C. ThompsonD.B. ChurchG. EdlowA.G. HaasW. PillaiS. ArditiM. AlterG. WaltD.R. FasanoA. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.J. Clin. Invest.202113114e14963310.1172/JCI14963334032635
    [Google Scholar]
  114. OkuyucuM. Yalcin KehribarD. ÇaprazM. ÇaprazA. ArslanM. ÇelikZ.B. UstaB. BirinciA. OzgenM. The relationship between COVID-19 disease severity and zonulin levels.Cureus2022148e2825510.7759/cureus.2825536158380
    [Google Scholar]
  115. DeeksS.G. TracyR. DouekD.C. Systemic effects of inflammation on health during chronic HIV infection.Immunity201339463364510.1016/j.immuni.2013.10.00124138880
    [Google Scholar]
  116. SandlerN.G. WandH. RoqueA. LawM. NasonM.C. NixonD.E. PedersenC. RuxrungthamK. LewinS.R. EmeryS. NeatonJ.D. BrenchleyJ.M. DeeksS.G. SeretiI. DouekD.C. INSIGHT SMART Study Group Plasma levels of soluble CD14 independently predict mortality in HIV infection.J. Infect. Dis.2011203678079010.1093/infdis/jiq11821252259
    [Google Scholar]
  117. BawahA. YakubuY. NangaS. The relationship between zonulin and liver function test in patients with human immune deficiency virus infection.J. Lab. Sci. Techno. South Africa202137176
    [Google Scholar]
  118. HuntP.W. SinclairE. RodriguezB. ShiveC. ClagettB. FunderburgN. RobinsonJ. HuangY. EplingL. MartinJ.N. DeeksS.G. MeinertC.L. Van NattaM.L. JabsD.A. LedermanM.M. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.J. Infect. Dis.201421081228123810.1093/infdis/jiu23824755434
    [Google Scholar]
  119. Serrano-VillarS. SainzT. MaZ.M. UtayN.S. Wook-ChunT. MannS. KashubaA.D. SieweB. AlbaneseA. Troia-CancioP. SinclairE. SomasunderamA. YotterT. DeeksS.G. LandayA. PollardR.B. MillerC.J. MorenoS. AsmuthD.M. Effects of combined CCR5/integrase inhibitors-based regimen on mucosal immunity in HIV-infected patients naïve to antiretroviral therapy: a pilot randomized trial.PLoS Pathog.2016121e100538110.1371/journal.ppat.100538126795282
    [Google Scholar]
  120. YosephB.P. KlingensmithN.J. LiangZ. BreedE.R. BurdE.M. MittalR. DominguezJ.A. PetrieB. FordM.L. CoopersmithC.M. Mechanisms of intestinal barrier dysfunction in sepsis.Shock2016461525910.1097/SHK.000000000000056527299587
    [Google Scholar]
  121. KlausD.A. MotalM.C. Burger-KleppU. MarschalekC. SchmidtE.M. Lebherz-EichingerD. KrennC.G. RothG.A. Increased plasma zonulin in patients with sepsis.Biochem. Med. (Zagreb)201323110711110.11613/BM.2013.01323457771
    [Google Scholar]
  122. LiuZ. LiC. HuangM. TongC. ZhangX. WangL. PengH. LanP. ZhangP. HuangN. PengJ. WuX. LuoY. QinH. KangL. WangJ. Positive regulatory effects of perioperative probiotic treatment on postoperative liver complications after colorectal liver metastases surgery: a double-center and double-blind randomized clinical trial.BMC Gastroenterol.20151513410.1186/s12876‑015‑0260‑z25881090
    [Google Scholar]
  123. FerrarisR.P. VinnakotaR.R. Intestinal nutrient transport in genetically obese mice.Am. J. Clin. Nutr.199562354054610.1093/ajcn/62.3.5407661115
    [Google Scholar]
  124. ZhangD. ZhangL. ZhengY. YueF. RussellR.D. ZengY. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients.Diabetes Res. Clin. Pract.2014106231231810.1016/j.diabres.2014.08.01725238913
    [Google Scholar]
  125. KümeT. AcarS. TuhanH. ÇatlıG. AnıkA. Gürsoy ÇalanÖ. BöberE. AbacıA. The relationship between serum zonulin level and clinical and laboratory parameters of childhood obesity.J. Clin. Res. Pediatr. Endocrinol.201791313810.4274/jcrpe.368228008865
    [Google Scholar]
  126. AasbrennM. LydersenS. FarupP.G. Changes in serum zonulin in individuals with morbid obesity after weight-loss interventions: a prospective cohort study.BMC Endocr. Disord.202020110810.1186/s12902‑020‑00594‑532698783
    [Google Scholar]
  127. RainoneV. SchneiderL. SaulleI. RicciC. BiasinM. Al-DaghriN.M. GianiE. ZuccottiG.V. ClericiM. TrabattoniD. Upregulation of inflammasome activity and increased gut permeability are associated with obesity in children and adolescents.Int. J. Obes.20164061026103310.1038/ijo.2016.2626876434
    [Google Scholar]
  128. OlivieriF. MaguoloA. CorradiM. ZusiC. HuberV. FornariE. MorandiA. MaffeisC. Serum zonulin as an index of glucose dysregulation in children and adolescents with overweight and obesity.Pediatr. Obes.20221710e1294610.1111/ijpo.1294635666025
    [Google Scholar]
  129. MokkalaK. TerttiK. RönnemaaT. VahlbergT. LaitinenK. Evaluation of serum zonulin for use as an early predictor for gestational diabetes.Nutr. Diabetes201773e253e25310.1038/nutd.2017.928319108
    [Google Scholar]
  130. DemirE. OzkanH. SeckinK.D. SahtiyancıB. DemirB. TabakO. KumbasarA. UzunH. Plasma zonulin levels as a non-invasive biomarker of intestinal permeability in women with gestational diabetes mellitus.Biomolecules2019912410.3390/biom901002430641999
    [Google Scholar]
  131. OhlssonB. Orho-MelanderM. NilssonP. Higher levels of serum zonulin may rather be associated with increased risk of obesity and hyperlipidemia, than with gastrointestinal symptoms or disease manifestations.Int. J. Mol. Sci.201718358210.3390/ijms1803058228282855
    [Google Scholar]
  132. WellsA.U. HiraniN. EganJ.J. GreavesM.S. HansellD.M. HarrisonN.K. HiraniN. HubbardR. LakeF. MillarA.B. WallaceW.A. WellsA.U. WhyteM.K. WilsherM.L. Interstitial lung disease guideline.Thorax200863Suppl. 5v1v5810.1136/thx.2008.10169118757459
    [Google Scholar]
  133. SchwarzM.I. KingT.E. Interstitial lung disease.PMPH-USA2011p. 1161
    [Google Scholar]
  134. SokolowskaM. FreiR. LunjaniN. AkdisC. Microbiome and asthma.Asthma Res. Pract.201841
    [Google Scholar]
  135. KnutsonT.W. BengtssonU. DannaeusA. AhlstedtS. KnutsonL. Effects of luminal antigen on intestinal albumin and hyaluronan permeability and ion transport in atopic patients.J. Allergy Clin. Immunol.19969761225123210.1016/S0091‑6749(96)70189‑68648017
    [Google Scholar]
  136. JalonenT. Identical intestinal permeability changes in children with different clinical manifestations of cow’s milk allergy.J. Allergy Clin. Immunol.199188573774210.1016/0091‑6749(91)90180‑V1955632
    [Google Scholar]
  137. BjarnasonI. ZanelliG. ProuseP. WilliamsP. GumpelM.J. LeviA.J. Effect of non-steroidal anti-inflammatory drugs on the human small intestine.Drugs198632Suppl. 1354110.2165/00003495‑198600321‑000073780475
    [Google Scholar]
  138. BjarnasonI. PetersT.J. LeviA.J. Intestinal permeability: clinical correlates.Dig. Dis.198642839210.1159/0001711403545563
    [Google Scholar]
  139. RittirschD. FlierlM.A. NadeauB.A. DayD.E. Huber-LangM.S. GrailerJ.J. ZetouneF.S. AndjelkovicA.V. FasanoA. WardP.A. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.Am. J. Physiol. Lung Cell. Mol. Physiol.201330412L863L87210.1152/ajplung.00196.201223564505
    [Google Scholar]
  140. GhanadiK. NaghdiN. The role of zonulin as a prognostic biomarker in liver diseases: a systematic review.Adv. Life Sci.20229277283
    [Google Scholar]
  141. CaniP.D. BibiloniR. KnaufC. WagetA. NeyrinckA.M. DelzenneN.M. BurcelinR. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.Diabetes20085761470148110.2337/db07‑140318305141
    [Google Scholar]
  142. de La SerreC.B. EllisC.L. LeeJ. HartmanA.L. RutledgeJ.C. RaybouldH.E. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation.Am. J. Physiol. Gastrointest. Liver Physiol.20102992G440G44810.1152/ajpgi.00098.201020508158
    [Google Scholar]
  143. MurphyE.A. VelazquezK.T. HerbertK.M. Influence of high-fat diet on gut microbiota.Curr. Opin. Clin. Nutr. Metab. Care201518551552010.1097/MCO.000000000000020926154278
    [Google Scholar]
  144. ZhangM. YangX.J. Effects of a high fat diet on intestinal microbiota and gastrointestinal diseases.World J. Gastroenterol.201622408905890910.3748/wjg.v22.i40.890527833381
    [Google Scholar]
  145. PacificoL. BonciE. MarandolaL. RomaggioliS. BascettaS. ChiesaC. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease.World J. Gastroenterol.20142045171071711410.3748/wjg.v20.i45.1710725493023
    [Google Scholar]
  146. HendyO.M. ElsabaawyM.M. ArefM.M. KhalafF.M. OdaA.M.A. El ShazlyH.M. Evaluation of circulating zonulin as a potential marker in the pathogenesis of nonalcoholic fatty liver disease.Acta Pathol. Microbiol. Scand. Suppl.2017125760761310.1111/apm.1269628430371
    [Google Scholar]
  147. KimA.S. KoH.J. Plasma concentrations of zonulin are elevated in obese men with fatty liver disease.Diabetes Metab. Syndr. Obes.20181114915710.2147/DMSO.S16306229719415
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673335863240829060545
Loading
/content/journals/cmc/10.2174/0109298673335863240829060545
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test