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Regulation of Intestinal Permeability in Health and Disease Regulation of Intestinal Permeability in Health and Disease Item Type Poster/Presentation Authors Fasano, Alessio Publication Date 2012 Keywords zonulin; Celiac Disease; Receptors, Cell Surface; Diabetes Mellitus, Type 1 Download date 04/10/2021 01:04:33 Item License https://creativecommons.org/licenses/by-nc-nd/4.0/ Link to Item http://hdl.handle.net/10713/2906 Regulation of Intestinal Permeability in Health and Disease DDW 2012 – S. Diego, CA Alessio Fasano, M.D. Mucosal Biology Research Center and Center for Celiac Research University of Maryland School of Medicine All disease begins in the gut - Hippocrates 460 BC The gut is not like Las Vegas: what happens in the gut does not stay in the gut – A.F. 2010 AC The intestinal mucosa is the battlefield on which friends and foes need to be recognized and properly managed to find the ideal balance between tolerance and immune response. Several Cells Play a Role in Maintaining the Gut Immune Homeostasis Epithelial cells Intestinal DCs B cells T cells The Paracellular Pathway PURIFICATION PROTOCOL FROM HUMAN INTESTINE 1 2 3 4 1 2 3 4 1: Tissue lysate …Tight junctions are a ‘dark horse’ implicated in a host of 2: Sephacryl-S300 disease states, ranging from acute injury to chronic 3: Q-sepharose inflammation and autoimmune diseases 4: Immuoaffinity Fasano A. et al Lancet 2000;355:1518-1519.- Coomassie Western blot Wang W et al J Cell Sci 2000;24:4435-4440 Characterization of Zonulin and Its Signaling Tripathi et al, PNAS 2009;106:16799-804. Zonulin Characterization in Sera of CD Patients a1 Zonulin b a2 HP2-2 HP1-1 HP1-2 b Tripathi et al, PNAS 2009;106:16799-804. Mechanisms of Zonulin Release CONTROL • CXCR-3 is a seven-transmembrane G couple protein receptor that is preferentially expressed on activated T GLIADIN/BACTERIA lymphocytes and subset of B and NK cells. • Three known CXCR3 ligands CXCL-9, -10, -11 are produced at the site of inflammation and elicit migration of pathological Th1 cells. • CXCR3 has been implicated as a potential target for CASEIN impeding T-cell-mediated destruction in autoimmune diseases such as multiple sclerosis and type 1 diabetes Zonulin Actin Nucleus El Asmar et al Gastroenterology 2002; Drago et al Scand J Gastroenterol 2006 Zonulin Signaling Working Hypothesis Inflammatory 1 + marker Zonulin HP2 a2 b EGFR 2 + - + Turn off 3 MMPs/ PAR2 ADAMS Pro-HB-EGF 2b + Tryptase IV Src 2a + Ras-MAP-kinase activation Proposed mechanisms through which zonulin activates EGFR. Zonulin can activate EGFR through direct binding (1) and/or through PAR2 transactivation (2). This second mechanism can be mediated by either Src signaling (2a) or by the release of MMPs and/or ADAMS that in turn will activate Pro-HB-EGF. When cell tryptase IV cleaves zonulin in its two subunits (so eliminating one of the three required disulfide bridges necessary for EGF activity), the molecule is not able to bind to EGFR (3), while will acquire a different function (Hb binding) and becomes an inflammatory marker. Tripathi et al, PNAS 2009;106:16799-804. Opening of the ZO-1 E-Cadherin Intestinal TJ Control In Vivo Effect of gliadin on Tight Junctional Proteins’ Arrangement 1mg gliadin Zonulin Characterization and Signaling Zonulin signaling Freeze-Fracture Following Pathway Activation Resting State Fasano et al, J Clin Invest 1995;96:710-20; el Asmar et al Gastroenterology 2002;123:1607-15 Zonulin Genetics Haptoglobin/Zonulin Evolution Fasano A. Physiol Rev. 2011 Jan;91(1):151-75 Haptoglobin/Zonulin Evolution Fasano A. Physiol Rev. 2011 Jan;91(1):151-75 Intestinal Barrier Dysfunction in Disease Pathology BACTERIAL TOXINS Bacteriodes fragilis (metalloprotease toxin) INFECTIONS: Clostridium difficile (toxins A, B) •E.Coli Clostridium perfrigens (enterotoxin) •Rotavirus E. coli (cytotoxic necrotizing factor 1) •Salmonella Ty. Helicobacter pylori (vacuolating toxin) •HIV Listeria monocytogenes (internalin) Vibrio cholerae (zonula occludens toxin) DRUGS: Tight Junction •alcohol Ischemia / •NSAID dysfunction / Reperfusion Injury •Tacrolimus injury AUTOIMMUNE DISORDERS: - Celiac disease - Multiple Sclerosis - Inflammatory bowel diseases - Diabetes Mellitus - Ankylosing spondylitis - IgA nephropathy Fasano, A. Pathological and therapeutic implications of macromolecules passage through the tight junction in Cereijido M, Anderson J, eds. Tight Junctions. CRC Press,2001: 697-722 Is impaired intestinal barrier a cause of disease or an epiphenomenon? • Multiple Sclerosis, StrokeStroke, Schizophrenia. • Asthma, COPD, ARDS • Dilatative cardiomyopathy, Ischemia- reperfusion • Systemic sclerosis Transplant Rejection • Type 1 Diabetes, Autoimmune thyroiditis • Celiac Disease, PBC, IBD.IBD, IBS • Glomerulosclerosis, Acute Renal Failure • Rheumatoid Arthritis • Tumors/Metastatic diseases Genetics: GWAS Studies Control Microbes? Gluten Celiac CD Not HLA Gen PAR-3 PP-1 CELIAC1 CELIAC2 CELIAC3 CELIAC4 TNFAIP3 REL IL18RAP IL2/IL21 TAGAP CCR3 Adapted from Xavier R.J. & Podolski D.K Nature 2007 Adapted from Schumann M et al GUT 2011 MLCK inhibition prevents immune- mediated barrier dysfunction and diarrhea 0.6 ) 1 - 100 0.5 x h ) 1 - BSA 1 - x h x 0.4 -4 H O 1 Fe(CN) 2 - l cm x 6 m 50 PIK 0.3 g x cm m 0 0.2 BSA flux ( BSA PIK 0.1 -50 Water flux out of lumen ( Water 0.0 anti-CD3: - - + + + + anti-CD3: - - + + + + PIK: 0 250 0 25 80 250 PIK: 0 250 0 25 80 250 PIK, membrane- Permeant Inhibitor of MLC Kinase Clayburgh et al. J Clin Invest (2005) The Leaky Gut Theory: How to Move From Fantasies to Facts How To Measure Gut Permeability: Physiological Site Restriction Sucralose Lactulose Sucrose PEG Mannitol Lactose Cr-EDTA Rhamnose Courtesy Jon Meddings Zonulin Gene Is Located on Chromosome 16 Chromosome 16 contains about 98 million bases, or some 3% of the human genome, encoding for ~1,300 genes. Fasano A. Physiol Rev. 2011 Jan;91(1):151-75 Distribution of Haptoglobin Alleles In Several Immune-Mediated Diseases A PCR Genotyping WB B Immunotyping HP 2-2 HP 1-2 HP 1-1 HP 2-2 HP 1-2 HP 1-1 Celiac Disease Crohn’s Disease Schizophrenia CKD Genotype Cntr Pts Cntr Pts Cntr Pts Cntr Pts HP 1-1 (no zonulin gene) 20.6 7.1 23.9 10.1 14.1 9.2 9.4 3.8 HP 1-2 (1 zonulin gene) 43.5 35.7 44.0 46.2 46.9 38.8 46.5 43.7 HP 2-2 (2 zonulin genes) 35.9 57.2 32.1 43.7 39.0 52.0 44.1 52.6 Maes M. et al. Psychiatry Res 2001;104:1-9; Tripati A . et al. Proc Natl Acad Sci U S A. 2009;106:16799-804 Mouse Models to Establish The Link Between Distribution of Haptoglobin Alleles And Susceptibility to Inflammation C57Bl/6 mouse transfected Transgenic C57Bl/6 mouse C57Bl/6 wild type mouse with human HP2 gene engineered by duplicating a chain (a1 a2) HP 1-1 (no zonulin gene) HP 1-2 (1 zonulin gene) HP 2-2 (2 zonulin genes) WB a2 a1 Impact of Zonulin Gene Expression on Gut Inflammation and TEER Changes Induced by DSS Histology TEER HP 2-2 mice C57Bl/6 wild type HP 2-2 mice untreated mice DSS-treated DSS-treated A B C Small intestine D E F Colon Serum Zonulin in Autoimmune Disorders * p < 0.0001 15 * * * * 12.5 10 7.5 5 3.4 3.0 zonulin ng/mg serum zonulin ng/mg serum protein 2.5 2.1 Cut-off 1.3 0.3 0.3 0.5 0 HC CD AIH PBC T1D APS-1 MS Clemente et al. Gastroenterology 2002;122 :A15 Serum Zonulin Levels and Their Correlation With Intestinal Permeability In Celiac Disease and Type 1 Diabetes Celiac Disease Type 1 Diabetes Zonulin-LA/MA A B N=339 N=89 N=97 C 4.04 0.12 3.5 0.1 3.03 0.08 2.5 /mg protein)/mg ng ( 2.02 0.06 LA/MA 1.5 zonulin 0.04 Serum Serum zonulin (ng/mg protein) 1.01 multiple R=0.36; Serum 0.02 intercept p=1.71E- 0.5 10; X variable 1 p=0.0004 00 0 T1DT1D T1DT1D Relatives Relatives controlsControls 0 1 2 3 4 Zonulin (ng/mg protein) Sapone et al Diabetes 2006; 55:1443-9 Prove of Concept on Role of Zonulin- Regulated Intestinal Permeability in Autoimmune Pathogenesis Genetics Environment Mucosal Barrier Autoimmunity NO ? Only CD Larazotide, the Zonulin Inhibitor H H N CH C N O C HO O H2 O C C C O CH C NH2 H2 HN O C H3C CH CH NH H2 CH3 C C CH3 O CH CH O NH CH3 C CH CH3 HN CH H C CH3 CH O O NH C CH H2N H C32H55N9O10 Exact Mass: 725.41 Mol. Wt.: 725.83 m/e: 725.41 (100.0%), 726.41 (35.6%), 727.41 (9.2%), 726.40 (3.3%) C, 52.95; H, 7.64; N, 17.37; O, 22.04 Di Pierro et al, J Biol Chem 2001;276:19160-5. Prove of Concept of the Role of Zonulin in Autoimmune Pathogenesis: The Animal Model of Type 1 Diabetes Evidence for Zonulin-Dependent Increased Intestinal Permeability in the Pathogenesis of Type 1 Diabetes Diabetes - Untreated No Diabetes – Larazotide Treated 300 0.7 300 0.7 0.6 0.6 250 250 0.5 0.5 LA/MA Ratio LA/MA 200 ICA + (100%) 200 Ratio LA/MA 0.4 0.4 150 150 ICA + (8%) 0.3 0.3 100 100 0.2 0.2 Serum glucose(mg/dl) Serum 50 50 0.1 glucose(mg/dl) Serum 0.1 0 0 0 0 30 37 44 51 58 65 72 30 37 44 51 58 65 72 Glucose Age (days) Age (days) LA/MA Watts et al PNAS 2005;102:2916-21 Blocking the Zonulin-Dependent Increased Intestinal Permeability Aborts The Autoimmune Process Islet Immunohistochemistry Insulin staining Glucagon staining Untreated BBDP rats that developed T1D A B Larazotide-treated BBDP rats that DID NOT develop T1D: No insulitis C D Prove of Concept of the Role of Zonulin in Autoimmune Pathogenesis: Human Clinical Trials in Celiac Disease Comprehensive Phase 1-2 Program of Larazotide Acetate in Celiac Disease has Studied ~500 Patients TRIAL DESIGN N -001 Phase 1, Single Escalating Dose in Healthy 24 Volunteers Safety -002 Phase 1b, Multiple Dose in Controlled Celiac Patients 21 -003 Phase 1, Multiple Escalating Dose in Healthy 24 Volunteers -004 Phase 2a, Multiple Dose in Controlled Celiac Patients Efficacy Gluten Challenge 2 weeks 86 -006 Phase 2b, Dose ranging in Controlled Celiac Patients 184 Gluten Challenge 6 weeks -06B Phase 2b, Controlled Celiac Patients 42 Gluten Challenge 6 weeks -011 Phase 2b, Dose ranging in Active Celiac patients, 8 105 weeks Total 486 Safety Profile of Larazotide Acetate to Date .
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