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L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France ALTERATIONS DE LA BARRIERE MUQUEUSE ET SYNDROME DE L'INTESTIN IRRITABLE Symposium Mayoly.

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Presentation on theme: "L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France ALTERATIONS DE LA BARRIERE MUQUEUSE ET SYNDROME DE L'INTESTIN IRRITABLE Symposium Mayoly."— Presentation transcript:

1 L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France ALTERATIONS DE LA BARRIERE MUQUEUSE ET SYNDROME DE L'INTESTIN IRRITABLE Symposium Mayoly sur le Syndrome de l'Intestin Irritable. Organisateur: Pr. Boucekkine Alger, 25 Avril 2010

2 TRILOGY OF IBS PERIPHERAL PATHOPHYSIOLOGY Altered gut sensitivity to Distension Colonic mucosal micro-inflammation Increased paracellular permeability Increased number of mast cells, immune cells (Weston et al.1993 and ref.) Increased number of mast cells, immune cells (Weston et al.1993 and ref.) Presence of pro-inflammatory cytokines (Gwee et al. 2003) Presence of pro-inflammatory cytokines (Gwee et al. 2003) Release of pro-inflammatory (eicosanoïds)(Jones et al.1982) and pronociceptive agents (Barbara et al. 2005) Release of pro-inflammatory (eicosanoïds)(Jones et al.1982) and pronociceptive agents (Barbara et al. 2005) colonic or intestinal level in PI-IBS (Dunlop,2000), colonic or intestinal level in PI-IBS (Dunlop,2000), intestinal in all Rome I (Marschall et al.2004) intestinal in all Rome I (Marschall et al.2004) colonic in IBS-D patients (Gesce et al. 2008) colonic in IBS-D patients (Gesce et al. 2008) Lower threshold of sensitivity (pain) to distension evidenced in 60-70% of IBS patients Lower threshold of sensitivity (pain) to distension evidenced in 60-70% of IBS patients Increased perception of pain for a given visceral stimulus (Whitehead et al.1998, ref.) Increased perception of pain for a given visceral stimulus (Whitehead et al.1998, ref.)

3 Trimble et al.1995

4 : Evidence (25 articles) of allodynia in 60-70% of IBS patients but not confirmed for all gut segments but not confirmed for all gut segments Trimble et al.1995

5 Dorsal root ganglion Mechanosensitive afferent Sensitized spinal circuits Repeated balloon distention Repetitive Stimulation Sensitizes the Spinal Cord Wind-up

6 Munakata J, Gastroenterology 1997; 112:55 Rectal Pain Threshold (mm Hg) Rectal Pain Threshold (mm Hg) Post sigmoid stimulation Post sigmoid stimulation Baseline IBS Controls HYPERALGESIA IN IRRITABLE BOWEL SYNDROME (Use of barostatic distensions) HYPERALGESIA IN IRRITABLE BOWEL SYNDROME (Use of barostatic distensions)

7 IBS pACC MCC Thalamus Pf, Re, Cl, Li Thalamus Pf, Re, Cl, Li Prefrontal Cortex Cing Cx included Prefrontal Cortex Cing Cx included Brain Activation with Noxious Visceral Stimulation Locus coeruleus Subnucleus reticularis dorsalis Spinal cord Lamina 1 Spinal cord Lamina 1

8 Evidence for colonic mucosal immune alterations and increased density of mast cell and immunocytes in IBS Mast cells CD3 + spastic colon ++ Hiatt 1962 Lymphocytes T NeutrophilsECCICC CD4 + CD8 + CD25 Patients Ref. IBS- D/C ++ Weston et al Jejun/ileum Cecum/colon IBS- D/C/A + IBS- D/C/A +PI Thorbloom et al Osullivan et al.2000 Dunlop et al IBS-PI++++ Spiller 2004 IBS-PI++++ Park et al IBS- D Chadwick et al IBS-D/C Barbara et al IBS- D+SII-C ++ ECC: enteric chromaffin cells; ICC : interstitial cell of Cajal; IBS-C: constipated patients; IBS-D: diarrheoic patients; IBC-A: alternated diarrhea-constipation; PI: post-infectious IBS. IBS-D: diarrheoic patients; IBC-A: alternated diarrhea-constipation; PI: post-infectious IBS. Chang et al IBS- D/ PI ++ Park et al IBS- D ++ ++

9 Lymphocytose ganglionnaire dans le SII Infiltration de lymphocytes dans les ganglions myentériques. La flèche noire indique un neurone et quelques lymphocytes à la base du neurone.Il ya plus de lymphocytes dans la zône délimitée par les les flêches bleues. Hématoxiline-éosine, X 380 (daprès Thorbloom et al. 2002)

10 Sang Colon (Ohman et al.2005) Activation des lymphocytes T circulants CD4 + et CD8 + et expression de MAdCAM par lendothélium colique dans lIBS IBS: D+C+A UCr: RCH en rémission; UCa: RCH active; CTRL: Témoins

11 Increased mast cell tryptase labeling in the sub-mucosa of IBS patients Proximal colon biopsies in IBS = density of mast cells amount of tryptase colocalisation nerve-mast cells COLONIC MAST CELLS IN CLONIC BIOPSIES OF IBS PATIENTS IBS CTRL ( Barbara et al., 2004)

12 Mastocyte Stress Allergie Inflammation Infection activation activation Système Système CRF IgE, SP,5-HT NGF, NPY Degranulation Secretion minutes heures GM-CSF, IL-1 PAF, ATP HistamineLeukotrienes Cytokines* proteasesNGF Chemokines * Cytokines: TNF, IL-3, IL-5, IL-4, IL-13, IL-10, GM-CSF (adapted from Shakoory et al,2004, Penicci et al.2003) Facteurs principaux produisant la dégranulation ou lactivation des mastocytes muqueux du tube digestif

13 Distribution of nerve terminals close to mast cell in IBS patients. MC Red: nerve terminals (enolase labeling) Blue: mast cells (alcian blue) ( Wang et al. Gut 2004 ) Mast cell number (mm2) (ileal mucosa) (X1000) PI-IBS……… 11.2 ± 2.8* (n=27) (n=27) Non PI-IBS… ±1.2* (n=29) (n=29) Control………..6.1±0.5 (n=12) (n=12) * : from control at p<0.01 PI-IBS CTRL

14 (Barbara et al. Gastro. 2004) RELATIONSHIP BETWEEN MAST CELL-NERVES CONNECTION AND PAIN IN IBS PATIENTS CONNECTION AND PAIN IN IBS PATIENTS Number of mast cells at a distance < 5µm from nerves Pain intensisity scoring Pain frequency scoring

15 Epithelial cells Is increased gut permeability able to initiate mucosal immune response and visceral hypersensitivity? immune response and visceral hypersensitivity? Increased paracellular permeability = Entry of pathogens, toxins, antigens, bacteria - activation of immunocytes - cytokines release - inflammatory mediators Nociceptivehypersensitivity PAIN Motilitydisorders ENSdisorders

16 T-cell B-cell Mastcell Granulocyte Sensory nerves (nociceptive fibers) Intestinal or colonic mucosa Epithelialcells Tight junction PathogensAllergens ( from Perdue et al ) (LPS, DNA,peptidoglycans,…etc.)

17 WTPAR-2 -/- * INFLUENCE OF FECAL SUPERNATANT FROM IBS PATIENTS INFUSED ON PARACELLULAR PERMEABILITY OF MICE COLONIC STRIPS Fecal supernatants (n=6) IBS-D fecal supernatants (n=4) IBS-D fecal supernatants (n=3) Increase in permeability triggered by apical application of IBS-D fecal supernatant is reduced by ser-protease inhibitor and is absent in PAR-2 -/- KO mice (Gecse et al. 2008)

18 (Gecse et al. 2008) INFLUENCE OF FECAL SUPERNATANT FROM IBS-D PATIENTS INFUSED INTRACOLONICALLY IN MICE ON COLONIC SENSITIVITY TO DISTENSION

19 P-MLC (green) ZO-1 (green) INFLUENCE OF FECAL SUPERNATANT FROM IBS-D PATIENTS ON COLONIC EPITHELIAL TJ INTEGRITY IN MICE P-MLC in colonic mucosa (Gecse et al. 2008) P-MLC is over expressed in colonic mucosa infused with IBS-D supernatant reflecting a EC cytoskeleton contractionC Resulting opening of TJs is associated with a reduced apical expression of ZO-1

20 Luminal ser- proteases PAR-2 activation Long-term hypersensitivity T-cell Afferent neurons SP IFN IFN Mast cell tryptase tryptase Increased permeability (mins to hours) Mucosal micro-inflammation (hours to weeks) Nerve terminal sensitization (weeks to months) Inflammatorymediators ( Bueno et al. 2008) Mechanisms involved in long-term sensitization of mucosal sensory nerves in IBS-D patients

21 enzymes Biliary salts bacteria (proteases?) Allergens, parasites stress sepsis Bacterial secetion or lysis (acetaldehyde, LPS…etc) Inflammation(gastroenteritis) Factors able to alter gut permeability/sensitivity in FGID

22 Piche et al. Gut 2009 IN VITRO MEASUREMENT OF PARACELLULAR PERMEABILITY OF COLONIC BIOPSIES (Ussing chambers) The degree of porosity of biopsies from IBS patients is higher than that of healthy subjects independently of bowel habit alterations. This altered permeability is associated with a decrease in the expression of ZO-1, a protein linking the actinomyosin apical ring to the proteins of the TJs

23 EFFECTS OF COLONIC BIOPSY SUPERNATANT ON CaCo2 CELL PERMEABILITY AND CORRELATIONS WITH SYMPTOM SCORES Increase of permeability of CaCo2 cells, 48h after mucosal exposure with supernatant of biopsies from IBS patients Changes in permeability of CaCo2 cells is correlated with the pain score of explored IBS patients Piche et al. Gut 2009

24 NormalIBS VAS score (visceral) VISCERAL PAIN* Zhou et al. Pain Lactulose/ Mannitol NormalIBS INTESTINAL PERMEABILITY RELATIONSHIPS BETWEEN GUT PERMEABILITY AND PAINFUL SENSATIONS TO DISTENSION MEASURED IN VIVO Pain measurement after repeated (2) 35mm Hg rectal distension performed during 30 sec. at 2 min. interval. *

25 Zhou et al. Pain FBDSI score CONTROLIBS RELATIONSHIPS BETWEEN GUT PERMEABILITY AND SOMATIC* SENSITIVITY IN IBS PATIENTS Patients with altered permeability skin thermal stimulus (Pelletier probe 3x3 cms) at 47°C applied to the left hand during 10 sec. *

26 CONCLUSIONS La douleur abdominale associée au SII à le plus souvent comme origine une hypersensibilité intestinale ou colique à la distension. Cette hypersensibilité est associée à une micro-inflammation de la paroi pouvant être considérée comme résultant d'une augmentation de la porosité de la muqueuse colique associée au passage de bactéries et toxines. Certains facteurs luminaux dont les protéases agissent sur les récepteurs des cellules épithéliales pour augmenter cette perméabilité Cette augmentation de perméabilité à été montrée, in vivo et in vitro, être corrélée aux symptômes


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