https://www.ibstreatmentcenter.com/Articles/ROMEIIIFBDpaper.pdf

Functional Bowel Disorders

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

Intestinal mucosal barrier function in health and disease.

Microbial Influences in Inflammatory Bowel Diseases

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673612600269.pdf

Crohn's disease

https://www.spg.pt/wp-content/uploads/2015/11/2013-ACG_Guideline_CeliacDisease_May_2013.pdf

ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease

Background: Epithelial barrier function is impaired in Crohn’s disease. Aim: To define the underlying cellular mechanisms with special attention to tight junctions. Methods: Biopsy specimens from the sigmoid colon of patients with mild to moderately active or inactive Crohn’s disease were studied in Ussing chambers, and barrier function was determined by impedance analysis and conductance scanning. Tight junction structure was analysed by freeze fracture electron microscopy, and tight junction proteins were investigated immunohistochemically by confocal laser scanning microscopy and quantified in immunoblots. Epithelial apoptosis was analysed in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and 4′,6-diamidino-2-phenylindole staining. Results: Patients with active Crohn’s disease showed an impaired intestinal barrier function as indicated by a distinct reduction in epithelial resistance. As distribution of conductivity was even, focal epithelial lesions (eg, microerosions) did not contribute to barrier dysfunction. Instead, freeze fracture electron microscopy analysis showed reduced and discontinuous tight junction strands. Occludin and the sealing tight junction proteins claudin 5 and claudin 8 were downregulated and redistributed off the tight junction, whereas the pore-forming tight junctions protein claudin 2 was strongly upregulated, which constitute the molecular basis of tight junction changes. Other claudins were unchanged (claudins 1, 4 and 7) or not detectable in sigmoid colon (claudins 11, 12, 14, 15 and 16). Claudin 2 upregulation was less pronounced in active Crohn’s disease compared with active ulcerative colitis and was inducible by tumour necrosis factor α. As a second source of impaired barrier function, epithelial apoptosis was distinctly increased in active Crohn’s disease (mean (SD) 5.2 (0.5)% v 1.9 (0.2)% in control). By contrast, barrier function, tight junction proteins and apoptosis were unaffected in Crohn’s disease in remission. Conclusion: Upregulation of pore-forming claudin 2 and downregulation and redistribution of sealing claudins 5 and 8 lead to altered tight junction structure and pronounced barrier dysfunction already in mild to moderately active Crohn’s disease.

/pdf/changes-in-expression-and-distribution-of-claudin-2-5-and-8-2hemmyisdi.pdf

Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease

Celiac disease–like abnormalities in a subgroup of patients with irritable bowel syndrome

Background: Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. Aim: To characterise the inherent pathomechanisms of G lamblia infection. Methods: Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I SC ) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. Results: In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Ω cm 2 ; p 2 ). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I SC increased from 191 (20) in control to 261 (12) µA/h/cm 2 in giardiasis. The bumetanide-sensitive portion of I SC in giardiasis was also increased (51 (5) vs 20 (9) µA/h/cm 2 in control; p + –glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) µA/h/cm 2 ). Conclusions: G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na + -dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.

/pdf/effect-of-chronic-giardia-lamblia-infection-on-epithelial-1rg8p8u75c.pdf

Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum.

https://www.cghjournal.org/article/S1542-3565(07)00329-1/pdf

Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome.

The decision whether to treat a patient with a pancreatic pseudocyst, as well as when and with what technique, is a difficult one. This review article is intended to help physicians base their therapeutic decisions on the current state of therapeutic technology and published data.

/pdf/pancreatic-pseudocysts-observation-endoscopic-drainage-or-1je8yqqp1b.pdf

Ulrich Wahnschaffe

Papers

Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease

Celiac disease–like abnormalities in a subgroup of patients with irritable bowel syndrome

Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum.

Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome.

Pancreatic Pseudocysts: Observation, Endoscopic Drainage, or Resection?