Duodenal low‐grade inflammation and expression of tight junction proteins in functional dyspepsia

Abstract

Background Duodenal changes in functional dyspepsia (FD) might be related to the development of symptoms. However, relationships among low‐grade inflammation, Helicobacter pylori infection, and protein expression by tight junctions (TJs) in the duodenum are unclear. We therefore aimed to determine whether duodenal inflammation and genes associated with TJ proteins are associated with FD. Methods We evaluated inflammatory cell infiltration of the duodenum, H pylori infection, and genes associated with TJ proteins in duodenal biopsy specimens from 35 patients with FD according to the Rome III diagnostic questionnaire and from 31 asymptomatic controls without structural diseases. We immunohistochemically detected eosinophils and mast cells and counted them. The expression of claudins, occludin, and zonula occludens (ZO)‐1 mRNA was evaluated using quantitative RT‐PCR. Infection with H pylori was determined by measuring serum antibodies, rapid urease or urea breath tests, and endoscopic findings. Results Sex, age, and H pyloriinfection rates did not differ between patients with FD and controls. The numbers of eosinophils and mast cells were significantly increased in patients with FD compared with controls and were significantly correlated. Inflammatory cell counts in the duodenum were not associated with H pylori infection status. Claudin‐3 mRNA expression was increased in the patients with FD. Conclusions Subtle inflammation identified in the duodenum of patients with FD might be associated with the onset and persistence of dyspeptic symptoms.

Comparative expression profiling in the intestine of patients with Giardia‐induced postinfectious functional gastrointestinal disorders

“…This is in line with previous studies that revealed a disrupted staining pattern, characterized by a redistribution of occludin from the apical membrane to the cytoplasma of enterocytes in IBS‐D patients 47‐50 . Furthermore, increased expression of claudin‐3 was recently reported in Helicobacter pylori‐ positive FD 51 and decreased claudin‐3 as well as occludin levels in FD 52 …”

“…This is in line with previous studies in which higher mast cell counts and increased tryptase levels have been described in duodenum, jejunum, ileum, colon, and rectum mucosa of PI‐IBS patients 56‐59 . Furthermore, similar findings have been reported in various non–PI‐IBS studies including FD 52,60,5150 . An increasing degree of tryptase expression has been found to correlate positively with the severity of IBS symptoms 61 .…”

Duodenal bile acids as determinants of intestinal mucosal homeostasis and disease

“…In most cases, it is unclear whether the loss of barrier is a cause or consequence of the disease but because of the proximity of the epithelium to the microbiota, epithelial pathology is a critical aspect of GI disease. In functional dyspepsia, for instance, the loss of tight junction protein zonula occludens‐1 (ZO‐1) and increases in duodenal permeability or reduced mucosal impedance (which is a surrogate marker for transepithelial permeability) have all been reported 5‐7 . While the cause of these changes is unclear, the co‐occurrence of immune cell gut homing 8 and changes to the microbiota 4 may imply that translocation of bacteria initiate low‐grade immune responses as part of the pathophysiology of FD 9 .…”

“…One possible interpretation is that the conjugated UDCA is negatively impacting the integrity of the epithelial tight junctions. Indeed, loss of duodenal barrier function is now a well‐established pathophysiology in patients with FD and this appears to be driven by downregulation of tight junctional protein ZO‐1 6 . In vitro and in vivo studies have demonstrated that tight junction integrity can be regulated by exposure to luminal bile acids with decreased expression of occludin, claudin 1, claudin 4, JAM‐A and ZO‐1 and ZO‐2 all associated with increases in luminal bile acid exposure 6,23‐25 .…”

“…Indeed, loss of duodenal barrier function is now a well‐established pathophysiology in patients with FD and this appears to be driven by downregulation of tight junctional protein ZO‐1 6 . In vitro and in vivo studies have demonstrated that tight junction integrity can be regulated by exposure to luminal bile acids with decreased expression of occludin, claudin 1, claudin 4, JAM‐A and ZO‐1 and ZO‐2 all associated with increases in luminal bile acid exposure 6,23‐25 . This loss of tight junctions appears to be mediated by signaling through the bile acid receptors TGR5 and FXR 26,27 .…”