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Patients with non-erosive gastro-oesophageal reflux disease are characterized by a significantly higher proportion of proximal acid refluxes and a higher sensitivity to short-lasting refluxes when compared with patients with oesophagitis. The highest proximal acid exposure and highest perception occurred in patients with non-erosive gastro-oesophageal reflux disease presenting with a normal pH-metric profile. The assessment of acid distribution and its perception in the oesophageal body can better identify reflux patients who should benefit from acid-suppressive treatment.

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-B in a variety of different cell types. The mechanisms/factors that negatively regulate NF-B in the human gut and the pathways leading to the sustained NF-B activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-␤1 (TGF-␤1) resulted in a marked suppression of TNF-␣؊induced NF-B p65 accumulation in the nucleus, NF-B binding DNA activity, and NF-B-dependent gene activation. TGF-␤1 also increased IB␣ transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-␤1 did not reduce TNFinduced NF-B activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IB␣ expression and reduced NF-B p65 accumulation in the nucleus. This effect was due to endogenous TGF-␤1. TGF-␤1 directly stimulated IB␣ promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-␤1 is a negative regulator of NF-B activation in the gut and that Smad7 maintains high NF-B activity in gut inflammation by blocking TGF-␤1 signaling.

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Background: In coeliac disease (CD) mucosa, the histological lesion is associated with marked infiltration of T helper cell type 1 (Th1) cells. However, the molecular mechanisms which regulate Th1 cell differentiation in CD mucosa are unknown. Aims: To analyse expression of transcription factors which control the Th1 cell commitment in CD. Patients: Duodenal mucosal samples were taken from untreated CD patients and normal controls. Methods: Interferon c (IFN-c) and interleukin (IL)-4 RNA expression was examined in T lamina propria lymphocytes by quantitative reverse transcription-polymerase chain reaction. T-bet and STAT-4, two Th1 promoting transcription factors, and STAT-6 and GATA-3, transcription factors which govern T helper cell type 2 (Th2) cell polarisation, were examined in duodenal biopsies by western blotting. The effect of gliadin and IFN-c on expression of T-bet was examined in an ex vivo culture of biopsies taken from normal and treated CD patients. Results: As expected, IFN-c but not IL-4 RNA transcripts were increased in the mucosa of CD patients in comparison with controls. CD mucosal samples consistently exhibited higher levels of T-bet than controls. However, no difference in active STAT-4 expression was seen between CD patients and controls, suggesting that Th1 polarisation was not induced by local IL-12. GATA-3 and STAT-6 were also low in both CD and control mucosa. In normal duodenal biopsies, IFN-c stimulated T-bet through a STAT-1 dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced T-bet and this effect was also inhibited by STAT-1 inhibition. Conclusions: This study shows that activation of STAT-1 by IFN-c promotes T-bet in CD mucosa.