New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4.

BACKGROUND: Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn's disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition. METHODS: Paired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model. RESULTS: In human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf. CONCLUSIONS: Expression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.

Treatment efficacy of a low FODMAP diet compared to a low lactose diet in IBS patients: A randomized, cross-over designed study.

BACKGROUND AND OBJECTIVE: A low FODMAP diet (LFD) has become a standard treatment in irritable bowel syndrome (IBS) patients. Compliant adherence to a LFD is challenging. We investigated the effect of a LFD compared to a less restrictive low lactose diet (LLD) in a randomized cross-over trial with IBS patients. METHODS: Twenty-nine IBS patients were randomly assigned to two groups. After a run-in phase of 14 days, patients received 21 days of either a LFD or LLD. This intervention was followed by a washout period of 21 days before crossing over to the alternate diet. Dietician led diet instruction was given continuously. An IBS Severity Scoring System (IBS-SSS) was filled in at the end of each study period. To enhance study adherence, daily symptoms were assessed using a Visual Analog Scale (VAS). RESULTS: IBS patients, irrespective of lactase deficiency, had a significantly reduced IBS-SSS score after both diets (LFD p = 0.002, LLD p = 0.007) without significant difference. On both diets, patients reported that IBS had less impact on their daily life compared to the time before the study (p < 0.01). On daily assessment, IBS patients on LFD reported significantly less abdominal pain (median VAS difference to baseline -0.8 (-2.8 to 2.7, p = 0.03) and less bloating (-0.5 (-4.1 to 3.4, p = 0.02) than patients on the LLD. CONCLUSION: Both diets improved the overall IBS severity significantly and patients' preference of the two diets was similar. LFD but not LLD effectively reduced pain and bloating in patients with IBS.

Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis.

BACKGROUND AND AIMS: pH-sensing ovarian cancer G-protein coupled receptor-1 [OGR1/GPR68] is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease [CD] patients, and the effect of Ogr1 deficiency in fibrogenesis. METHODS: Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate [DSS]-induced chronic colitis and the heterotopic intestinal transplantation model were used. RESULTS: Increased expression of fibrosis markers was accompanied by an increase in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines [TGFB1 and CTGF] and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared with grafts from wild-type mice. CONCLUSIONS: OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.