IBS is a functional bowel disorder characterized by abdominal pain or discomfort associated with changes in bowel habit. Despite the prevalence and socioeconomic impact of IBS the pipeline for novel drugs is limited and only few drugs reach phase II and III clinical trials. One of the main reasons for the obvious lack of therapeutic possibilities and progress herein is the poor understanding of mechanisms relevant to this disorder. At Gut Research, dept. AMC, we overcome this relative standstill by performing hypothesis driven pre-clinical investigations that, when successful, are translated into well conducted clinical trials.

Pre-clinical investigations

Bidirectional brain-gut interactions are highly relevant in IBS and this complexity should be taken into account when performing pre-clinical investigations. Hence, we use the rat maternal separation model. Stressful early life events are known to predispose to IBS and stress at adult age is a well-known trigger for symptoms. Exactly these events are mimicked in this model and lead to a post stress IBS-like phenotype in predisposed (maternal separated) rats. For more information about the maternal separation model, click here.

Gut Research results obtained with the maternal separation model

  • Our recent publication on ‘susceptibility-transfer across generations’ shows how original scientific concepts and hypotheses can be successfully investigated in this model. Further, we recently addressed a novel scientific concept in this model: reversal of post-stress visceral hypersensitivity by lipid raft modulation (publication in preparation).
  • Gut Research publications on pharmacological interventions: in addition to other compounds we successfully used this model to study the effect of mast cell stabilization and specific H1-receptor antagonists, a specific TRPV-1 antagonist (collaboration with GlaxoSmithKline,UK), anti-NGF, neomycin and a CRH-receptor antagonist.
  • Dietary interventions: other labs used this model to successfully evaluate probiotic treatments. In our group we recently studied the effect of long chain n-3 polyunsaturated fatty acids (article submitted).

Translational research

Successful mast cell interventions in the maternal separation model were translated into a clinical trial where we showed effectiveness of the mast cell stabilizer and histamine-1-receptor (H1R) antagonist ketotifen in IBS patients. From tissue samples obtained in this trial we next concluded that H1R antagonism was the most probable mechanism of action of ketotifen. We subsequently tested two highly selective and peripherally restricted H1R antagonists in our rat model; both showed reversal of post stress visceral hypersensitivity. Based on these results one of these antagonists was recently evaluated in a new clinical trial (conducted at Catholic University of Leuven) with positive outcome.

Successful translation into patient trials clearly shows the accurate predictive value of our pre-clinical IBS model.

Irritable Bowel Syndrome (IBS)