Translational research in motor and sensory function of the upper GI tract

Translational research in motor and sensory function of the upper GI tract Niels van Lelyveld Background and aim: Functional dyspepsia (FD) is a common disorder seen in daily clinical practice, characterized by the presence of pain or discomfort in the upper abdomen in the absence of organic, systemic, or metabolic disease. Since reliable markers are not available (anatomic or biochemical abnormalities), the diagnosis is based upon symptoms. It is well established that motoric and sensory abnormalities are highly prevalent in FD patients. The key issue here is, whether gastric (dys)function is related to specific upper abdominal symptoms, and can be regarded as a etiologic factor of FD. The clinical importance of this is evident, since gastric sensory or motor dysfunctions may serve as important therapeutic targets. The aim of the current thesis was to improve the understanding of the aetiology of dyspeptic symptoms. Methods: For that purpose, we have investigated: (1) the relationship between dyspeptic symptoms and gastric motor and sensory function, (2) molecular factors potentially underlying the gastroduodenal motor and sensory abnormalities and/or the generation of upper abdominal symptoms. We investigated the (patho)physiology of upper gastrointestinal motility and the generation of upper abdominal sensations in functional dyspeptic patients using several techniques; three-dimensional ultrasonography (3D-US) to study total and partial gastric volume changes, the C-octanoic breathtest for the measurement of gastric emptying, and the nutrient drinktest to determine maximum drinking capacity. In our attempt to identify molecular factors underlying the gastroduodenal motor and sensory abnormalities and/or symptoms we focused on serotonergic signalling. mRNA expression levels of genes encoding proteins involved in serotonergic signalling were quantified by real-time PCR in mucosal biopsy specimens. Furthermore, the genotype distribution of functional polymorphisms was analyzed. Results and conclusions: Although impaired proximal gastric relaxation and delayed gastric emptying are highly prevalent in this patient group, we were not able to establish a relationship between gastric (dys)function and upper abdominal sensations experienced in daily life. The results of this thesis question the role of these pathophysiologic mechanisms in the generation of dyspeptic symptoms. Therefore, we have concluded that limited effect on symptoms may be expected when targeting these specific mechanisms. Several components of mucosal serotonergic signalling are higher in the duodenum compared to the stomach. Therefore we conclude that serotonin, released by EC cells, predominantly contributes to gastroduodenal function at the level of the duodenum. Examination of serotonergic signalling components in patients with idiopathic gastroparesis revealed that delayed gastric emptying and upper abdominal symptoms do not result from altered mucosal 5-HT biosynthetic and uptake capacity. However, a decreased expression of the 5-HT 4 (c) splice variant in the duodenum of FD patients may exert a modest effect on 5-HT availability, and be of importance in the pathogenesis of gastroparesis. Interestingly, tertiary referral FD patients have a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls. Therefore, a second messenger abnormality may be one of the molecular factors underlying the gastric motor and sensory dysfunction and upper abdominal symptoms observed in FD.