Serotonergic and non-serotonergic targets in the pharmacotherapy of visceral hypersensitivity

Abstract  Visceral hypersensitivity is considered a key mechanism in the pathogenesis of functional gastrointestinal (GI) disorders. Targeting visceral hypersensitivity seems an attractive approach to the development of drugs for functional GI disorders. This review summarizes current knowledge on targets for the treatment of visceral hypersensitivity, and the status of current and future drug and probiotic treatment development, and the role of pharmacogenomic factors.     

Reproducibility and symptomatic predictors of a slow nutrient drinking test in health and in functional dyspepsia

Abstract  Impaired accommodation to a meal has been recognized as a pathophysiological mechanism in functional dyspepsia (FD). Based on observations in tertiary care patients, the drinking test has been proposed as a non-invasive tool to estimate accommodation. Our aim was to assess the reproducibility of the drinking test and its correlation with demographic, symptomatic and pathophysiological parameters in secondary care FD patients and healthy controls. Thirty-four healthy controls and 78 FD patients completed a drinking test (3 respectively 2 times), a gastric emptying study and an FD symptom questionnaire. Factors influencing maximal volume and gastric emptying were determined, and the reproducibility of the drinking test was investigated. The maximal satiety was reached at a lower volume in patients (489 ± 276 and 503 ± 248 mL for first and second test respectively vs 937 ± 428 and 1048 ± 421 mL, P  < 0.0001). The ingested amount depended on age, sex and baseline FD symptom score. Patients' sex, final satiety score, total score for stomach complaints at screening and total symptom score before test accounted for the total symptom score after the test. The slow nutrient drinking test confirms its possible role as an attractive non-invasive and reproducible tool for the diagnosis of impaired accommodation and for the assessment of treatment responsiveness.     

Mechanisms of serotonergic agents for treatment of gastrointestinal motility and functional bowel disorders

Abstract  Most of the body's serotonin is released in the gut where it plays an important role in the control of gastrointestinal (GI) motility, sensitivity and muscle tone by activating different receptor subtypes. This review focuses on the known effects of selective serotonin reuptake inhibitor and serotonin receptor agonists and antagonists on the sensorimotor function of the GI tract and describes the therapeutic potential of these actions for GI motility and functional bowel disorders.     

Mechanisms underlying duodeno-gastric reflux in man

BACKGROUND: Recent studies suggest that duodeno-gastro-oesophageal reflux (DGER) contributes to the occurrence of reflux oesophagitis and Barrett's oesophagus. The mechanisms underlying duodeno-gastric reflux (DGR), a prerequisite for DGER, are poorly understood. AIMS: To study the occurrence of DGR in relation to interdigestive and postprandial gastroduodenal motility. SUBJECTS AND METHODS: Ten healthy subjects underwent stationary gastroduodenal manometry with simultaneous duodenal and antral Bilitec recording 4 h before and 5 h after ingestion of a liquid meal. Eight volunteers underwent the same study, with administration of erythromycin postprandially. RESULTS: During the interdigestive phase II, all volunteers had short DGR episodes. Postprandially, DGR occurred in all subjects, on average 39 +/- 28 min after the start of the meal, and was cleared from the stomach after 242 +/- 23 min. Induction of increased antral motility and of a premature phase III, by administration of erythromycin, was associated with faster gastric DGR clearance. However, there was no direct temporal relationship between erythromycin-induced gastric phase III and erythromycin-induced DGR clearance. CONCLUSION: In healthy subjects, duodenogastric reflux occurs sporadically in the interdigestive state and is a normal phenomenon in the postprandial period. Erythromycin induces faster clearance of DGR from the stomach, which depends on enhanced antral contractile activity rather than premature phase III.     

Normal values for the satiety drinking test in healthy children between 5 and 15 years

Abstract  In adults, a slow caloric drinking test has been proposed as a non-invasive tool to estimate gastric accommodation and to quantify meal-induced symptoms in functional dyspepsia (FD). The same test has been proposed for paediatric FD, but normal values are only available for adolescents and adults. The aim of the study was (i) to establish normal values for the satiety drinking test in young children and (ii) to study the influence of demographic factors. In all, 59 healthy children [27 girls; age range 5–16 years, body mass index (BMI) 17.4 ± 2.5 kg m⁻²] were studied in the morning after an overnight fast. They drank a liquid nutrient meal (1.5 kcal mL⁻¹) from beakers that were filled by a peristaltic pump filled at a rate of 15 mL min⁻¹ with. For every 5 min, satiety was scored on a graphic rating scale grade 0–5 (1 = threshold, 5 = maximum), until a score of 5 was reached. Values are given as mean ± SEM and compared by t -test; correlation analysis was performed using Spearman rank test. All children performed the test as indicated except for one 5 years old who stopped prematurely for dislike of the taste. The endpoint was reached at 360 ± 23 mL (540 ± 34 kcal), and was age-dependent (Spearman r  = 0.28, P  = 0.03). No correlation was found between the maximum volume ingested and gender, weight, height or BMI. Age-dependent normal ranges were determined for ages 5–16 at 3-year intervals, and were found to increase with age. We established feasibility of and normal values for a non-invasive satiety drinking test in children with an age range of 5–15 years. This tool can now be used in the assessment of paediatric FD and eating disorders.     

Intestinal immune activation in presumed post-infectious functional dyspepsia

Abstract  Functional dyspepsia (FD) symptoms may develop after an acute gastroenteritis. In post-infectious (PI) irritable bowel syndrome, persisting low-grade colonic inflammation and increased enterochromaffine cells (EC) counts have been reported. The aim was to compare signs of inflammation and EC hyperplasia on duodenal biopsies in presumed PI-FD and unspecified-onset (U-)FD. Duodenal biopsies were obtained in 12 U-FD and 12 PI-FD (on average 13 months after the acute event) patients. The presence of intra-epithelial, intravillar, and the number of CD3, CD4, CD8 and CD68+ cells per crypts, and the mean number of Chromogranine A (CA) positive cells per villus were compared. We also measured gastric emptying and assessed proximal stomach function with a barostat. Data are shown as mean ± SEM. Focal aggregates of T cells and focal CD8+ aggregates, were found in PI-FD but not in U-FD patients (respectively 5/12 vs 0/12, P  = 0.02 and 5/9 vs 0/11, P  < 0.01). In patients with focal aggregates, gastric emptying was delayed (189 ± 37 min vs 98 ± 11 min, P  = 0.002). The number of CD4+ cells per crypt (0.52 ± 1.6 vs 1.22 ± 2.18, P  = 0.04), and the number of intravillar CD4+ cells (0.5 ± 0.2 vs 2.7 ± 0.7, P  = 0.01) were reduced, while the number of CD68+ cells per crypt was increased (0.64 ± 0.13 vs 0.40 ± 0.05, P  = 0.03) in PI-FD. The number of EC and CA were comparable. PI-FD is associated with persisting focal T-cell aggregates, decreased CD4+ cells and increased macrophage counts surrounding the crypts. This may indicate impaired ability of the immune system to terminate the inflammatory response after acute insult.     

Chemosensitivity of the human gastrointestinal tract in health and in disease

Although visceral sensitivity in man comprises chemosensitivity, thermosensitivity and mechanosensitivity, only the latter has been intensively studied. Studies in health have aimed at characterising the type of mechanoreceptors involved in visceral mechanosensitivity,. Several authors have studied the prevalence and relevance to the symptom pattern of hypersensitivity to visceral balloon distention in patients with functional gastrointestinal disorders. Chemosensitivity of the gastrointestinal tract in man has received much less attention. In this issue of Neurogastroenterology and Motility, intraluminal application of capsaicin is described as a tool to study chemosensitivity of the proximal gastrointestinal tract. The authors report how activation of chemosensitive pathways induces symptoms that differ from those induced by activation of mechanosensitive pathways, and propose to use capsaicin as a tool to study the prevalence and role of hypersensitivity to visceral chemosensitivity in patients with functional gastrointestinal disorders. Our current knowledge of visceral chemosensitivity of the human gastrointestinal tract in health and in disease is reviewed, with a specific focus on the interaction between mechano- and chemosensitive pathways.     

Neural mechanisms of early postinflammatory dysmotility in rat small intestine

Although human postinflammatory dysmotility is known, so far animal studies have primarily investigated changes during inflammation. Here, we focused on postinflammatory changes in rat jejunal myenteric plexus and jejunal motility. Evolution of ethanol/2,4,6-tri-nitrobenzene sulphonic acid (TNBS)-induced inflammation was assessed histologically and by measuring myeloperoxidase activity (MPO). Electromyography and immunohistochemistry were performed 1 week after ethanol/TNBS and also after N(G)-nitro-L-arginine methyl ester (L-NAME) administration. Ethanol/TNBS induced a transient inflammation, with normalization of MPO and histological signs of an early phase of recovery after 1 week. The number of cholinergic neurones was not altered, but myenteric neuronal nitric oxide synthase (nNOS)-immunoreactivity was significantly lower in the early phase of recovery after TNBS compared with water (1.8 +/- 0.2 vs 3.5 +/- 0.2 neurones ganglion(-1), P < 0.001). Interdigestive motility was disrupted with a loss of phase 1 quiescence, an increase of migrating myoelectric complex cycle length, a higher number of non-propagated activity fronts and a decrease of adequately propagated phase 3 s after TNBS. Administration of L-NAME resulted in a similar disruption of interdigestive motility patterns. In the early phase of recovery after ethanol/TNBS-induced jejunal inflammation, a loss of motor inhibition occurs due to a decrease of myenteric nNOS activity. These observations may provide a model for early postinflammatory dysmotility syndromes.     

Prolonged duodenal acid perfusion and dyspeptic symptom occurrence in healthy volunteers

Abstract  The pathophysiology of functional dyspepsia (FD) is unknown and several mechanisms associated with specific symptom patterns have been recently proposed. Increased duodenal acid exposure has been supposed to be associated with nausea, but recently an increase of severity of several dyspeptic symptoms was noted in a subset of dyspeptic patients. As its pathogenetic role is still unclear, we evaluated an involvement of duodenal acid exposure in symptom generation by inducing a hyperacidity status of the duodenum. Twelve young adult healthy volunteers in a randomized, double-blind protocol, underwent duodenal acid (0.2 N, 5 mL min⁻¹) or saline perfusion, antropyloroduodenal manometry and duodenal pH monitoring both during fasting and postprandially. Every 15 min, severity of discomfort, fullness, bloating, belching, nausea, heartburn, epigastric burning, satiety and pain were evaluated by visual analogue scale. During acid perfusion, symptom scores for discomfort, bloating, nausea, epigastric burning were significantly higher ( P  < 0.01) compared to saline. Postprandial antral motility index was lower (2.96 ± 1.8 vs 3.62 ± 1.8, P  = 0.01) and jejunal motility index higher (4.87 ± 1.0 vs 4.37 ± 1.4, P  = 0.01) during acid perfusion. Occurrence and duration of phases III of the migrating motor complex showed no difference. Duodenal acid perfusion causes a sensitization to dyspeptic symptoms and induces antral hypomotility and jejunal hypercontractility. Through these mechanisms, increased duodenal acid exposure may play a role in the pathophysiology of FD symptoms.