Sébastien Kindt

Impaired gastric accommodation and its role in dyspepsia

The accommodation reflex is an important mechanism of normal gastric physiology. In functional dyspepsia, impairment of accommodation has been found in 40% of cases, but it has been described in several other upper gastrointestinal disorders, such as diabetic gastropathy and postfundoplication syndrome. This review focuses on the pathways involved in the normal accommodation reflex, the relevance of impaired gastric accommodation as a cause of morbidity and the methods used to assess gastric accommodation in humans. The available medical and therapeutic strategies based on the actual knowledge of the physiology and pharmacology of the accommodation reflex are outlined, with a focus on the role of nitrergic neurones and serotonergic receptors.

Immune dysfunction in patients with functional gastrointestinal disorders

Abstract  There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)‐5, IL‐10, IL‐13 and interferon γ (IFN‐γ)] and monocytic [IL‐10, IL‐12, tumour necrosis factor (TNF)‐α] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti‐CD28 or lipopolysaccharide (LPS) in controls (n = 32), irritable bowel syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non‐cardiac chest pain (NCCP) (n = 15). Serum IL‐6 and IL‐10 concentrations were compared, and the immunophenotype was assessed using fluorescent‐activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL‐5 and IL‐13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL‐12 and lymphocytic IL‐10 expression were reduced in IBS and FD, while IFN‐γ expression was also reduced in FD patients. Except for an increase in the numbers of CD3+CD45RA+CD45RO+ cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL‐10 levels and more CD3+CD45RA+CD45RO+ cells, while TNF‐α levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these 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.

Influence of buspirone on gastric sensorimotor function in man

Background  Previous studies have suggested involvement of 5HT1 receptors in the control of gastric tone.

Longitudinal and cross-sectional factors associated with long-term clinical course in functional dyspepsia: a 5-year follow-up study.

OBJECTIVES:Functional dyspepsia (FD) is a heterogeneous disorder with different pathophysiological mechanisms underlying the symptom pattern, but little is known about its clinical course. The aims of this study were to study the long-term evolution of symptoms in a clinical FD population and to identify factors associated with outcome.METHODS:FD patients who previously underwent gastric function testing and filled out a dyspepsia symptom score (DSS) were contacted. At follow-up, patients indicated whether symptoms had worsened, remained unchanged, improved, or disappeared. Anxiety and depression, DSS, chronic fatigue symptoms, irritable bowel syndrome (IBS) comorbidity, and FD-specific quality of life (QoL) were assessed using mailed questionnaires. Bivariate associations between different patient characteristics and DSS and QoL at follow-up were tested; multiple linear regression was used to identify factors associated with the outcomes, both longitudinally and cross-sectionally.RESULTS:Data were obtained from 253 patients (84.9% of the eligible and consenting population (n=298) and 53.2% of the original population (n=476)). The mean duration of follow-up was 68±2 months. Disappeared, improved, unchanged, and worsened symptoms were reported by 17.4, 38.3, 30.8, and 13.4% of the patients, respectively. Correlations between dyspepsia symptoms at initial visit and follow-up were small to moderate in magnitude. DSS at initial visit and trait anxiety were longitudinally associated with DSS at follow-up, with a trend found for weight loss; depression, chronic fatigue, and IBS at follow-up were cross-sectionally associated with DSS. Trait anxiety, weight loss, and DSS at initial visit were independently associated with QoL at follow-up; depression as well as DSS and chronic fatigue at follow-up were cross-sectionally associated.CONCLUSIONS:About half of FD patients reported disappeared or improved symptoms after a mean follow-up of 5 years. Although stability of symptom levels is low to moderate, DSS at initial visit, trait anxiety, and initial weight loss are more strongly associated with outcome than gastric sensorimotor function.

Influence of intra-oesophageal capsaicin instillation on heartburn induction and oesophageal sensitivity in man

Abstract  Heartburn is the most typical gastro‐oesophageal reflux disease (GERD) symptom. The transient receptor potential vanilloid receptor‐1 (TRPV1) is a candidate mediator of heartburn. Exposure of TRPV1 to capsaicin is characterized by activation, followed by desensitization. Our aim was to investigate the effect of intra‐oesophageal capsaicin instillation on oesophageal symptom perception (activation) and on sensitivity to oesophageal acid perfusion and oesophageal balloon distention (desensitization). In a first protocol (n = 10), saline or capsaicin solution were instilled in the mid‐oesophagus and symptoms were rated at 5‐min intervals for 60 min. In a second study (n = 10), oesophageal 0.1 N hydrochloric acid perfusion was performed 60 min after pretreatment with saline, low or high dose capsaicin. In a third study (n = 10), sensitivity to oesophageal balloon distention was determined before and at 30‐min intervals up to 90 min after pretreatment with saline, low or high dose capsaicin. Areas under the curve (AUC) for symptom intensities under different conditions were calculated and compared with Kruskal–Wallis test. Oesophageal capsaicin instillation induced transient symptoms of retrosternal and epigastric burning in a dose‐dependent fashion. After oesophageal capsaicin or saline instillation, there was no difference in symptom pattern and intensities induced by oesophageal acid perfusion. After oesophageal capsaicin or saline instillation, sensitivity to oesophageal balloon distention and oesophageal compliance were not significantly altered. Oesophageal instillation of the TRPV1 receptor agonist capsaicin induces symptoms of retrosternal and epigastric burning in a dose‐dependent fashion. Pretreatment with capsaicin does not desensitize the oesophagus to acid perfusion or to balloon distention.

Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man.

Abstract  Ghrelin increases gastric tone in the fasting state and enhances gastric emptying in gastroparesis. The aims of the study were to evaluate the effect of ghrelin on postprandial gastric tone and on meal‐induced satiety in health. Ten healthy volunteers underwent a barostat study on two occasions. After determination of intra‐abdominal pressure (minimal distending pressure, MDP), isobaric volume measurement was performed for 90 min at MDP + 2 mmHg. After 20 min, ghrelin (40 μg) or saline was administered i.v. over 30 min in a double‐blind‐randomized cross‐over design, followed 10 min later by a liquid meal (200 mL, 300 kcal). Stepwise isobaric distentions (+2 mmHg per 2 min) were performed 60 min after the meal. Data (mean ± SEM) were compared using paired Student’s t‐test and anova. Separately, a satiety drinking test (15 mL min−1 until satiety score 5) was performed on 10 subjects twice, after treatment with placebo or ghrelin. Ghrelin infusion significantly inhibited gastric accommodation (mean volume increase adjusted means 108.0 ± 50 vs 23.0 ± 49 mL, P = 0.03, ancova with the premeal postinfusion volume as covariate) and reduced postprandial gastric volumes (197.2 ± 24.6 vs 353.5 ± 50.0 mL, P = 0.01). Pressures inducing perception or discomfort during postprandial gastric distentions were not altered. During satiety testing, ghrelin did not alter nutrient volume ingested till maximal satiety (637.5 ± 70.9 vs 637.5 ± 56.2 mL, ns). Ghrelin administered during the meal significantly inhibits gastric accommodation in health, but this is not associated with early satiation.

Relationship between symptom pattern, assessed by the PAGI-SYM questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract  The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = −0.27), bloating (r = −0.23), heartburn/regurgitation (r = −0.21), and upper abdominal pain (r = −0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.

Gastrointestinal motility changes and myenteric plexus alterations in spontaneously diabetic biobreeding rats

Background/Aims Type 1 diabetes is often accompanied by gastrointestinal motility disturbances. Vagal neuropathy, hyperglycemia, and alterations in the myenteric plexus have been proposed as underlying mechanism. We therefore studied the relationship between vagal function, gastrointestinal motiliy and characteristics of the enteric nervous system in the biobreeding (BB) rat known as model for spontaneous type 1 diabetes. Methods Gastric emptying breath test, small intestinal electromyography, relative risk-interval variability, histology and immunohistochemistry on antral and jejunal segments were performed at 1, 8 and 16 weeks after diabetes onset and on age-matched controls. Results We observed no consistent changes in relative risk-interval variability and gastric emptying rate. There was however, a loss of phases 3 with longer duration of diabetes on small intestinal electromyography. We found a progressive decrease of nitrergic neurons in the myenteric plexus of antrum and jejunum, while numbers of cholinergic nerve were not altered. In addition, a transient inflammatory infiltrate in jejunal wall was found in spontaneous diabetic BB rats at 8 weeks of diabetes. Conclusions In diabetic BB rats, altered small intestinal motor control associated with a loss of myenteric nitric oxide synthase expression occurs, which does not depend on hyperglycemia or vagal dysfunction, and which is preceded by transient intestinal inflammation.

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.