Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women.

OBJECTIVE: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD. METHODS: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years). RESULTS: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C. CONCLUSIONS: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

A rare cause of obstructive jaundice and weight loss in Von Recklinghausen's disease.

We present the case of a patient with the rare triad of Von Recklinghausen's disease associated with a somatostatinoma and a gastrointestinal stromal tumour (GIST). The patient had recurrent jaundice, the typical somatostatinoma syndrome, positive MR imaging but negative 68Ga-DOTATOC PET scanning in a histopathology-proven somatostatinoma tumour.

The effect of two sports drinks and water on GI complaints and performance during an 18-km run.

Gastrointestinal (GI) complaints are frequently experienced during running. Sports drinks to prevent dehydration and hypoglycemia during exercise are generally used. The aim was to investigate the effect of 3 different drinks on GI complaints and performance during competitive running in a controlled field study. Ninety-eight well-trained subjects (90 M, 8 F, age 41 +/- 8 y) performed a competitive 18-km run three times within 8 days. The study was a controlled, standardized field experiment following a randomized, crossover design. Three different drinks were compared: water, a sports drink (CES), and a sports drink with added 150 mg/l caffeine (CAF). The incidence of GI complaints and the effect of the drinks on performance was studied. Each subject consumed 4 times 150 ml as follows: at the start, after 4.5 km, 9 km, and 13.5 km. Fluid intake was controlled. Incidence and intensity of GI complaints during the run were determined using a 10 points scale questionnaire. There were no significant differences in performance between the 3 drinks. Run time (18 km, mean +/- SD): WAT 1 : 18 : 03 +/- 08 : 30, CES 1 : 18 : 23 +/- 08 : 47, CAF 1 : 18 : 03 +/- 08 : 42. The use of carbohydrate-containing sports drinks led to higher incidences of all types of GI complaints compared to water. Significant differences (p < 0.05) were reached for flatulence; incidence: WAT 17.9 %, CES 28.6 %, CAF 30.6 %, and reflux; incidence: WAT 55.7 %, CES 78.6 %, CAF 72.5 %. There were no significant differences in intensity of the GI complaints. Addition of caffeine to CES had no effect on GI complaints, compared to CES alone. We conclude that sports drinks used during an 18-km run in cool environmental conditions do not support the performance better than mineral water. The use of sports drinks during an 18-km run leads to a higher incidence of both upper and lower GI complaints compared to water. Addition of caffeine to the sports drink has no effect on either running performance or GI complaints.

Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls.

BACKGROUND: Serotonin, a key denominator of the brain-gut axis, is involved in the regulation of gastrointestinal motility, secretion, and perception as well as cognition and mood. AIM: To assess the effects of an acutely lowered serotonin synthesis, using the acute tryptophan depletion (ATD) method, on visceral perception, affective memory performance, and mood in diarrhoea predominant irritable bowel syndrome patients (d-IBS) and controls. METHODS: In a randomised, double blind, crossover design, 14 d-IBS patients and fourteen matched controls were studied under ATD and placebo conditions, respectively. Perception of urge and pain was scored during rectal distensions. Affective memory performance, mood, and biochemical parameters of serotonergic metabolism were simultaneously assessed. RESULTS: ATD significantly decreased plasma tryptophan (67.0 (2.0) v 24.9 (2.0) mumol/l) and 5-hydroxyindole acetic acid concentrations (29.9 (1.0) v 15.8 (0.6) nmol/l). ATD was associated with significantly increased urge scores specifically in the lower pressure range and overall increased pain scores. ATD significantly lowered the perceptual threshold for first perception compared with placebo (patients 10.6 (1.2) v 13.6 (0.8) mm Hg, controls 12.6 (1.3) v 15.7 (1.2) mm Hg) but not for maximal tolerable discomfort (patients 50.5 (3.6) v 51.6 (3.3) mm Hg, controls 50.9 (3.3) v 48.8 (2.9) mm Hg). ATD induced a significant shift in affective memory bias towards preferential loss of positive material but no significant changes in mood. ATD did not differentially affect the patient or control group. CONCLUSIONS: We have provided evidence that serotonergic modulation by ATD affects both visceral perception as well as cognition in d-IBS and controls. Simultaneous measurement of brain and gut function and the application of ATD contribute to the elucidation of the complex pathophysiology of IBS.

Systematic review: serotonergic modulators in the treatment of irritable bowel syndrome--influence on psychiatric and gastrointestinal symptoms.

BACKGROUND: Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome. AIM: To analyse, systematically, randomized controlled trials studying the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline irritable bowel syndrome symptomatology and possible differential effects of serotonergic modulation on this symptomatology. METHODS: A standardized qualitative analysis was performed of studies investigating the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome using a blind review approach. The studies were ranked according to their total quality score (maximum 100 points). RESULTS: Eleven studies fulfilled the entry criteria, six of which scored above 55 points. An association between gastroenterological and psychiatric changes was present in five of the six studies. CONCLUSIONS: The results strengthen the serotonergic association between gastroenterological and psychiatric symptoms. Adjusted guidelines for combined gastrointestinal and psychiatric assessments are recommended in order to further elucidate the serotonergic interaction between gastrointestinal and psychiatric symptoms.

The effect of different dosages of guar gum on gastric emptying and small intestinal transit of a consumed semisolid meal.

BACKGROUND: There is no consensus about the effect of guar gum supplementation on gastrointestinal transit. It has been suggested that guar gum slows gastric emptying and intestinal transit, thus inducing an increased feeling of satiety. OBJECTIVE: To investigate whether addition of guar gum to a semisolid meal affects gastrointestinal transit. DESIGN: Eight male subjects were randomly studied four times. They consumed a standard semisolid test meal containing either 0 g, 2.5 g, 3.5 g, or 4.5 g of guar gum. The test meals contained 1 mCi 99mTc-hepatate for scintigraphy and 5 g lactulose for the H2-breath test. Scintigraphic scanning was performed for at least two hours, and gastric half-emptying time (T1/2) was calculated. Breath samples were collected at 15 minute intervals and analyzed for H2-enrichment. The orocecal transit time (OCTT) was then determined. A parameter of intestinal transit (PIT) was obtained by subtracting the T1/2 from the OCTT. RESULTS: There were no significant differences (in minutes) between the different tests in both T1/2 (0 g, t = 88.2 +/- 11, 2.5 g, t = 83.3 +/- 11.9, 3.5 g, t = 83.3 +/- 13.6, 4.5 g, t = 72.4 +/- 7.2, p = 0.86) and PIT (0 g, t = 149.9 +/- 26.6, 2.5 g, t = 145.5 +/- 25.6, t = 3.5 g, t = 175.3 +/- 17.6, t = 4.5 g, t = 152.6 +/- 22.4, p = 0.52). CONCLUSION: Addition of guar gum to a semisolid meal up to a dosage of 4.5 g does not affect gastrointestinal transit. Other mechanisms than gastrointestinal motility are involved in a possible satiating effect of guar gum supplementation.

Gastrointestinal function during exercise: comparison of water, sports drink, and sports drink with caffeine.

Caffeine is suspected to affect gastrointestinal function. We therefore investigated whether supplementation of a carbohydrate-electrolyte solution (CES) sports drink with 150 mg/l caffeine leads to alterations in gastrointestinal variables compared with a normal CES and water using a standardized rest-exercise-rest protocol. Ten well-trained subjects underwent a rest-cycling-rest protocol three times. Esophageal motility, gastroesophageal reflux, and intragastric pH were measured by use of a transnasal catheter. Orocecal transit time was measured using breath-H(2) measurements. A sugar absorption test was applied to determine intestinal permeability and glucose absorption. Gastric emptying was measured via the (13)C-acetate breath test. In the postexercise episode, midesophageal pressure was significantly lower in the CES + caffeine trial compared with the water trial (P = 0.017). There were no significant differences between the three drinks for gastric pH and reflux during the preexercise, the cycling, and the postexercise episode, respectively. Gastric emptying, orocecal transit time, and intestinal permeability showed no significant differences between the three trials. However, glucose absorption was significantly increased in the CES + caffeine trial compared with the CES trial (P = 0.017). No significant differences in gastroesophageal reflux, gastric pH, or gastrointestinal transit could be observed between the CES, the CES + caffeine, and the water trials. However, intestinal glucose uptake was increased in the CES + caffeine trial.

Effects of pre- and post-absorptive factors on the lactulose/rhamnose gut permeability test.

It is assumed that the outcome of the lactulose/rhamnose gut permeability test is not influenced by pre- or post-absorptive factors. The aim of our study was to investigate the role of a pre-absorptive factor, i.e. small-intestinal transit, and a post-absorptive factor, i.e. renal clearance. Ten healthy male subjects were studied. Urinary lactulose and rhamnose excretion was measured after intraduodenal administration of lactulose and rhamnose following induction of increased intestinal permeability using chenodeoxycholic acid (chenodiol), in the absence and in the presence of accelerated intestinal transit. Urinary sugar excretion was measured after intravenous administration of either a regular dose (50 mg/50 mg) or a high dose (250 mg/250 mg) of lactulose/rhamnose. The intraduodenal experiments showed that a combination of accelerated small-bowel transit and increased permeability did not lead to significant differences in the recovery of lactulose (P=0.647) or rhamnose (P=0.889), or in the lactulose/rhamnose ratio, compared with those under conditions of increased permeability alone (P=0.68). However, lactulose recovery was significantly lower (P=0.025) after intravenous administration of a high dose of the sugars. There was no significant difference in urinary rhamnose recovery (P=0.575) between the high and the regular doses. This resulted in a significantly lower lactulose/rhamnose ratio (P=0.021) after intravenous administration of a high dose, compared with a regular dose, of the sugars. In conclusion, the assumption that post-absorptive processes do not influence the outcome of the lactulose/rhamnose permeability test appears not to be valid.

Effect of dehydration on gastrointestinal function at rest and during exercise in humans.

Dehydration leads to the aggravation of gastrointestinal (GI) complaints during exercise. The aim of this study was to examine the effect of dehydration on various GI parameters during strenuous exercise. Ten healthy well-trained men were investigated in dehydrated and in euhydrated conditions. Dehydration took place before the experiments using a dehydration regimen in a sauna leading to a 3% loss of body mass. Each experiment consisted of 1 h pre-exercise rest, 1.5 h cycling at 70% maximal exercise intensity, and 3.5 h post-exercise rest. During cycling, liquid gastric emptying (GE), orocaecal transit time (OCTT) and intestinal permeability and glucose absorption were measured. The GI-symptoms were scored using a questionnaire. Body temperature, plasma volume and vasopressin were measured before and after cycling. The GE was significantly slower during dehydration [median time to peak 13C enrichment in the breath sample (13C-TTP) 23.6 min, range 13.7-50.0 min, P = 0.02] than in the control situation (median 13C-TTP 17.1 min, range 9.8-38.4 min). The OCTT was unchanged (median 173 min, range 98-263 min compared to median 128 min, range 98-195 min, P = 0.18). Dehydration did not change intestinal permeability, glucose absorption, plasma volume, rectal temperature or plasma vasopressin concentration. In the dehydration experiment, exercise induced a significant increase in nausea (P = 0.01) and epigastric cramps (P = 0.05), in contrast to the control situation. In both experiments, exercise led to a significant increase in rectal temperature and plasma vasopressin concentration, and a significant decrease in plasma volume. The increase in plasma vasopressin concentration was significantly higher in the dehydration experiment (P = 0.015). No significant differences in either the post-exercise rectal temperatures or in plasma volumes was observed. The difference in GE between the two experiments was significantly correlated with the difference in nausea score (r = 0.87, P = 0.002). We concluded that dehydration leads to a delayed GE but not to differences in OCTT, intestinal permeability or glucose uptake during intense cycling. The delay in GE is significantly associated with an increase in exercise-induced nausea.

The effect of physical exercise on parameters of gastrointestinal function.

Exercise decreases splanchnic bloodflow. Therefore exercise may induce alterations in gastrointestinal (GI) function. In the present study we investigated the effect of high-intensity exercise on oesophageal motility, gastro-oesophageal reflux, gastric pH, gastric emptying, orocaecal transit time (OCTT), intestinal permeability and glucose absorption simultaneously, using an ambulatory protocol. Ten healthy well-trained male subjects underwent a rest-cycling-rest, and a rest-rest-rest protocol (60-90-210 min). Oesophageal motility, gastro-oesophageal reflux and intragastric pH was measured using a trans-nasal catheter. OCTT was measured via breath H2 measurement. A sugar absorption test was applied to determine intestinal permeability and glucose absorption. Gastric emptying was measured using the 13C-acetate breath test. Peristaltic velocity was increased during cycling, compared to rest (4.92 (2.86) vs. 4.03 (1. 48) cm s-1, P = 0.015). Peristaltic contraction pressure at the mid-oesophagus and the duration of the peristaltic contractions at the mid- and distal oesophagus was lower during cycling. There were no differences between the pre-exercise, the exercise and the post-exercise episodes for gastric pH or for both the number and duration of reflux episodes, in both the rest and cycling trials. Neither gastric emptying nor OCTT showed differences between rest and cycling. The lactulose/rhamnose ratio and intestinal glucose absorption were significantly decreased in the cycling trial. Our model enables multiple GI-measurements during exercise. Cycling at 70% Wmax does not lead to differences in reflux, gastric pH or gastrointestinal transit in healthy trained individuals. The distal oesophageal pressure decreases and peristaltic velocity increases. The lactulose/rhamnose ratio and jejunal glucose absorption are decreased during exercise.

Performance of the [13C]-acetate gastric emptying breath test during physical exercise.

BACKGROUND: The gastric emptying rate of liquids can be determined non-invasively using the [13C]-acetate breath test at rest. The aims of our study were to validate this test during physical exercise against the double-sampling method and to evaluate the time needed for intestinal absorption and the delay between absorption and appearance of 13CO2 in breath, both at rest and during exercise. DESIGN: Fifteen well-trained male subjects were investigated. Gastric emptying was determined simultaneously measuring the 13CO2 breath enrichment after intragastric administration of 0.5 L of carbohydrate solution with 150 mg of [13C]-acetate added and by the double-sampling technique (n = 9). In separate tests, 150 mg of [13C]-acetate was also applied intraduodenally and intravenously (n = 6), both at rest and during exercise. Time-to-peak (TTP) 13CO2 enrichment was determined using a curve fit and was considered as the parameter for gastric emptying. RESULTS: TTP enrichment derived from the breath test significantly correlated with the gastric emptying half-time obtained from the gastric aspirates. During exercise, median TTP enrichment values after intragastric, intraduodenal (i.d.) and intravenous (i.v.) administration of [13C]-acetate were 22.3, 10.3 and 5.4 min respectively. During exercise, i.d. and i.v. values were reached significantly earlier than at rest. CONCLUSION: The [13C]-acetate breath test can be used as a non-invasive method to determine relative gastric emptying rates of liquids during exercise, but the results are influenced by the rate of absorption and the time needed for subsequent oxidation of [13C]-acetate and exhalation of 13CO2.

The sensitivity of the lactulose/rhamnose gut permeability test.

BACKGROUND: The lactulose/rhamnose (L/R) intestinal permeability test is widely used. However, different quantities and proportions of lactulose and rhamnose are used. The aim of this study was to determine whether a low dosage of lactulose is able to discriminate between normal and increased permeability. MATERIALS AND METHODS: Two groups of 10 healthy subjects were studied. In group 1, three different iso-osmolar test solutions were administered on 3 days. The solutions consisted of 10 g of L with 1 g of R, 5 g of L with 0.5 g of R and 1 g of L with 0.1 g of R in 65 mL of water. Group 2 ingested these solutions 1 h after ingestion of 750 mg of chenodeoxycholeic acid (CDCA), which is known to increase permeability. The urinary L/R ratio was determined using high-performance liquid chromatography. Data are presented as medians (range). RESULTS: In group 1, no differences were observed between the three solutions. In Group 2, there was a significant difference (P = 0.045) between the three solutions. The L/R ratios were 0.0079 (0.0024-0.0152) (1L to 0.1R), 0.0138 (0.0066-0.0192) (5L to 0.5R) and 0.0144 (0.0074-0.0374) (10L to 1R). The L/R ratio differed significantly between Groups 1 and 2 (P < 0.001) using the 5L to 0.5R and 10L to 1R solutions respectively. CONCLUSION: If the permeability is increased, the urinary L/R ratio depends on the quantity of lactulose and rhamnose administered in equal proportion. 5L to 0.5R is sufficient to discriminate between a normal and a moderately increased permeability.