Anne C. Haddad

Human Interdigestive Motility: Variations in Patterns From Esophagus to Colon

In most fasting mammals, motility of the foregut and small intestine undergoes regular cycles of activity. Much of the expanding knowledge of this phenomenon comes from species other than humans; however, disorders of these patterns are proposed as being clinically important. We report studies in 16 healthy humans in whom motility was recorded from intraluminal pressure sensors, both when fasting and after a meal, for prolonged periods. The recording system spanned the area from stomach to proximal colon in all subjects and included the lower esophagus in 11 of the 16 studied. Half the interdigestive cycles involved the esophagus, approximately one-third began in the gastroduodenal region, and the remainder commenced more distally. Fewer than half the migrating motor complexes were recognizable beyond the midpoint of the small bowel, and less than 10% reached the distal ileum. The migrating motor complex was more prominent at night; and its progression through the jejunum was then slower. Small meals (345-395 kcal) interrupted fasting patterns for 90-240 min, but the amount of fat did not influence the duration of these disruptions. Motility varied widely between and within individuals, and differences between normal patterns in the jejunum and ileum were particularly striking. Thus, levels of recordings must be defined accurately if putative abnormalities, of possible clinical significance, are to be interpreted correctly. Relating local motor patterns to the maximal rate of rhythmic contractions, which reflects the frequency of slow waves and is a guide to the level of the small bowel, may be helpful in this regard.

GR 38032F (Ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist known to have antiemetic effects, influences colonic transit in health, a randomized, double-blind, placebo-controlled crossover study was performed. Using a radiopaque marker technique, colonic transit was quantified in 39 healthy volunteers (19 men, 20 nonpregnant women) 18–70 years of age. On a standard 25-g fiber diet, 16 mg of GR 38032F was given orally thrice daily. Gastrointestinal peptides (peptide YY, human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, substance P) were also measured in plasma fasting and postprandially. Mean total colonic transit time on placebo was 27.8 hr, while on GR 38032F it was 39.1 hr (P<0.0005). Transit times through the left colon (P<0.0005) and rectosigmoid (P<0.05) were prolonged by the drug, but right colonic transit was not significantly altered. Transit times did not correlate with age or gender, but subjects with shorter transit times were significantly more affected than were those with longer transit times. The peak release of peptide YY was minimally decreased following GR 38032F (P<0.01), but the peak and integrated postprandial responses of human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, and substance P were not significantly altered by the drug. We conclude that 5HT3 receptors may be involved in the regulation of colonic transit in healthy man.

Variation of Muscle Tone in the Human Colon

It was hypothesized that the human colon is able to relax or constrict to receive materials arriving from above or to hasten distal passage of contents. Dilatation is also a feature of several pathophysiological states and, therefore, the propensity of the colon to dilate might be important in disease. An electromechanical barostat was applied to the human colon, and changes in colonic tone were recorded in response to physiological perturbations. In 16 studies of 14 healthy volunteers, the colon was prepared for colonoscopy and a manometry-barostat assembly was positioned in the ascending (n = 5), transverse (n = 4), or descending (n = 7) colon. The influences of food and overnight sleep were recorded. The barostat continuously monitored, at a constant pressure, the volume of air within a highly compliant 10-cm bag. Changes in tone, as reflected by changes in bag volume, were usually unassociated with waves of intraluminal pressure recorded from adjacent manometric sites. Thus, the barostat revealed a motor phenomenon not readily apparent by conventional manometry. Food caused an immediate though slowly progressive increase in tone; however, bag volumes were greatest during overnight sleep and were decreased on waking. The barostat has the potential to explore another possibly important aspect of colonic function in humans.

Colonic Tone and Motility in Patients With Irritable Bowel Syndrome

In this study, our aim was to test the hypothesis that colonic tone is abnormal in patients with irritable bowel syndrome (IBS). We studied eight patients with IBS and eight age-matched asymptomatic control subjects, in whom tone and motility were measured by an electronic barostat and by pneumohydraulic perfusion manometry, respectively. Tone and motility were recorded from the descending colon for a 14-hour period--3 hours awake, 7 hours asleep, 2 hours fasting after awakening, and 2 hours postprandially. In patients with IBS and in healthy subjects, colonic tone decreased by up to 50% during sleep and increased promptly on awakening. Fasting colonic tone (as quantified by the volume in the barostat balloon) in the awake state was not significantly higher in patients with IBS than it was in healthy subjects (125 +/- 13 versus 152 +/- 15 ml; P = 0.19). Tone increased postprandially in both study groups, and the increase was greater in healthy subjects than it was in patients with IBS (P < 0.05). The motility index during fasting was greater in patients with IBS than it was in healthy control subjects (3.2 +/- 0.6 versus 1.6 +/- 0.4; P = 0.05), and the postprandial increase in motility index was greater in the healthy subjects. Preprandially and postprandially, we noted a trend for high-amplitude prolonged contractions to be more frequent in patients with IBS than in healthy subjects. We conclude that colonic tone in patients with IBS showed the same nocturnal and postprandial variations as it did in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of morphine and atropine on motility and transit in the human ileum.

We examined motility of the ileocecal region, pressures at the ileocecal sphincter, and ileal flow after therapeutic doses of morphine and atropine. Using a factorial design in two cells of 8 (2(3] subjects, drugs were given during fasting and postcibally. Morphine (100 micrograms/kg body wt as a bolus intravenously) and atropine (7 micrograms/kg body wt as a bolus) stimulated migrating bursts of phasic activity (similar to phase III of the migrating motor complex). Morphine initially stimulated ileal flow, but atropine could not be shown to have this effect. Atropine reduced markedly the occurrence of sporadic pressure waves in the ileum, but morphine did not. Whereas atropine delayed mouth-to-ileum transit of polyethylene glycol, given in a mixed meal, morphine did not. Naloxone, in the dosage used (40 micrograms/kg body wt as a bolus, followed by 10 micrograms/kg body wt X h) had no independent effects on motility or flow, but did blunt the stimulatory effects of morphine and atropine on migrating motor complexes. We could not demonstrate an effect of any drug on the transit of lactulose from terminal ileum to cecum. Neither morphine nor atropine had impressive effects on tone at the ileocecal sphincter. These observations, while not specifying the mechanisms for constipation after opiates or anticholinergics, highlight the complexities of small bowel transit in humans and point out that the antidiarrheal effects of drugs are probably multifactorial.

Control of muscle tone in the human colon

Human colonic muscle tone varies diurnally and postprandially in predictable ways. Increased tone reduces the capacity of the colon to store contents after a meal, whereas increased distensibility (lesser tone) during sleep enlarges the storage capabilities and may slow transit. We tested the hypothesis that antidiarrhoeal drugs would also alter tone which, in turn, might reduce diarrhoea by facilitating the storage and salvage of fluids. Using a colonic barostat to create low pressure, isobaric colonic distension in healthy volunteers, we found that intravenous atropine (0.01 mg/kg) relaxed the colon during fasting, reduced the postprandial increase in tone, and enhanced relaxation in the late (1-2 hour) postprandial period. Intravenous morphine (0.1 mg/kg) caused variable effects soon after injection but, in fasting subjects, the descending colon relaxed 70-90 minutes after morphine. These changes in colonic motility were not always obvious by conventional manometric recording. Colonic distensibility is increased by antidiarrhoeal drugs and this effect may contribute to their efficacy in slowing colonic transit and augmenting absorption.

Effect of selective 5HT3 antagonist (GR 38032F) on small intestinal transit and release of gastrointestinal peptides

Antagonists of 5-hydroxytryptamine type 3 (5HT3) receptors reduce the nausea induced by cisplatinum, but the effects of these agents on 5HT3 receptors in the human gut remain to be defined. We examined the actions of one of these drugs (Glaxo GR 38032F) on small intestinal transit and mouth-to-cecum transit times in healthy man. We also quantified its effects on the release of peptide YY (PYY), neurotensin, human pancreatic polypeptide, gastrin-cholecystokinin, and motilin. Ten healthy volunteers were enrolled in a randomized, double-blind, placebo-controlled crossover study. Following a single intravenous dose of GR 38032F (0.15 mg/kg), we measured the time to appearance in plasma of sulfapyridine after injection of salicylazosulfapyridine into the duodenum. This was used as a measure of duodenocecal transit. The appearance of hydrogen in breath after ingestion of a meal containing lactulose was also correspondingly used to quantify the mouth-to-cecum transit of the “head” of the meal. Gastrointestinal hormones were assayed in plasma by specific RIAs; samples were drawn fasting (10 min after injection) and after breakfast (358 calories: 15.7 g protein, 55.4 g carbohydrate, 8.1 g fat). The postprandial integrated response and peak release of PYY was decreased by GR 38032F. There was also a trend for the peak release of neurotensin to be reduced. GR 38032F did not significantly alter small intestinal transit times or mouth-to-cecum transit times. We conclude that GR 38032F does not have a major effect on small intestinal transit in health.

Fecal short-chain fatty acid concentrations and effect on ileal pouch function

Random stool samples were obtained from 14 ileal pouch-anal anastomosis (IPAA) patients 43 ± 5 (mean ± SEM) months after surgery, and the concentrations of individual short-chain fatty acids (SCFAs) were determined by gas liquid chromatography. Stool frequency was determined from a diary recorded for 15 days prior to stool sampling. The frequency, amplitude, and duration of phasic contractions (PCs) within the pouch following infusion of a physiologic concentration of SCFAs and normal saline randomly into the pouch of six IPAA patients were determined manometrically. The mean total SCFA concentration after IPAA did not differ significantly from normal stools (83 ± 20 mM after IPAAvs.97 ± 10 mM for controls;P> 0.05). In the IPAA patients, regression analysis demonstrated aninverserelationship between stools per day and total SCFA concentration (r = 0.73;P< 0.001). Moreover, no change in frequency (3.0 ± 0.9vs.3.2 ± 0.8 PCs/30 minutes), amplitude (26 ± 5vs.25 ± 4 mmHg), or duration (23 ± 3vs.26 ± 2 seconds) of PCs was found after SCFA infusion compared with saline control (P >0.1). These findings demonstrate that SCFAs are present in ileal pouch effluent and that stool frequency may be related to fecal SCFA concentration. Also, the normal contractile response of the terminal ileum to SCFAs does not occur in the ileal pouch.