Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]

How exocrine pancreatic secretion is regulated is only partly known. It is assumed that interaction of several neural and hormonal mechanisms is involved. In man, the intestinal component of these control mechanisms is very important while extra-intestinal mechanisms (such as the cephalic and the gastric phase) play lesser roles. Regulation of pancreatic secretion by the intestine is composed of three main mechanisms. 1. The proximal intestinal (duodenal) phase of the secretory response to a meal is elicited by nutrients within the proximal intestinal lumen. It is mediated mainly by interactions between cholinergic reflexes and release of the peptide hormone cholecystokinin (CCK). Recent data suggest that part of the action of CCK is not exerted directly on the acinar cellular level, but rather by modulation of cholinergic inputs. 2. The distal intestinal (ileal) phase is elicited by contact of the distal intestinal mucosa with nutrients that pass through the ileal lumen due to physiological malabsorption. The ileum (in contrast to the duodenum) induces net-inhibition of pancreatic secretion. The mediation is unknown, candidate mediators are PYY and GLP-1. 3. Intestinal feedback-regulation of pancreatic secretion in humans is controlled by intraluminal protease activity; this mechanism is not covered in the present paper.     

Cholecystokinin cells purified by fluorescence-activated cell sorting respond to monitor peptide with an increase in intracellular calcium.

Cholecystokinin (CCK) is secreted from specific enteroendocrine cells of the upper small intestine upon ingestion of a meal. In addition to nutrients, endogenously produced factors appear to act within the gut lumen to stimulate CCK release. One such factor is a trypsin-sensitive CCK-releasing peptide found in pancreatic juice, known as monitor peptide. This peptide is active within the intestinal lumen and is hypothesized to stimulate CCK secretion by interacting directly with the CCK cell. We have found that monitor peptide releases CCK from isolated rat intestinal mucosal cells and that this effect is dependent upon extracellular calcium. In the present study, we used monitor peptide as a tool for isolating CCK cells from a population of small intestinal mucosal cells. Dispersed rat intestinal mucosal cells were loaded with the calcium-sensitive fluorochrome Indo-1, and CCK secretory cells were identified spectrofluorometrically by their change in fluorescence when stimulated with monitor peptide. Cells demonstrating a change in their emission fluorescence ratio were sorted using a fluorescence-activated cell sorter. More than 90% of the sorted cells stained positively for CCK with immunohistochemical staining. Furthermore, sorted cells secreted CCK when stimulated with membrane-depolarizing concentrations of potassium chloride, dibutyryl cAMP, calcium ionophore, and monitor peptide. These findings indicate that functional intestinal CCK cells can be highly enriched using fluorescence-activated cell sorting. Furthermore, monitor peptide appears to interact directly with CCK cells to signal CCK release through an increase in intracellular calcium.     

Effect of a new cholecystokinin antagonist (FK 480) on gene expression of cholecystokinin and secretin in rat intestine

The effects of a new cholecystokinin (CCK) antagonist (FK 480; 0.1 mg/kg per day given by intragastric administration to rats for 3 days) on the expression of the CCK and secretin genes, plasma CCK immunoreactivity, and CCK content in the intestinal mucosa were examined. FK 480 increased the level of CCK mRNA in the intestine to 1.7 times the level in control rats, but did not affect the level of secretin mRNA. It did not increase plasma CCK immunoreactivity or CCK content in the intestinal mucosa. These results suggest that the ingested FK 480 directly increased CCK mRNA level in the intestine and produced a dissociation between the synthesis and release of CCK.     

Clinical endocrinology and metabolism. Cholecystokinin

Cholecystokinin (CCK) is a peptide hormone discovered in the small intestine. Together with secretin and gastrin, CCK constitutes the classical gut hormone triad. In addition to gallbladder contraction, CCK also regulates pancreatic enzyme secretion and growth, intestinal motility, satiety signalling and the inhibition of gastric acid secretion. CCK is, however, also a transmitter in central and intestinal neurons. Notably, CCK is the most abundant neuropeptide in the human brain. Owing to difficulties in developing accurate assays, knowledge about CCK secretion in disease is limited. Available data indicate, however, that proCCK is expressed in certain neuroendocrine tumours and sarcomas, whereas the secretion of CCK is impaired in celiac disease and bulimia nervosa. Stimulation with exogenous CCK has proved useful in diagnostic tests of gallbladder and pancreatic diseases, as well as medullary thyroid carcinomas.     

Effects of psychological stress on small intestinal motility and expression of cholecystokinin and vasoactive intestinal polypeptide in plasma and small intestine in mice

AIM: To investigate the effects of psychological stress on small intestinal motility and expression of cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP) in plasma and small intestine, and to explore the relationship between small intestinal motor disorders and gastrointestinal hormones under psychological stress. METHODS: Thirty-six mice were randomly divided into psychological stress group and control group. A mouse model with psychological stress was established by housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. CCK and VIP levels in plasma and small intestine in mice were measured by radioimmunoassay (RIA). RESULTS: Small intestinal transit was inhibited (52.18±19.15% vs70.19±17.79%, P<0.01) in mice after psychological stress, compared to the controls. Small intestinal CCK levels in psychological stress mice were significantly lower than those in the control group (0.75±0.53 μg/g vs1.98±1.17 μg/g, P<0.01), whereas plasma CCK concentrations were not different between the groups. VIP levels in small intestine were significantly higher in psychological stress mice than those in the control group (8.45±1.09 μg/g vs7.03±2.36 μg/g, P<0.01), while there was no significant difference in plasma VIP levels between the two groups. CONCLUSION: Psychological stress inhibits the small intestinal transit, probably by down-regulating CCK and up-regulating VIP expression in small intestine.     

Intestinal phase of pancreatic polypeptide release: the effect of segmental perfusion of the small intestine with various secretagogues

The purpose of this study was to examine the effect of various nutrients perfused selectively into isolated sections of the small intestine on the release of pancreatic polypeptide (PP). Six dogs were prepared with chronic gastric, duodenal, and three permanent intestinal fistulas (one distal to the ligament of Treitz, one in the terminal ileum, and one halfway between). After a 24-h fast, the duodenum was perfused for 45 min (200 ml/h) via the duodenal limb with HCl (30 mM), an amino acid solution (50 mM), or sodium oleate (NaO, 40 mM). In separate studies, the jejunal and ileal segments were isolated by inflating two balloon catheters via the intestinal fistula, and these segments were perfused as described earlier. Plasma PP, cholecystokinin (CCK)-33, and secretin levels were measured. Results of this study showed that the perfusion of all segments of the small intestine with amino acid caused a significant elevation of plasma PP levels. Perfusion of the duodenum and jejunum but not the ileum with a fatty acid resulted in a significant elevation of plasma levels of PP. Perfusion of HCl into any segment did not affect plasma levels of PP. This study shows that PP is released by the presence of nutrients in all segments of the small intestine, and that a PP elevation was always accompanied with a rise in plasma levels of CCK-33.     

Gastrointestinal motility in obesity

Abstract. Gastrointestinal motility is closely linked to the rate at which nutrients become systemically available. Regulation of gastric emptying represents the most important brake against delivery of nutrients to the intestine in excess of digestive and absorptive capacity. In man, gastric emptying is slowed in proportion to the energy density of the meal, which will level out the rate of energy delivery to the duodenum. Studies suggest a more rapid gastric emptying in obesity, although the opposite has been reported in some experimental settings. Moreover, gastric volume is larger in obese individuals and appropriate satiety signals are not triggered in response to gastric distension. Postprandial intestinal transit time in obesity is similar to that in normal-weight subjects, however, despite this fact, intestinal absorption of nutrients is more efficient in obesity. Several regulatory mechanisms for gastrointestinal motility, such as the autonomous and enteric nervous systems and gastrointestinal regulatory peptides, are also of importance for feeding behaviour and metabolism. Dysfunction of the autonomous nervous system has been observed, the sensitivity to cholecystokinin is decreased in obesity, and plasma concentrations of somatostatin and neurotensin are lower than in normal-weight subjects. These changes in regulatory mechanisms favour rapid gastrointestinal transit of ingested nutrients and promote rapid intestinal absorption in obesity and decreased satiety in response to ingested food. It is presently not known whether the observed changes in gastrointestinal motility in obesity represent a primary feature linked to the pathogenesis of such disease.     

Effects of cholecystokinin-receptor blockade on pancreatic and biliary function in healthy volunteers

This study used the specific cholecystokinin (CCK)-receptor antagonist loxiglumide to evaluate whether endogenous CCK, which is released after a meal, regulates pancreatic and biliary functions. Eight healthy volunteers were studied twice on separate days. The subjects received a continuous intraduodenal infusion of a 750-kcal liquid test meal for 2 hours either with or without IV infusion of 5 mg.kg-1.h-1 of loxiglumide. Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK. Loxiglumide markedly decreased the meal-stimulated outputs of amylase, trypsin, and chymotrypsin by 55%-70% of control values but only slightly decreased duodenal volume (25% inhibition of mean integrated secretion). Loxiglumide abolished gallbladder emptying induced by infusion of nutrients and even increased gallbladder volumes when compared with prior fasting values. Correspondingly, loxiglumide almost abolished the output of bilirubin after infusion of nutrients. However, loxiglumide failed to alter the increase in circulating concentrations of glucose, insulin, and C peptide after infusion of nutrients. The present results show that CCK is one of several factors that regulate pancreatic protein secretion after absorption of nutrients. However, CCK is probably not involved in regulation of pancreatic secretion of fluid. In contrast, gallbladder function is mainly regulated by CCK, both in terms of its emptying after intestinal absorption of nutrients and in terms of maintenance of its fasting volume. Cholecystokinin does not play a major physiological role as an insulinotropic factor.     

Effect of Intraduodenal and Intravenous Amino Acids on Proximal Gastric Motor Function in Man

The present study was performed to investigate the effect of amino acids during the intestinal and postabsorptive phase of digestion on proximal gastric motor function measured with an electronic barostat. Eight healthy volunteers participated in three experiments performed during continuous infusion of: (1) intravenous and intraduodenal saline, (2) intraduodenal amino acids, and (3) intravenous amino acids. Both intraduodenal and intravenous amino acids induced gastric relaxation and increased gastric compliance. Only during intraduodenal amino acids did plasma CCK levels increase significantly. Correlation between intragastric volume measurements (with pressure set at MDP + 2 mm Hg) and plasma CCK levels was 0.90 (P < 0.001) during the early intestinal phase. Relaxation of the proximal stomach is related to plasma CCK in the early intestinal phase, whereas in the postabsorptive phase of amino acids other mechanisms play a role in proximal gastric relaxation.     

Cholecystokinin immunoreactivity in the digestive tract of bowfin (Amia calva), bluegill (Lepomis macrochirus), and bullfrog (Rana catesbeiana)

The distribution of the intestinal hormone, cholecystokinin (CCK), was studied in the gastrointestinal tract of a holostean fish, the bowfin (Amia calva), and compared to a teleostean fish, the bluegill (Lepomis macrochirus), and an amphibian, the bullfrog (Rana catesbeiana), using an antiserum specific for the carboxyl terminal tetrapeptide of CCK in an unlabeled biotin-avidin immunoperoxidase procedure. In the bowfin CCK immunostained cells were detected only in the anterior and mid-intestine; the stomach and the rest of the gastrointestinal tract were negative. Immunoreactive cells were open in appearance and were scattered along the intestinal mucosal epithelium, with cells in mid-intestine relatively more abundant than in anterior intestine. These relative distributions were confirmed by radioimmunoassay of tissue extracts. Additional immunostained cells of uncertain function were detected in the lamina propria of the intestine. In bluegill gut immunoreactive cells were observed in the anterior and mid-intestine and in the pyloric caeca, where cells were clustered near the intestinal opening. Immunoreactive cells occurred relatively uniformly along the anterior and mid-intestine. Bullfrog CCK-containing cells were detected both in the antral stomach and in the duodenum. CCK in gut tissues likely originated in the intestine. The redistribution of CCK cells toward the anterior part of the intestine during evolution coincides with the development of a compact pancreas in higher classes of vertebrates. Such a redistribution constitutes an adaptive placement of endocrine cells for signaling during the intestinal phase of digestion.     

Nutrient regulation of human intestinal sugar transporter (SGLT1) expression.

BACKGROUND: The activity of most intestinal nutrient transporters is adaptively regulated by the type and amounts of nutrients entering the intestinal lumen. The concentration and activity of the intestinal Na+/glucose cotransporter (SGLT1) are regulated by dietary sugars in most animal species. The activity and abundance of SGLT1 in biopsy specimens removed from human jejunal regions exposed to, and having limited access to, luminal nutrients have been measured and compared. AIMS: To study the effects of luminal nutrients on the expression of SGLT1 in the human intestine. PATIENT AND METHODS: Brush border membrane vesicles (BBMV) were prepared from biopsy specimens removed from the intestine of a 50 year old man who had developed a high output jejunal fistula, and adjacent mucosal fistula, a condition present for 12 months after surgery for a strangulated hernia. BBMV prepared from intestine exposed to luminal nutrients, and from dysfunctional intestine with a limited exposure to nutrients, were used to measure Na+ dependent glucose transport and abundance of SGLT1 protein. RESULTS: The levels of SGLT1 activity and abundance in the BBMV prepared from control biopsy specimens were similar to those found in BBMV prepared from the intestine of healthy individuals. BBMV from the dysfunctional intestine, exposed to limited levels of luminal nutrients, had reduced levels of SGLT1 activity. This reduction in SGLT1 activity and abundance was above that associated with any villus atrophy, as assessed by the abundance/activity of lactase and villin concentrations. CONCLUSIONS: These data indicate that the activity and expression of SGLT1 in human intestine is maintained by the presence of luminal nutrients.     

Regulation of gastrointestinal functions by the ileocecal area]

The importance of the distal small intestine and the ileocecal region for the regulation of gastrointestinal functions in humans has not been investigated in depth until recently. A regulatory role is postulated because even in healthy subjects, undigested nutrients pass across the ileocecal junction after most meals (physiologic malabsorption). Nutrient exposure of the ileocecal region causes slowing of gastric emptying and small intestinal transit, and decrease in small intestinal motor activity; under certain experimental conditions, ileal nutrients induce conversion of intestinal motility from digestive to interdigestive patterns. In addition, the secretory activity of the proximal gastrointestinal tract is inhibited by the ileocecal region. Inhibition of gastric secretion and exocrine pancreatic secretion are well established responses to ileal nutrient exposure; inhibition of bile secretion likely occurs, but is not proven. The intermediary mechanisms of these effects have not been clarified; the most likely candidates include endorphins, peptide YY (PYY), and glucagon-like-peptide-1 (GLP-1). Overall, the available data support the concept that the ileocecal region participates in the physiologic control of gastrointestinal motor and secretory functions. Whether disturbances of these regulatory mechanisms participate in the pathophysiology of gastrointestinal disease has not been investigated.     

Effects of cholecystokinin receptor blockade on circulating concentrations of glucose, insulin, C-peptide, and pancreatic polypeptide after various meals in healthy human volunteers.

This study used a cholecystokinin (CCK) antagonist to evaluate whether CCK that is released after regular meals regulates meal-stimulated insulin secretion. Several experiments were performed in eight to 10 healthy male volunteers, each in duplicate. The subjects received different meals either with or with i.v. infusion of 5 mg/kg/h of the CCK antagonist loxiglumide (Rotta, Italy). The mixed solid-liquid meals of 600, 800, or 1,000 kcal consisting of regular German food were given orally. In addition, studies were carried out in which a liquid test meal of 750 kcal was infused into the duodenum over a 2-hour period to exclude effects of the CCK antagonist on gastric emptying. Finally, the subjects received an oral load of 100 g glucose either with or without i.v. infusion of loxiglumide. Loxiglumide at the dose used completely abolishes the actions of endogenous CCK and of exogenous CCK when given at doses that mimic postprandial circulating concentrations of this peptide at various target organs such as gallbladder, pancreas, stomach, and intestine. Loxiglumide also markedly reduced the increase in pancreatic polypeptide seen after the intraduodenal infusion of nutrients. However, loxiglumide at this dose did not alter the increase in circulating concentrations of glucose, insulin, and C-peptide after any of the various oral meals, after the intraduodenal administration of nutrients, and after the oral load of glucose. Although the present study does not rule out that in some conditions CCK may increase insulin secretion in humans, the results do rule out that CCK acts as a major physiologic incretin in healthy humans.     

Isolation and bioactivity of putative cholecystokinin-releasing peptide from rat small intestinal mucosa.

Pancreatic exocrine secretion in the conscious rat is regulated by proteases in the intestine secreted by the pancreas, and cholecystokinin (CCK) is known to be involved in the mechanism. The authors proposed that the release of CCK was regulated by a CCK-releasing factor secreted into the intestinal lumen from the proximal intestine. We isolated and partially purified a CCK-releasing factor from rat small intestine by gel filtration and high performance liquid chromatography. The partially purified CCK-releasing factor increased pancreatic exocrine secretions and plasma CCK concentrations in conscious rats and this activity was abolished after the incubation with trypsin. The bioactivity of the partially purified CCK-releasing factor was confirmed.     

Isolation and bioactivity of putative cholecystokinin-releasing peptide from rat small intestinal mucosa

Pancreatic exocrine secretion in the conscious rat is regulated by proteases in the intestine secreted by the pancreas, and cholecystokinin (CCK) is known to be involved in the mechanism. The authors proposed that the release of CCK was regulated by a CCK-releasing factor secreted into the intestinal lumen from the proximal intestine. We isolated and partially purified a CCK-releasing factor from rat small intestine by gel filtration and high performance liquid chromatography. The partially purified CCK-releasing factor increased pancreatic exocrine secretions and plasma CCK concentrations in conscious rats and this activity was abolished after the incubation with trypsin. The bioactivity of the partially purified CCK-releasing factor was confirmed.     

Role of cholecystokinin in the control of food intake

CCK appears to regulate short-term control of food intake by acting as a satiety signal. Larger doses of CCK may decrease food intake by aversive actions (malaise, nausea, cramps), presumably by effects on gastrointestinal motility. In rats and most likely humans CCK is released from the upper intestine after a mixed meal and appears to activate afferent vagal fibers by causing pyloric contraction with resultant gastric distention or directly binding to the gastric afferent vagus which courses to the nucleus solitarius with further projections to the paraventricular nucleus and ultimately the ventromedial hypothalamus. Peripherally released CCK may also bind to CNS receptors in the area postrema overlying the nucleus solitarius. Central nervous system CCK released from the paraventricular nucleus may also exert a satiety effect. The satiety effect of CCK appears to be a physiologic action of the peptide since antibodies to CCK and CCK receptor antagonists can increase food intake. CCK is probably just one of several satiety signals but can cause a profound decrease in food intake when administered exogenously in pharmacologic doses. Administration of exogenous CCK, as well as endogenous CCK released by oral protease inhibitors, can decrease food intake in humans. Studies designed to examine the effect of chronic administration of CCK on food intake will be necessary to determine if the peptide has a role in the management of obesity and bulimia.     

Cholecystokinin and secretin prevent the intestinal mucosal hypoplasia of total parenteral nutrition in the dog.

Because the pancreas undergoes involutional changes during total parenteral nutrition (TPN) and because pancreatico-biliary secretions are trophic to the intestine, we studied jejunal and ileal structure and function and exocrine pancreatic function before and after 6 weeks of TPN in two groups of beagle dogs, one of which had TPN alone, the other having TPN plus daily stimulation of pancreatico-biliary secretions with intravenous infusions of cholecystokinin (CCK) and secretin. The injections of 1 U each per kg of body weight per day of CCK and secretin completely prevented the proximal and distal small bowel mucosal hypoplasia which developed in the TPN alone group. They also resulted in significant increases in in vivo galactose absorption (64 mM) per unit length of jejunum and ileum. However, there was no significant change in mucosal alpha-glucosidase and catalase activity or in in vitro mucosal uptake of 1 mM [14C]leucine when expressed per unit weight of intestinal mucosa. The capacity of the pancreas to respond to CCK and secretin was unaffected by excluding food from the intestine with 6 weeks of TPN in terms of pH, volume, and peak secretion rates of bicarbonate and protein, but maximum amylase output (units per 15 min per kg of body weight) fell significantly (P less than 0.05) from a mean of 1022 +/- 155 to 874 +/- 426 in TPN alone group and to 472 +/- 79 in the TPN dogs given CCK and secretin. These results show that daily CCK and secretin is trophic to the intestine of dogs nourished by TPN but do not indicate whether this trophic effect is attributable to CCK alone, secretin alone, the combination of the two hormones, or to the resultant stimulation of pancreatico-biliary secretions.     

Peptides of digestive system and brain. Model of the cholecystokinin

The systemic administration of exogenous cholecystokinin (CCK), (a peptide released into the circulation when nutrients arrive in small intestine) provokes inhibition of food intake in numerous animal species and a sensation of satiation in humans. The mechanism involved requires participation of vagal afferent neurons to transmit information, possibly on gastric distension, to brain stem. Two crucial questions remain unanswered: does peripheral endogenous cholecystokinin transport information necessary for satiation at end of normal meals and if so, how and when is this message coded and deciphered; other studies have demonstrated that very small doses of exogenous cholecystokinin (too low to induce satiation if administrated peripherally) will induce satiety if injected into cerebral ventricles or directly into cerebral parenchyma. This suggest but does not prove that cerebral endogenous CCK also plays a role in satiety. It is not known how the satiating action of centrally-administered CCK is related to that of peripherally-administered CCK. Current studies aim at establishing a coherent schema of neuro-endocrine mechanisms implicated (from the gastrointestinal wall via the brain to a motivated behaviour) in the fact that food taken during a meal induces the end of the latter.     

Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice

BACKGROUND AND AIMS: Postoperative ileus after abdominal surgery largely contributes to patient morbidity and prolongs hospitalization. We aimed to study its pathophysiology in a murine model by determining gastric emptying after manipulation of the small intestine. METHODS: Gastric emptying was determined at 6, 12, 24, and 48 hours after abdominal surgery by using scintigraphic imaging. Intestinal or gastric inflammation was assessed by immune-histochemical staining and measurement of tissue myeloperoxidase activity. Neuromuscular function of gastric and intestinal muscle strips was determined in organ baths. RESULTS: Intestinal manipulation resulted in delayed gastric emptying up to 48 hours after surgery; gastric half-emptying time 24 hours after surgery increased from 16.0 +/- 4.4 minutes after control laparotomy to 35.6 +/- 5.4 minutes after intestinal manipulation. The sustained delay in gastric emptying was associated with the appearance of leukocyte infiltrates in the muscularis of the manipulated intestine, but not in untouched stomach or colon. The delay in postoperative gastric emptying was prevented by inhibition of intestinal leukocyte recruitment. In addition, postoperative neural blockade with hexamethonium (1 mg/kg intraperitoneally) or guanethidine (50 mg/kg intraperitoneally) normalized gastric emptying without affecting small-intestinal transit. The appearance of intestinal infiltrates after intestinal manipulation was associated with increased c-fos protein expression in sensory neurons in the lumbar spinal cord. CONCLUSIONS: Sustained postoperative gastroparesis after intestinal manipulation is mediated by an inhibitory enterogastric neural pathway that is triggered by inflammatory infiltrates recruited to the intestinal muscularis. These findings show new targets to shorten the duration of postoperative ileus pharmacologically.     

Disturbed Motilin and Cholecystokinin Release in the Irritable Bowel Syndrome

Background: The irritable bowel syndrome (IBS) is associated with motor abnormalities in the small intestine and colon. Neuropeptides may have an important role in initiating and regulating the intestinal motility. Motilin has been proposed to initiate the peristaltic reflex in the small intestine and cholecystokinin the gastrocolic reflex. Methods: In 18 patients with IBS and 11 healthy control subjects plasma motilin and cholecystokinin (CCK) concentrations were measured after intraluminal stimulation of water and a fat-rich meal. Results: The IBS patients had reduced motilin secretion after both water intake and the fat meal. In contrast, the fat meal elicited an exaggerated and prolonged CCK release in the IBS patients. Conclusions: Disturbed motilin and CCK release may partly be responsible for the intestinal dysmotility in the IBS patients.