Claude Rozé

Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat

Short-chain fatty acids (SCFAs) are recognized as the major anions of the large intestinal content in humans, but their effect on colonic motility is controversial. This study explores the colonic motor effect of SCFAs and their mechanisms in the rat. Colonic motility (electromyography) and transit time (plastic markers) were measured in conscious rats while SCFAs were infused into the colon, either alone or after administration of neural antagonists or immunoneutralization of circulating polypeptide YY (PYY). SCFA-induced PYY release was measured by RIA and then simulated by infusing exogenous PYY. Intracolonic infusion of 0.4 mmol/h SCFAs had no effect, whereas 2 mmol/h SCFAs reduced colonic motility (36 ± 3 vs. 57 ± 4 spike bursts/h with saline, P< 0.05) by decreasing the ratio of nonpropulsive to propulsive activity. This resulted in an increased transit rate ( P < 0.01). Neither α-adrenoceptor blockade nor nitric oxide synthase inhibition prevented SCFA-induced motility reduction. Intraluminal procaine infusion suppressed the SCFA effect, indicating that a local neural mechanism was involved. SCFA colonic infusion stimulated PYY release in blood. Immunoneutralization of circulating PYY abolished the effect of SCFAs on colonic motility, whereas exogenous PYY infusion partly reproduced this effect. SCFAs modify colonic motor patterns in the rat and increase transit rate; local nerve fibers and PYY are involved in this effect.

PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine

Dietary proteins are mostly absorbed as di- and tripeptides by the intestinal proton-dependent transporter PepT1. We have examined the effects of leptin on PepT1 function in rat jejunum and in monolayers of the human enterocyte-like 2 cell Caco-2. Leptin is produced by the stomach and secreted in the gut lumen. We show here that PepT1 and leptin receptors are expressed in Caco-2 and rat intestinal mucosal cells. Apical (but not basolateral) leptin increased Caco-2 cell transport of cephalexin (CFX) and glycylsarcosine (Gly-Sar), an effect that was associated with increased Gly-Sar uptake, increased membrane PepT1 protein, decreased intracellular PepT1 content, and no change in PepT1 mRNA levels. The maximal velocity (Vmax) for Gly-Sar transport was significantly increased by leptin, whereas the apparent Michaelis-Menten constant (Km) did not change. Furthermore, leptin-stimulated Gly-Sar transport was completely suppressed by colchicine, which disrupts cellular translocation of proteins to plasma membranes. Intrajejunal leptin also induced a rapid twofold increase in plasma CFX after jejunal perfusion with CFX in the rat, indicating enhanced intestinal absorption of CFX. These data revealed an unexpected action of gastric leptin in controlling ingestion of dietary proteins.

Erythromycin Enhances Fasting and Postprandial Proximal Gastric Tone in Humans

BACKGROUND & AIMS Low doses of erythromycin induce antral contractions and accelerate gastric emptying. However, the effect of erythromycin on the proximal stomach remains unknown. The aim of this study was to assess the effect and mechanism(s) of action of erythromycin on proximal gastric tone in humans. METHODS Gastric tone was measured using an electronic barostat in two groups of 6 subjects both in the fasting state and after a 200-kcal meal. On different occasions, subjects received saline, atropine alone (6 micrograms.kg-1.h-1 for 30 minutes), erythromycin alone (1.5 mg/kg in the fasting state and 1.5 and 3.0 mg/kg in the postprandial state), and erythromycin plus atropine. RESULTS Low-dose (1.5 mg/kg) erythromycin enhanced fasting gastric tone, but only the 3.0-mg/kg dose reduced the duration of meal-induced relaxation (37 +/- 14 vs. 105 +/- 20 minutes; P < 0.01). Atropine did not change the fasting or postprandial gastric tone as well as the erythromycin-induced responses. Plasma motilin levels were unaffected by erythromycin infusion. No correlation was observed between gastric tone and plasma motilin or erythromycin levels. CONCLUSIONS Erythromycin enhances fasting and postprandial proximal gastric tone in humans by a mechanism that does not seem to involve endogenous motilin release or a cholinergic pathway.

Comparison of the postprandial release of peptide YY and proglucagon-derived peptides in the rat.

Abstract Endocrine L-cells of the distal intestine synthesize both peptide YY (PYY) and proglucagon-derived peptides (PGDPs), whose release has been reported to be either parallel or selective. Here we compare the release mechanisms of PYY, glucagon-like peptide-1 (GLP-1), and oxyntomodulin-like immunoreactivity (OLI) in vivo. Anaesthetized rats were intraduodenally (ID) given either a mixed semi-liquid meal or oleic acid, or they received oleic acid or short chain fatty acids (SCFA) intracolonically (IC). The ID meal released the three peptides with a similar time-course (peak at 30 min); ID oleic acid produced a progressive release of PYY and OLI, while GLP-1 release was less. IC oleic acid or SCFA released smaller (but significant) amounts of PYY but no OLI or GLP-1. Hexamethonium inhibited most of the response to the ID meal and ID oleic acid, but did not change the PYY response to IC oleic acid. NG-nitro-l-arginine methyl ester (l-NAME, a nitric oxide synthase inhibitor) inhibited meal-induced PYY release and left OLI and GLP-1 unaffected. BW10 (a gastrin-releasing peptide antagonist) had no effect on the meal-induced release of either peptide. These results suggest a parallel initial release of PYY, OLI and GLP-1 after the ID meal, or oleic acid, by an indirect mechanism triggered in the proximal bowel, using nicotinic synapses, and involving nitric oxide release for PYY and an unknown mediator for PGDPs. For PYY there is a later phase of peptide release, probably induced by direct contact between nutrients and colonic L-cells.

Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans

Transient lower esophageal sphincter (LES) relaxations (TLESRs) are the main underlying mechanism of gastroesophageal reflux. Although CCK acts through CCK-A receptors to increase the TLESRs induced by gastric distension, the respective roles of endogenous CCK and fundic tone in triggering postprandial TLESRs remain unknown. The aim of this study was to determine the effect of the CCK-A receptor antagonist, loxiglumide, on postprandial LES function and fundic tone in humans. LES motor events and fundic tone were simultaneously monitored in two groups of healthy volunteers. Recordings were performed during fasting and for 3 h after a liquid meal (200 ml/200 kcal) administered either orally or intraduodenally at a rate mimicking gastric emptying. Each subject received loxiglumide (10 mg. kg-1. h-1) or saline (control) in randomized order, which was started 40 min before the meal and maintained for 3 h thereafter. After the oral meal, loxiglumide significantly reduced TLESRs (P = 0.002) without significantly affecting LES pressure and fundic tone. After duodenal infusion of the meal, loxiglumide totally abolished the increase in TLESRs, reduced LES pressure fall (P < 0.02), and strongly inhibited fundic relaxation (P = 0.0001). We concluded that endogenous CCK is involved in the postprandial control of both LES function and fundic tone through activation of CCK-A receptors.Transient lower esophageal sphincter (LES) relaxations (TLESRs) are the main underlying mechanism of gastroesophageal reflux. Although CCK acts through CCK-A receptors to increase the TLESRs induced by gastric distension, the respective roles of endogenous CCK and fundic tone in triggering postprandial TLESRs remain unknown. The aim of this study was to determine the effect of the CCK-A receptor antagonist, loxiglumide, on postprandial LES function and fundic tone in humans. LES motor events and fundic tone were simultaneously monitored in two groups of healthy volunteers. Recordings were performed during fasting and for 3 h after a liquid meal (200 ml/200 kcal) administered either orally or intraduodenally at a rate mimicking gastric emptying. Each subject received loxiglumide (10 mg ⋅ kg-1 ⋅ h-1) or saline (control) in randomized order, which was started 40 min before the meal and maintained for 3 h thereafter. After the oral meal, loxiglumide significantly reduced TLESRs ( P = 0.002) without significantly affecting LES pressure and fundic tone. After duodenal infusion of the meal, loxiglumide totally abolished the increase in TLESRs, reduced LES pressure fall ( P < 0.02), and strongly inhibited fundic relaxation ( P = 0.0001). We concluded that endogenous CCK is involved in the postprandial control of both LES function and fundic tone through activation of CCK-A receptors.

Simultaneous assessment of liquid emptying and proximal gastric tone in humans

BACKGROUND Barostat is the only technique that allows assessment of gastric tone in humans. Our aim was to simultaneously assess gastric emptying and relaxation in response to a liquid meal. METHODS Gastric tone was monitored using an electronic barostat in six healthy subjects after three liquid meals (200 mL, 400 mL, 600 mL, 1 kcal/mL). Scintigraphic imaging was obtained by using double isotopic labeling (technetium 99m for liquid of the 200 mL meal and xenon 133 for air into the barostat). RESULTS Profound gastric relaxation was detected in every subject. The duration of proximal gastric relaxation increased with meal size. The proximal stomach remained relaxed through the duration of gastric emptying. Gastric tone returned to the fasting values simultaneously with completion of liquid emptying. Repeated measures after the 200-mL meal showed that amplitude (i.e., maximal volume change) and duration of relaxations were reproducible. However, the presence of the bag slightly accelerated gastric emptying and modified the intragastric distribution of the meal. CONCLUSIONS The barostat is a sensitive and reproducible technique to measure gastric relaxation following liquid meals in humans. The results also suggest that the role of gastric tone as the driving force of gastric emptying of liquids has been overestimated.

Mechanisms of peptide YY release induced by an intraduodenal meal in rats: neural regulation by proximal gut

Abstract Peptide YY (PYY) release in anaesthetized rats was studied during the 2 h following the intraduodenal administration of a semi-liquid meal of 21 kJ. Surgical and pharmacological manipulations were performed in order to analyse the mechanisms of PYY release. Postprandial PYY release was suppressed or strongly decreased by caecocolonectomy, truncal vagotomy, tetrodotoxin, hexamethonium, sensory denervation by perivagal capsaicin, and by the NO-synthase inhibitor L-N-arginine methyl ester, while atropine, adrenergic blockers, antagonists of type-A or type-B cholecystokinin (CCK) receptors or bombesin receptors had no effect. Comparing the digestive transit of the semi-liquid meal with the amount of PYY contained in the small bowel wall showed that nutrients had not reached the area rich in cells containing PYY by 30 min, the time at which there was a large PYY release in plasma. By 120 min, the meal front had travelled 72% of the small intestine length, just beginning to reach the PYY-rich part of the ileum. We conclude that the main postprandial PYY release studied in this model comes from ileal and colonic L-cells indirectly stimulated through a neural mechanism originating in the proximal gut and involving sensory vagal fibres, nicotinic synapses and NO release, while CCK and bombesin do not seem to be physiologically involved.

Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat

The effect of caseinomacropeptide (CMP) (the [106-169] fragment of kappa-casein produced during digestion of milk protein), was studied in anesthetized rats using bile diversion for a pure pancreatic juice collection system. Intraduodenal administration of CMP induced a dose-related specific stimulation of pancreatic secretion which was nearly abolished by devazepide, atropine, hexamethonium, vagotomy or perivagal capsaicin pretreatment. Moreover, CMP did not inhibit in vitro trypsin activity. These results demonstrate that CMP is more likely to stimulate pancreatic secretion specifically through cholecystokinin release and activation of a vago-vagal cholinergic reflex loop than by inhibition of luminal trypsin, in anesthetized rats.

Peptide YY release after intraduodenal, intraileal, and intracolonic administration of nutrients in rats

Peptide YY (PYY) release was studied by measuring radioimmunoassayable PYY in the arterial plasma of anaesthetized rats receiving into the duodenum, ileum or colon either a complete semi-liquid meal (3 ml, 21 kJ) or elemental nutrients as isocaloric or isoosmolar solutions. PYY release induced by the intraduodenal meal peaked at 60 min and lasted more than 120 min. The integrated response of PYY over 120 min was larger when the meal was administered into the duodenum than into the ileum. The undigested meal induced no release of PYY over a 120-min period when administered into the colon. When injected into the duodenum in isocaloric amounts to the meal, glucose and amino acids led to the release of as much PYY as did the meal, whereas oleic acid led to the release of less PYY. Part of these responses were due to osmolarity, since administration of intraduodenal hyperosmolar saline led to the release of about half as much PYY as did hyperosmolar glucose. In moderate amounts, and injected as a solution isoosmolar to plasma, oleic acid was a major PYY releaser; the amounts released were at least two times larger when oleic acid was administered into the duodenum than into the ileum and colon. Isoosmolar glucose and amino acids led to the release of no PYY when injected into the duodenum, but were nearly as active as oleic acid in the colon. Short-chain fatty acids induced the release of PYY when injected into the colon, but not into the ileum. Hexamethonium suppressed PYY release induced by the intraduodenal meal, but did not change PYY release induced by glucose or oleic acid in the colon. Urethane anaesthesia did not reduce PYY release induced by the intraduodenal meal. These results suggest that two mechanisms at least contribute to PYY release in the rat. An indirect, neural mechanism, involving nicotinic synapses, is prominent in the proximal small intestine; the stimulation is transmitted to ileal and colonic L-cells by undetermined pathways, but contact of nutrients with L-cells is not needed. Another mechanism, probably direct and quantitatively smaller, occurs in the distal intestine when nutrients come into contact with the mucosa containing L-cells. Glucose, fatty acids and amino acids stimulate differentially the proximal and distal mechanisms.

Several receptors mediate the antisecretory effect of peptide YY, neuropeptide Y, and pancreatic polypeptide on VIP-induced fluid secretion in the rat jejunum in vivo

Several Y receptor subtypes have been cloned and/or pharmacologically characterized that mediate the effects of the regulatory peptides peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). These peptides possess antisecretory properties on the intestine. This effect can be blocked in vivo by neural antagonists, suggesting the intervention of neural receptors, although epithelial PYY-preferring receptors have been evidenced on jejunal crypt cells. The purpose of the present experiments was to compare the antisecretory properties in vivo of a series of PYY and NPY derivatives with various affinities for different Y receptor subtypes, in order to determine which subtypes were involved. A model of VIP-stimulated secretion by rat jejunal loops was used. The results were compared with the binding affinities for PYY-preferring receptors determined on rat jejunal crypt cell membranes. Full-length PYY(1-36) was about three times more potent than NPY(1-36), and 10 times more potent than PP in the low dose range. PP, however, had a low efficacy limited to about 50% inhibition of VIP effect. Both Y1 agonists ([Leu31, Pro34]PYY and [Leu31,Pro34]NPY), and Y2 agonists [C-terminal fragments ranging from PYY (3-36) and NPY(3-36) to PYY(22-36) to NPY(22-36)] displayed potent antisecretory properties. PYY derivatives and fragments were always more potent than their respective NPY counterparts. In contrast, Y1 derivatives and PP had very low affinity for the epithelial PYY receptor as measured in vitro by radioreceptor assay. These data suggest that the antisecretory effect of PYY/NPY/PP peptides in vivo involves the effects of several receptors: a Y2-like, PYY-preferring receptor identical to the epithelial receptor, a Y1-like receptor, and a third receptor with high affinity for PP.