Intestinal Stimulation Research Articles

Intestinal chemo‐ and mechano‐sensitivity: selective modification of small intestinal sensitivity by lipids

Intestinal chemo-nociception is a recently described mechanism of perception of intraluminal stimuli that might involve pathways independent from mechano-nociception. To investigate whether intraluminal lipids not only modify mechano-sensitivity, but also influence chemo-sensitivity. Nineteen healthy volunteers ingested an orojejunal tube assembly for mechanical and chemical stimulation of the proximal jejunum. Volume-controlled distension of a jejunal balloon and capsaicin perfusion were performed during simultaneous infusion of saline or a 10% lipid emulsion. A standard questionnaire evaluated quality and intensity of symptoms induced by intestinal stimulation. Balloon volumes to induce perception thresholds were significantly reduced during lipid perfusion (P < 0.05), while balloon pressures remained unaltered (P > 0.05). Saline infusion (2.5 mL/min) did not alter thresholds of perception. Lipid infusion also increased intensity of perception during given distension volumes (P < 0.05). Lipid infusion did neither affect perception quality induced by capsaicin, nor perception thresholds, nor intensity of perception during capsaicin perfusion (P > 0.05). The quality of sensations induced by capsaicin perfusion was similar to sensations during distension, except of sensation of warmth, that was almost exclusively reported during capsaicin perfusion. Intraluminal lipids selectively modify intestinal mechano-perception and do not alter chemo-perception. Intestinal chemo-nociception and mechano-nociception are two mechanisms of intestinal perception that involve distinct sensory pathways.

Pacing the gut in motility disorders

Similar to cardiac pacing, gastrointestinal (GI) pacing is an attractive idea and may become a promising therapy, as the GI organs, like the heart, have their own natural pacemakers. Over the past 10 years, electrical stimulation of the gut has received increasing attention among researchers and clinicians. Several clinical studies have shown that gastric electrical stimulation (GES) with short pulses is able to reduce nausea and vomiting in patients with gastroparesis and that GES with long pulses is able to pace the intrinsic gastric slow waves and thus normalize gastric dysrhythmia. However, possible placebo effects cannot be ruled out, although recent animal studies have revealed various peripheral and central mechanisms involved with GES. Electrical stimulation of the small intestine, colon, or anal sphincter also has been reported for the treatment of dumping syndrome, constipation, and fecal incontinency. Similarly, there is a lack of placebo-controlled studies. In our opinion, pacing of the gut has great potential for the treatment of various GI motor disorders. However, none of the commercially available devices is designed for pacing the gut. The lack of well-suited devices and the invasive nature of gut pacing slow down the progress and clinical applications of gut pacing.

Role of the Jejunum Versus Ileum on Intestinal Gas Dynamics During a Balanced Meal in Healthy Subjects

Under physiological conditions, the human gut adapts intestinal gas propulsion and evacuation to prevent intestinal gaseous complaints In this study we aimed to determine influences of the jejunum versus ileum on intestinal gas dynamics during a balanced meal. Paired studies were randomly performed with seven women and three men, ages 28-42. A mixed liquid meal was infused (1 kcal/min) into the duodenum. After 30 min, gas was infused (12 ml/min) into the jejunum or ileum for 150 min. Gas expulsion was measured, and perception and girth changes were assessed. Postprandial intestinal gas propulsion was uneventful and recovery complete, with -7+/- 58 and -92+/- 44 ml final intestinal gas retention for jejunal and ileal gas infusion, respectively. Neither significant differences in abdominal perception nor changes in abdominal girth were seen. During a balanced meal, intestinal gas is effectively propulsed aborally, and this does not depend on the site of the small intestinal stimulation.

Zinc-secreting Paneth Cells Studied by ZP Fluorescence

We have used a new family of zinc-specific-responsive fluorescent dyes (ZPs) to study the sequestration and secretion of zinc from Paneth cells, which are located in the bases of the crypts of Lieberkühn within the rat small intestine. Vivid ZP fluorescence zinc staining of Paneth cell secretory granules is seen in both cryostat sections and isolated crypts, providing firm evidence for a pool of labile (rapidly exchangeable) zinc within these cells. We further demonstrate that this ionic zinc pool is secreted under physiological conditions. In vivo stimulation of the small intestine by IP injection of the secretagogue pilocarpine results in discrete zinc staining within the lumens of subsequently isolated crypts, concomitant with a decrease in the zinc staining of Paneth cell granules located within the same crypts. In contrast, the secretion of zinc into the lumens of isolated crypts stimulated in vitro with either carbachol or LPS (lipopolysaccharide) is not observed. However, a distinct change in Paneth cell morphology, suggesting attempted secretion, is seen in response to the direct application of cholinergics but not LPS. These findings suggest that zinc is coreleased with other Paneth cell anti-microbials, and that the intact intestine is necessary for secretion into the crypt lumen.

Effects of intestinal electrical stimulation on intestinal dysrhythmia and symptoms in dogs.

The aim of this study was to investigate the effect of intestinal electrical stimulation on small intestinal dysrhythmia and motion sickness-like symptoms induced by vasopressin. Female dogs chronically implanted with two pairs of electrodes on jejunum serosa were used in a four-session study. Saline and vasopressin were infused in sessions 1 and 2, respectively. Sessions 3 and 4 were the same as session 2, except a long- or short-pulse intestinal electrical stimulation was applied on the proximal pair of electrodes. Intestinal slow waves and motion sickness-like symptoms were recorded in each session. Results were as follows. (1) Vasopressin induced intestinal dysrhythmia, uncoupling of slow waves, and vomiting and motion sickness-like symptoms (P < 0.05, ANOVA). (2) Intestinal electrical stimulation with long pulses, but not short pulses, was capable of preventing vasopressin-induced intestinal dysrhythmia. (3) Intestinal electrical stimulation with short pulses, but not long pulses, prevented vomiting and the motion sickness-like symptoms. It is concluded that vasopressin induces intestinal dysrhythmia. Long-pulse intestinal stimulation normalizes vasopressin-induced intestinal slow-wave abnormalities with no improvement in symptoms. Short-pulse stimulation prevents emetic symptoms induced by vasopressin but has no effect on slow waves. These data suggest different mechanisms involved with different methods of intestinal stimulation.

Cutaneous lymphocyte antigen expression on human effector B cells depends on the site and on the nature of antigen encounter.

In contrast to T cells, information on skin-homing B cells expressing the cutaneous lymphocyte antigen (CLA) is sparse. CLA expression on human B cells was investigated among circulating immunoglobulin-secreting cells (ISC) and among antigen-specific antibody-secreting cells (ASC) elicited by parenteral, oral or rectal primary immunization, or by parenteral or oral secondary immunization with Salmonella typhi Ty21a. CLA expression was examined by combining cell sorting with an enzyme-linked immunospot assay. Among all ISC, the proportion of CLA(+) cells was 13-21%. Parenteral immunization induced antigen-specific ASC of which 13% were CLA(+), while oral and rectal immunizations were followed by only 1% of CLA(+) ASC (p<0.001). Oral re-immunization was followed by an up-regulation of CLA (34-48%) regardless of the route of priming. Parenteral re-immunization elicited ASC of which 9-14% were CLA(+). In conclusion, the expression of CLA on human effector B cells depends on the site of antigen encounter: intestinal stimulation elicits cells with no CLA, while parenteral encounter elicits significant numbers of CLA(+) cells. Even though primary antigen encounter in the intestine failed to stimulate CLA expression, up-regulation of CLA was found upon intestinal antigen re-encounter. These findings may be of relevance in the pathogenesis of some cutaneous disorders.

Collapse of the lateral intercellular space (LIS) limits anion secretion during acute cAMP stimulation of murine small intestine

Collapse of the lateral intercellular space (LIS) limits anion secretion during acute cAMP stimulation of murine small intestine

Delayed liquid gastric emptying induced by electric stimulation of small intestine depends on nitric oxide pathway in conscious dogs

pressure in the 1200 ml balloon was raised by 3 mmHg/min from 1 mmHg to 12 mmHg (ramp phase) and was kept at this level tor 5 rain (tonic: phase), Adaptive accommodation during the toinc phase is the intragastric volume increase attained during the tonic phase, Maximum accommodation capacity is the rate of volume increase (ml/s) in the tonic phase. At'commodatinn time is the time from the start of the tonic phase to the end of adaptive accommodation. The volume response was investigated in each individual on two separate days, once during fasting conditions and once following 200 ml of a liquid meal (Nutridrink | 200 kcal/200 ml) given 15 min before the start of the distension. Results: In response to the test meal, healthy controls had a signibcant increase in maximum gastric volume (from 428-+ 60 to 734 _+ 31 ml, p = 0.0005), adaptive accommodation during tonic phase (from 223 -+ 37 to 435 -+ 41 ml, p = 0002), and in accomnmdation time (from 91 _+ i4 to 190 -+ 23 s, p = 0.003) The test meal had, hm,vever, no efi~.'ct on maximum accommodation capacity (2.4-+0,4 vs. 23_+0.2 mL/s, p=0+8) The most pronounced difi'erences between health3, controls and patients with tunctiona| dyspepsia were seen during lasting: adaptive accommodation during tonic phase (223-+ 37 ml in healthy persons and 132 -+ ]9 ml in patients, p = 004) and maximum accommodation capacity (2.4 _+ 0.4 vs. 0.8 _+ 0.1 ml/s, p = 0.0009), After tbe meal, there were no sigmficant differences between the groups. In patients with diabetes, the most pronounced difterences were seen after the meal: adaptive accommodation during the tonic phase (435 -+ 41 ml in heahhy controls vs. 274_+ 51 ml in diabetics, p = 0+03)+ Using these relatively low pressures the symptom scoring was inconsistent. Conclusion: This barostat technique allows detailed analysis of the gastric volume responses, Patients with functional dyspepsia and healthy controls differed significantly during lasting conditions concerning the rate and extent of adaptive accommodation during the tonic phase of distenmon, Diabetics, however, differed from controls mainly in adaptive accommodation during the tonic phase of distension after a meal.

Sustained inhibitory effects of intestinal electric stimulation on intestinal motility in conscious dogs

Sustained inhibitory effects of intestinal electric stimulation on intestinal motility in conscious dogs

Changes in cerebral near infrared spectroscopy parameters during manual acupuncture needle stimulation

Near-infrared spectroscopy (NIRO 300, Hamamatsu Photonics, Japan) was used to monitor human cerebral function in the central region during manual acupuncture needle stimulation of the large intestine 4 (LI.4) point in 16 adult volunteers (9 females, 7 males; mean age 23.9 +/- 6.0 (SD) years, range 19-45 years). We found a significant (p < 0.001) decrease in oxyhaemoglobin after needle insertion and stimulation (duration 20 sec.), accompanied by an increase (p = 0.003) in deoxyhaemoglobin. A repeat stimulation showed similar effects. Cytochrome oxidase aa3 remained unchanged during stimulation. The results demonstrate that near-infrared spectroscopy may be a noninvasive method of measuring regional changes in cerebral haemodynamics resulting from peripheral acupuncture stimulation.

Oral, gastric and intestinal influences on human feeding

Direct infusion of specific nutrients or foods into different areas of the gastrointestinal tract, and techniques to distend the stomach, are useful tools enabling eating behaviour to be studied without the influence of orosensory factors. Using these techniques, the role of nutrients on gastrointestinal mechanisms of satiation as well as the interactions between the various systems in the control of feeding can be examined. Recent research in humans investigating the relative contribution of signals arising from different areas of the gastrointestinal tract has demonstrated that optimal control of appetite occurs only when orosensory signals are coupled with signals arising from the stomach and intestine. Interactions between gastric and intestinal signals do however combine to produce a more potent suppression of appetite and food intake than when either of these sites is stimulated alone. Gastric distension probably exerts a predominate influence on appetite suppression compared with intestinal stimulation, whereas nutrient stimulation of the intestine may function to modulate the sensations arising from gastric distension to elicit a meal-like sensation of satiety. In addition, these studies have highlighted that previous hypotheses concerning differential fat and carbohydrate satiation may require an orosensory component and probably do not reflect an inherent difference in the physiological effects of these macronutrients at the level of the GI tract. The interaction of orosensory influences, such as palatability, with negative feedback signals arising from the GI tract can be further studied using a combination of these techniques with measurement of microstructure of feeding in humans.

Conditioned taste aversion to gut distension in rats

The aim of this work was to study the negative effects of the intestinal stimulation by a method that is sensitive to assess internal malaise and discomfort. Effects of volumetric and “isometric” gut distension on the behavior were compared in the small and the large intestines, respectively. Chronically separated (Thiry-Vella) intestinal loops prepared from the upper jejunum and/or from the uppermost segment of the colon were stimulated with a rubber balloon. Conditioned taste aversion (CTA) series were accompanied with recording satiety and aversive behavioral indexes. Both isometric and volumetric stimuli elicited taste aversion. No essential differences between the two intestinal parts were found. Behavioral indices supported intake data: satiety indexes were similar to each other, whereas aversive indexes were high during stimulation and lower during testing. Data were consistent over conditions and time, proving the reliability of the method. Results are compared to earlier taste reactivity records.

Vasoactive intestinal peptide stimulation modulates the expression of Bcl-2 family members in the adrenal gland of the lizard Podarcis sicula.

The adrenal gland of the lizard Podarcis sicula is formed by a dorsal ribbon of chromaffin cells, generally defined as medullary tissue, arranged along a central part of steroidogenic cells considered as cortical tissue. These two tissues produce catecholamines and steroids as part of the hypothalamo-hypophyseal-adrenal gland axis. Recent studies have demonstrated that Podarcis sicula adrenal gland is not only under hypothalamo-hypophyseal axis control but that several peptides may influence the physiological activity of the gland; among these, vasoactive intestinal peptide is able to enhance strongly both catecholamine and steroid hormone production. The aim of the present study was to verify whether vasoactive intestinal peptide administration could become deleterious. For this reason, we monitored the pattern of expression of two members of the Bcl-2 family, Bcl-2 and Bax, in control and vasoactive intestinal peptide treated specimens. Furthermore, we also tested if peptide treatment induces apoptosis by TUNEL assay.

Reduced hindbrain and enteric neuronal response to intestinal oleate in rats maintained on high-fat diet

Rats maintained on a high-fat diet (HF) reduce their food intake less in response to intestinal infusion of oleic acid than rats maintained on a low-fat diet (LF). Inhibition of gastric emptying by intestinal infusion of oleate also is attenuated in rats fed a high-fat diet. It is well documented that intestinal oleate reduces food intake and inhibits gastric emptying via vagal sensory neurons. In addition, activation of intrinsic myenteric neurons participates in oleate-induced changes in gastrointestinal motility. To determine whether diminished behavioral and gastric reflex responses to intestinal oleate infusion is accompanied by reduced vagal sensory and myenteric neuronal activation, we examined expression of Fos-like immunoreactivity (Fos-li) in the dorsal hindbrains and the small intestinal enteric plexuses of rats maintained on HF or LF, following, intraintestinal infusion of oleate (0.06 kcal/ml) or the oligosaccharide, maltotriose (0.26 kcal/ml). Following oleate infusion there was a dramatic increase in the number of Fos-li nuclei in the NTS and AP of LF rats but not in HF rats. There also were significantly more Fos-li neuronal nuclei in the upper small intestinal submucosal and myenteric plexuses of the LF rats than the HF rats. In contrast to the effects of oleate infusion, maltotriose infusion significantly and similarly increased Fos-li nuclei in the hindbrains of both LF and HF rats. The results indicate that adaptation to high-fat diet selectively reduces vagal and enteric neuronal sensitivity to intestinal oleate and suggests that reduced sensitivity to the satiation and gastric inhibitory effects of oleate in high-fat fed rats may be mediated by a selective reduction in the neuronal response to intestinal stimulation by fatty acid.

Effects of M1 and CCK antagonists on latency of pancreatic amylase response to intestinal stimulants

In six conscious dogs with gastric and duodenal cannulas, secretin (164 pmol. kg(-1). h(-1) iv) was given to provide a flow of pancreatic juice of approximately 1 drop/s. Amylase activity was measured in each drop before and after rapid intravenous injection of caerulein (7.4 pmol/kg) or intraduodenal injection of L-tryptophan (1 mmol), sodium oleate (3 mmol), and HCl (3 mmol). All experiments were repeated in the presence of the M1 receptor antagonist telenzepine (81 nmol. kg(-1). h(-) iv) and the cholecystokinin (CCK) receptor antagonist L-364718 (0.1 mg/kg iv). Latency of amylase response (time between injection of stimulant and sustained increase in amylase activity greater than mean + 3 SD of prestimulatory activity) to tryptophan (17 +/- 7 s; n = 6) and oleate (16 +/- 5 s) was significantly (P < 0.05) shorter than to caerulein (28 +/- 4 s) and HCl (120 +/- 47 s). Telenzepine significantly increased the latency of amylase response to tryptophan and oleate by >10-fold but not the latency to caerulein or HCl. L-364718 abolished the amylase response to all stimulants. These findings indicate that the early amylase response to intraduodenal tryptophan and oleate is mediated by a neural enteropancreatic reflex ending on M1 receptors rather than by hormone release. However, the activation of (possibly vagal) CCK receptors is essential to run the reflex. The early amylase response to intraduodenal HCl is probably mediated by the release of CCK into the blood circulation.

Canine vagus nerve stores cholecystokinin-58 and -8 but releases only cholecystokinin-8 upon electrical vagal stimulation

Cholecystokinin-58 has been shown to be the major form of cholecystokinin (CCK) released to the circulation upon lumenal stimulation of the small intestine in humans and dogs. In anesthetized dogs, electrical vagal stimulation evokes pancreatic exocrine secretion that is in part mediated through the release of CCK. We studied the molecular form of CCK stored in canine vagus nerves and that released into circulation upon electrical vagal stimulation. Gel filtration and radioimmunoassay of the water and acid extracts of canine vagus nerves indicated CCK-8 (35%) and CCK-58 (65%) as the major molecular forms in the vagus nerve. Both forms of CCK isolated from the vagal extracts were equally bioactive as the standard CCK-8 and CCK-58, respectively, in stimulation of amylase release from isolated rat pancreatic acini. Analysis of plasma collected after electrical vagal stimulation indicated that CCK-8 is the only form released into the circulation. The release of CCK-8 upon electrical vagal stimulation was not affected by application of lidocaine to the upper small intestinal mucosa, suggesting that it was released from vagal nerve terminals.

Entrainment of segmental small intestinal slow waves with electrical stimulation in dogs.

The aim of this study was to derive effective pacing parameters for the entrainment of segmental intestinal myoelectrical activity. The study was performed in 12 dogs. Four pairs of electrodes were implanted on the serosa of the jejunum. Electrical stimulation of the small intestine was performed via the most proximal pair. For the slow waves within a distance of 5 cm, a complete entrainment was achieved with a pacing frequency of 1.1 times the intrinsic frequency (IF), a pulse width of 140 msec, and an amplitude of 4 mA. The time required for the entrainment was 25.6 +/- 2.7 sec. The maximum driven frequency was 1.38 +/- 0.03 IF. The percentage of the entrainment at this frequency was 44.0 +/- 3.9%. The data indicate that pacing is able to completely entrain segmental intestinal myoelectrical activity, suggesting that normalization of intestinal myoelectrical dysrhythmia is feasible with pacing.

Stimulation of the Small Intestine by Nutrients in Relation to Phase of the Migrating Motor Complex

Background: The relationship between the preceding phase of the migrating motor complex (MMC) and postprandial motility in the small intestine was studied. Methods: In eight healthy subjects small-bowel manometry was performed, and a 55-ml caloric liquid bolus (280 kJ) containing paracetamol and 14C-D-xylose was instilled into the duodenum during phase I and late phase II of the intestinal MMC, respectively, in randomized order. Blood samples were drawn at regular intervals and analysed for insulin, gastrin, glucose, paracetamol, and 14C-D-xylose. Results: After bolus administration during late phase II a phase-III-like activity succeeded by quiescence occurred in the duodenum in seven of eight subjects, whereas administration during phase I initiated irregular contractions in seven of eight subjects (P < 0.05). The caloric bolus induced a significant increase in serum insulin and gastrin. Areas under the curves for serum insulin, gastrin, glucose, paracetamol, and 14C-D-xylose were not modulated by the preceding phase of the MMC. Conclusions: The present study shows that a nutrient bolus instilled into the intestinal lumen induces MMC-like activity when administered during late phase II. These findings provide further evidence of interference between MMC and postprandial motility.

Involvement of the autonomic nervous system in thermogenesis induced by intestinal osmotic stimulation

Involvement of the autonomic nervous system in thermogenesis induced by intestinal osmotic stimulation

Plasma Cholecystokinin, Plasma Peptide YY and Gallbladder Motility in Patients with Slow Transit Constipation: Effect of Intestinal Stimulation

Background/Aim: Because cholecystokinin and peptide YY are gut hormones with potent effects on gastrointestinal motility, we determined whether abnormalities of cholecystokinin and peptide YY exist in slow transit constipation. Methods: Plasma concentrations of these hormones before, during and after intraduodenal infusion of a liquid meal in 21 patients with slow transit constipation were compared with the results in 8 healthy controls. Results: Fasting levels of plasma cholecystokinin (3.1 ± 0.2 vs. 2.4 ± 0.2 pM; p = 0.02) were higher in patients. Basal plasma peptide YY (11.4 ± 1.4 vs. 8.9 ± 0.7 pM; p = 0.1) tended to be higher in patients. After the meal (60–90 min), incremental cholecystokinin (p < 0.05), but not peptide YY, was significantly higher in patients. During intraduodenal infusion of the meal (0–60 min), incremental plasma cholecystokinin (251 ± 20 pM·min) and peptide YY (1,146 ± 186 pM·min) in patients were almost similar to control values (262 ± 22 and 901 ± 166 pM·min). Gallbladder volumes before, during and after the meal were not different between the 2 groups. Gastric emptying of a solid meal was delayed in the majority of patients (12 of 18). Abnormalities of plasma cholecystokinin were observed only in patients with delayed gastric emptying. Conclusion: Plasma levels of cholecystokinin are elevated in the fasting state and decrease more slowly after stimulation, but maximum release in response to intestinal nutrients is not altered in patients with slow transit constipation. The abnormality seems to be confined to a subgroup of patients with delayed gastric emptying.