Altered Gastrointestinal Transit Research Articles

Polysaccharides from Passion Fruit Peels: From an Agroindustrial By-Product to a Viable Option for 5-FU-Induced Intestinal Damage.

Gastrointestinal mucositis is a serious and dose-limiting toxic side effect of oncologic treatment. Interruption of cancer treatment due to gastrointestinal mucositis leads to a significant decrease in cure rates and consequently to the deterioration of a patient's quality of life. Natural polysaccharides show a variety of beneficial effects, including a gastroprotective effect. Treatment with soluble dietary fiber (SDF) from yellow passion fruit (Passiflora edulis) biomass residues protected the gastric and intestinal mucosa in models of gastrointestinal injury. In this study, we investigated the protective therapeutic effect of SDF on 5-FU-induced mucositis in male and female mice. Oral treatment of the animals with SDF did not prevent weight loss but reduced the disease activity index and preserved normal intestinal function by alleviating diarrhea and altered gastrointestinal transit. SDF preserved the length of the colon and histological damage caused by 5-FU. SDF significantly restored the oxidative stress and inflammation in the intestine and the enlargement and swelling of the spleen induced by 5-FU. In conclusion, SDF may be a promising adjuvant strategy for the prevention and treatment of intestinal mucositis induced by 5-FU.

Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice.

Gut microbiota is essential for the development of the gastrointestinal system, including the enteric nervous system (ENS). Perturbations of gut microbiota in early life have the potential to alter neurodevelopment leading to functional bowel disorders later in life. We examined the hypothesis that gut dysbiosis impairs the structural and functional integrity of the ENS, leading to gut dysmotility in juvenile mice. To induce gut dysbiosis, broad-spectrum antibiotics were administered by gavage to juvenile (3weeks old) male C57Bl/6 mice for 14days. Bile acid composition in the intestinal lumen was analysed by liquid chromatography-mass spectrometry. Changes in intestinal motility were evaluated by stool frequency, transit of a fluorescent-labelled marker and isometric muscle responses of ileal full-thickness preparations to receptor and non-receptor-mediated stimuli. Alterations in ENS integrity were assessed by immunohistochemistry and Western blot analysis. Antibiotic treatment altered gastrointestinal transit, luminal bile acid metabolism and bowel architecture. Gut dysbiosis resulted in distorted glial network, loss of myenteric plexus neurons, altered cholinergic, tachykininergic and nitrergic neurotransmission associated with reduced number of nNOS neurons and different ileal distribution of the toll-like receptor TLR2. Functional defects were partly reversed by activation of TLR2 signalling. Gut dysbiosis caused complex morpho-functional neuromuscular rearrangements, characterized by structural defects of the ENS and increased tachykininergic neurotransmission. Altogether, our findings support the beneficial role of enteric microbiota for ENS homeostasis instrumental in ensuring proper gut neuromuscular function during critical stages of development.

Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol

ObjectiveAcute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users. Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice.MethodsAdult male DIO and lean mice were treated daily with vehicle or THC (2mg/kg for 3 weeks and 4 mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, whole gut transit and gut microbiota were measured longitudinally.ResultsTHC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice.ConclusionsChronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity.

Systemic and anti-nociceptive effects of prolonged lidocaine, ketamine, and butorphanol infusions alone and in combination in healthy horses

BackgroundProlonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses.MethodsEight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15mL/kg/hr with drug doses as follows: L – 1.3 mg/kg then 3 mg/kg/hr; B – 0.018 mg/kg then 0.013 mg/kg/hr; K – 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours.ResultsFour of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period.ConclusionsDrug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients.

An in vitro rat model of colonic motility to determine the effect of β-casomorphin-5 on propagating contractions.

Beta-casomorphin-5 (βCM-5) is a milk-derived bioactive peptide that slows gastro-intestinal transit (GIT) in vivo and blocks the peristaltic reflex in the guinea pig colon in vitro. We wanted to establish an in vitro model system in which effects of dairy-derived substances containing opioid peptides on intestinal motility can be assessed and used to predict in vivo outcomes. Because βCM-5 is an opioid agonist that acts on enteric neurons, we used this substance to compare two different isolated colonic tissue preparations to determine which would more closely mimic the in vivo response previously reported in the literature. We compared and characterized the effects of βCM-5 on spontaneous contractions in isolated segments of distal colon (1 cm length) compared with propagating contractions along the isolated intact large intestine (22 cm length). In short segments of distal colon, βCM-5 increased the tension and frequency of spontaneous contractions in a concentration-dependent manner. At 20 μM βCM-5 tension increased by 71 ± 17% and the frequency doubled (n = 9), effects inhibited by naloxone (n = 7) and therefore mediated by opioid receptors. In contrast 20 μM βCM-5 disrupted propagating contractions in the large intestine preparation. At 20 μM βCM-5 reduced the proportion of contractions initiated in the proximal colon reaching the rectum by 83 ± 11% (n = 5) and this effect was also inhibited by naloxone, consistent with altered GIT reported in vivo. Our results demonstrate that the isolated whole large intestine provides an ideal preparation that mimics the reduced propagation of GIT in vivo in response to an opioid agonist, whereas short colon segments did not. The findings of the current study reveal that preserving large segments of intact large intestine, and hence intact enteric neural circuitry provides an ideal in vitro model to investigate the effect of opioid receptor modulators on intestinal transit.

Is Ramosetron Really Useful to Treat Diabetic Diarrhea With Rapid Small Bowel Transit?: Author's Reply

TO THE EDITOR: I appreciate for Dr. Lee's comments.1 The 5-hydroxytryptamine (5-HT) receptors (the original 5-HT M receptor) are distributed widely in both the gastrointestinal (GI) tract and the central nerve system, and result in increased intestinal secretion and alteration of peristaltic activity. The action of 5-HT3 receptor antagonists (5-HT3RAs) to modify contraction-relaxation responses would be dependent on the relative balance of excitatory-inhibitory tone. Therefore, 5-HT3RAs might reduce motor activity in the presence of an abnormally increased basal activity. Ramosetron, a selective 5-HT3 receptor antagonist, has been confirmed to have an inhibitory effect on lower GI transit. This drug has been known to be effective for diarrhea predominant irritable bowel syndrome in both animal and clinical studies. But its effects and mechanisms on the upper GI tract (stomach and small intestine) have not been verified. Classic sympathetic, parasympathetic autonomous nervous system, and the enteric nervous system (ENS) are important for the regulation of enteric function. Diabetes results in abnormalities of the ENS, such as loss of neurons containing nitric oxide synthase, which mediates GI tract relaxation, and an increase in the serotonin contents, which regulate GI tract contraction. An imbalance between the inhibitory and excitatory ENS could be one of the causes of diabetic diarrhea. The 5-HT3 receptor antagonist inhibits the excitatory neurons of ENS thus plays a role in regulating a balance of the ENS components in diabetic patients.2,3 Based on these mechanisms, Murao and Hosokawa2 reported the effect of ramosetron, which was developed as an antiemetic drug for cancer chemotherapy and for the treatment of diabetic diarrhea. In our study, the effect was well demonstrated by its inhibitory effects on accelerated GI transit caused by 5-HT, thyrotropin-releasing hormone and mustard oil.3 However, Hirata et al4 showed recently that ramosetron significantly inhibited the delayed gastric emptying in a corticotrophin releasing factor and soybean oil-induced rat model, in comparison with anti-diarrheal agent and spasmolytics. We should consider the differences in the dose of ramosetron and the action mechanism of the substance that caused changes in altered GI transit. There were conflicting results from animal experiments on the same drug.3,4 This could be an evidence presenting the different treatment effects of ramosetron in patients with autonomic neuropathy, diabetic diarrhea and gastroparesis.

Effects of Ramosetron on Gastrointestinal Transit of Guinea Pig

Background/AimsA selective 5-hydroxytryptamine (5-HT) type 3 receptor antagonist, ramosetron, inhibits stress-induced abnormal defecation in animals and is currently used as a therapeutic drug for irritable bowel syndrome with diarrhea. The aim of this study is to investigate the effect of ramosetron on altered gastrointestinal (GI) transit.MethodsMale guinea pigs weighing approximately 300 g were used. The effect of ramosetron was investigated on altered GI transit induced by thyrotropin-releasing hormone (TRH), 5-HT, or mustard oil (MO). GI transit was evaluated by the migration of charcoal mixture from the pylorus to the most distal point, and expressed as a percentage (%) of charcoal migration (cm) of the total length of total small intestine (cm).ResultsThe average charcoal transit was 51.3 ± 20.1% in the control (vehicle) group, whereas in the ramosetron group charcoal moved 56.6 ± 21.9%, 46.9 ± 9.14% and 8.4 ± 5.6% of the total small intestine at the concentrations of 10, 30 and 100 µg/kg, respectively. GI transit after administration of TRH (100 µg/kg), 5-HT (10 mg/kg) or MO (10 mg/kg) was accelerated compared to vehicle (5-HT, 94.9 ± 9.22%; TRH, 73.4 ± 14.7%; MO, 81.0 ± 13.7%). Ramosetron inhibited GI transit altered by 5-HT, TRH or MO.ConclusionsRamosetron modulated GI transit. We suggest that ramosetron may be therapeutically useful for those with accelerated upper GI transit.

Melatonin, a Potential Therapeutic Agent for Smooth Muscle-Related Pathological Conditions and Aging

Increases or decreases in the contractile response of smooth muscle underlie important pathological conditions such as hypertension, incontinence and altered gastrointestinal transit. These disorders are also frequently encountered in the aged population. Oxidative stress and inflammation are key features in the initiation, progression, and clinical manifestations of smooth muscle disorders. Melatonin, the major secretory product of the pineal gland, has free radical scavenging and antioxidative properties and protects against oxidative insult. Recently, widespread interest has grown regarding the apparent protective effects of melatonin on smooth muscle dysfunction. "In vitro" studies have shown that melatonin decreased vascular tone of vascular beds from control, hypertensive or aged animals, through the reduction of adrenergic contraction and the increase in acetylcholine-induced relaxation. "In vivo", melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. In the gastrointestinal tract, melatonin treatment improves age-related impairments in gallbladder contractility and prevents deleterious effects of cholecystitis on smooth muscle and the enteric nervous system through suppression of oxidative stress. In addition, melatonin improves colonic transit time in constipation-predominant IBS patients. Melatonin is also able to restore impaired contractility of the detrusor muscle from old animals through normalization of Ca(2+) dependent and independent contraction, mitochondrial polarity, neuromuscular function and oxidative stress, which would explain the effects of melatonin counteracting cystometric changes in senescent animals. It also reverses bladder damage following ischemia/reperfusion. In conclusion, melatonin may be a promising candidate for future research of agents that modulate smooth muscle motility.

Epidural analgesia after scoliosis surgery: electrophysiologic and clinical assessment of the effects of bupivacaine 0.125% plus morphine versus ropivacaine 0.2% plus morphine

Study Objective To study the electrophysiologic and clinical effects of epidural morphine combined with either bupivacaine 0.125% or ropivacaine 0.2%. Design Comparative, randomized, double-blind study. Settings Intensive care unit and hospital ward of a university hospital. Patients 18 adult ASA physical status I and II patients with degenerative or idiopathic scoliosis, undergoing posterior spinal fusion with instrumentation. Interventions Patients received epidural administration of 10-mL bolus of either bupivacaine or ropivacaine followed by a 6-mL/h infusion for 48 hours of unlabeled local anesthetic. In all patients, epidural morphine 5 mg was added daily. Measurements Assessment was focused mainly on somatosensory cortical evoked potentials, soleus H-reflex, and F waves. These electrophysiologic data were recorded before and after epidural medications. Second, respiratory rate, Pa co 2, visual analog score (VAS), and side effects such as postoperative nausea and vomiting (PONV), gastrointestinal (GI) transit delay, and urinary retention were noted. Main Results Bupivacaine 0.125% + morphine was given to 9 patients, and ropivacaine 0.2% + morphine was given to 9 other patients. H-reflex, F waves, and somatosensory cortical evoked potential recording remained unchanged across the time of assessment. Respiratory rate and Pa co 2 values were normal. VASs were indifferently low at rest, but they were lower with bupivacaine than with ropivacaine on mobilization. The frequency of PONV was indifferently high. No altered GI transit or urinary retention was noted. Conclusion After epidural administration during the study conditions, bupivacaine 0.125% and ropivacaine 0.2% combined with morphine allow for neurologic examination.

Investigation on the relationship between cannabinoid CB1 and opioid receptors in gastrointestinal motility in mice

1. This study investigated whether (a) cannabinoid CB(1) receptor knockout (CB(1)(-/-)) mice displayed altered gastrointestinal transit and (b) cannabinoid CB(1) and opioid receptors functionally interact in the regulation of gastrointestinal transit. 2. Gastrointestinal transit was assessed by the Whole Gastrointestinal Transit, measuring the excretion time of an intragastrically administered marker (whole intestine), and the Upper Gastrointestinal Transit, measuring the distance covered by the marker in the small intestine. 3. CB(1)(-/-) and homozygous CB(1)(+/+) (CB(1)(+/+)) mice did not differ in both whole gut and small intestine transit. CB(1)(-/-) and CB(1)(+/+) mice were equally responsive to the inhibitory effect of morphine (10 mg kg(-1)) and loperamide (3 mg kg(-1)) on whole gut transit.4. Additionally, in CD1 mice the cannabinoid CB(1) receptor antagonist, rimonabant (0-0.5 mg kg(-1)), failed to block the inhibitory effect of morphine (0-1.25 mg kg(-1)) and loperamide (0-0.5 mg kg(-1)) on transit in small and whole intestine. Similarly, the opioid receptor antagonists, naloxone (0-1 mg kg(-1)) and naltrexone (0-10 mg kg(-1)), failed to block the inhibitory effect of the cannabinoid WIN 55,212-2 (0-3 mg kg(-1)) on transit in small and whole intestine.5. These results suggest that (a) compensatory mechanisms likely developed in CB(1)(-/-) mice to overcome the lack of inhibitory function of endocannabinoid system; (b) cannabinoid and opioid receptor systems did not interact in regulating gastrointestinal transit in mice.

Effects of Giardia lamblia infection on gastrointestinal transit and contractility in Mongolian gerbils.

To determine if Giardia lamblia infection is associated with altered gastrointestinal transit and smooth muscle contractile function, Mongolian gerbils were infected orogastrically with 2 x 10(5) trophozoites (infected) or vehicle (uninfected controls). At the time of peak colonization, control and infected animals were infused either orogastrically or intraduodenally with 51Cr. Gastric emptying of isotope and intestinal transit (measured by the geometric center of distribution of intestinal 51Cr transit) were significantly (P < 0.05) greater in the infected compared to control animals in both the fasted and the fed states. Then, to determine whether Giardia lamblia has an effect on the contractility of longitudinal and circular smooth muscle, isometric tension of jejunal segments was recorded. The development of active tension with stretch and the dose-response curve to bethanechol were significantly increased in the longitudinal muscle of infected animals compared to controls. However, the circular smooth muscle did not show a similar increase in contractility. These findings suggest that an altered gastrointestinal transit and smooth muscle contractility may be involved in the pathophysiology of giardiasis.

Small intestinal structure and passive permeability in systemic sclerosis.

Seventeen patients with proven systemic sclerosis had a peroral jejunal biopsy performed. Four biopsies were regarded as showing abnormalities, which were mostly confined to the deeper structures, although in two there was a minimal degree of villous atrophy without epithelial cell changes. Passive intestinal permeability, as assessed by the cellobiose/mannitol test, was normal in all patients. In contrast, seven patients had a low xylose test result, which in five of them could be accounted for by impaired renal function, small intestinal bacterial contamination, or altered gastrointestinal transit. These results indicate that passive intestinal permeability is unaltered in systemic sclerosis, and that malabsorption, when it occurs, is caused by other factors.