Temporal relationships between wall motion, intraluminal pressure, and flow in the isolated rabbit small intestine

Intraluminal manometry is a tool commonly used to record motility in the human digestive tract. The recorded signal results from a combination of factors, including the hydrodynamic pressure transmitted through the intestinal contents due to contraction of the gut wall and the force of the gut wall acting on the sensors in regions of a luminal occlusion. However, the actual relationships between small bowel wall contraction, the measured intraluminal pressure, and the resultant flow have not been directly addressed. Video recording and high-resolution fiber-optic manometry were used to create spatiotemporal video maps of diameter and intraluminal pressure from isolated segments of rabbit small intestine. In the unstimulated gut, longitudinal muscle contractions were the only detectable motor pattern; circular muscle contractions were elicited by distension or erythromycin (1 μM). Longitudinal muscle contractions were not lumen-occlusive, although they caused measurable low-amplitude changes in pressure. Localized nonpropagating circular muscle contractions caused small localized, nonpropagating peaks of intraluminal pressure. Propagating contractions of circular muscle evoked larger, propagating pressure changes that were associated with outflow. Propagating circular muscle contractions often caused dilation of aboral receiving segments, corresponding to "common cavities"; these were propulsive, despite their low intraluminal pressure. The highest-amplitude pressure events were caused by lumen-occlusive circular muscle contractions that squeezed directly against the catheter. These data allow us to define the complex relationships between wall motion, intraluminal pressure, and flow. A strong correlation between circular and longitudinal muscle contraction and intraluminal pressure was demonstrated. Common-cavity pressure events, caused by propulsion of content by circular muscle contractions into a receptive segment, were often of low amplitude but were highly propulsive. Studies of wall motion in isolated preparations, combined with manometry, can assist in interpretation of pressure recordings in vivo.     

Enteric alpha-2 adrenoceptors: pathophysiological implications in functional and inflammatory bowel disorders

The gastrointestinal tract is innervated by extrinsic noradrenergic nerves which regulate various digestive functions, including mucosal secretions, bowel propulsion and gut sensations, via activation of alpha2-adrenoceptors. These receptors are mostly involved in the prejunctional modulation of enteric neurotransmission, but they act also at extra-neural postjunctional sites. Alpha2-adrenoceptor population consists of distinct subtypes, designated as alpha2A, alpha2B and alpha2C, endowed with different physiological and pharmacological properties, and the attempts to classify alpha2-adrenoceptors at gastrointestinal level have indicated a large predominance of alpha2A subtypes. Studies in humans have shown a favourable influence of alpha2-adrenoceptor activation on colonic tone and sensation, and there is clinical evidence indicating that alpha2-agonists can improve intestinal functions and induce a satisfactory relief of symptoms in patients with irritable bowel syndrome. In addition, genetic investigations have highlighted significant associations of alpha2-adrenoceptor gene polymorphisms with constipation and somatic symptoms in functional disorders of lower digestive tract. Post-operative ileus is a common surgical complication characterized by severe alteration of gut motility, resulting mainly from neurogenic and inflammatory mechanisms. Experiments in models of post-operative ileus have demonstrated an intense expression of alpha2-adrenoceptors in monocytes recruited into the intestinal muscularis, and provided consistent evidence that these receptors promote post-operative gut dysfunctions by hampering enteric neurotransmission and contributing to local inflammatory reaction. Changes in the enteric nervous system are being increasingly recognized also as major determinants of digestive symptoms associated with bowel inflammation. In this regard, studies based on functional and molecular approaches concur in suggesting that the expression of enteric alpha2-adrenoceptors is up-regulated in the presence of intestinal inflammation, and that alpha2-mediated mechanisms are responsible for gut motor alterations occurring at both inflamed and non-inflamed sites. The present review discusses pathophysiological implications of enteric alpha2-adrenoceptors, in the attempt to highlight potential therapeutic applications for drugs targeted on these receptors.     

Intestinal propulsion of a solid non-deformable bolus

A mathematical model of a segment of the gut with an enclosed pellet is constructed. The gut is represented as a thin deformable soft biological shell with the pellet modeled as a non-deformable solid. Mechanical properties of the gut wall were represented as longitudinal and circular smooth muscle layers embedded in stroma that satisfies the general type of nonlinear orthotropy. Deformations of the wall are finite. Bolus propulsion is numerically simulated by generation and propagation of an electromechanical wave along the syncytia. Pharmacological manipulation is applied to model 5-HT type 3 antagonist (Lotronex, GlaxoSmithKline) and 5-HT type 4 agonist (Zelnorm, Novartis, AB) drugs on the dynamics of bolus progression. The results lead to new quantitative insights into the complex spatio-temporal patterns of gastrointestinal transit. It is demonstrated that the reciprocal relationship in contraction of the longitudinal and circular smooth muscle syncytia is necessary to provide the "mixing" type of movements during the preparatory phase of propulsion. Strong simultaneous contractions of the both smooth muscle layers are required to expel the "mixed" pellet from the segment. The model is implemented as an interactive software system, Gut Discovery(www.aincompany.com), and accurately predicts the effects of drugs on gut motility.     

Movements of the large intestine in the anuran larvae, Xenopus laevis

1. The contractile behavior of the large intestine of Xenopus laevis tadpoles was studied. 2. The large intestine is divided into a colon and rectum, and shows three types of movements: rhythmic ascending (antiperistaltic) waves of contraction originating at the anal end of the large bowel, rhythmic longitudinal contractions in the rectum and colon, and irregular contractions. The first two patterns occur in the large bowel in situ and thus appear mature. The last one occurred only in older preparations, and thus appeared pathological. 3. Antiperistaltic waves of contractions and longitudinal contractions are generated independent of each other, suggesting that circular muscles and longitudinal muscles contract separately. 4. Acetylcholine, adrenaline and noradrenaline augment motility. 5. The premetamorphic motility of the large bowel is similar to that seen in adult frogs. Comparable motility was not observed elsewhere in the larval alimentary tract. The large intestine appears to be the first portion of the anuran alimentary tract to acquire the adult physiological and morphological profile.     

Differential alterations in tachykinin NK2 receptors in isolated colonic circular smooth muscle in inflammatory bowel disease and idiopathic chronic constipation

Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are intestinal disorders which disrupt normal colonic motility. Enteric tachykinins are well-recognised to play a role in the motor control of the gut, and increased colonic levels of substance P are seen in IBD, whereas decreased levels have been reported in ICC. In this investigation, we have characterised the tachykinin receptor population of normal human colonic circular smooth muscle and examined any changes that occur in IBD and ICC. The selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A(4-10), caused concentration-dependent contractions in healthy tissues; neither NK1 receptor-selective nor NK3 receptor-selective agonists were contractile. In diseased preparations also, only [beta-Ala8]neurokinin A(4-10) caused contractions with EC50 values similar to health. The maximum contractile responses (Emax), however, were significantly decreased in both forms of IBD but significantly increased in ICC. The muscarinic acetylcholine receptor agonist, carbachol, also caused contractions in diseased tissues, but EC50 and Emax values were not significantly different from health. The differential changes in contractility found in IBD and ICC are specific to NK2 receptors, and may reflect the altered levels of substance P or other tachykinins found in these intestinal disorders.     

Endocrine cells in atresic chick embryo intestine: histochemical and immunohistochemical study

Intestinal motility disorders are an important problem in the postoperative management of patients with intestinal atresia. Intestinal motility could be initiated by luminal factors that activate intrinsic and extrinsic primary afferent nerves involved in the peristaltic reflex. Endocrine cells act as a key point, because they transfer information regarding the intestinal contents and intraluminal pressure to nerve fibers lying in close proximity to the basolateral surface of the epithelium. In chick embryo, experimental intestinal atresia is associated with disorders in the development of the enteric nervous system, related to the severity of intestinal dilation. Our aim was to investigate the distribution pattern of endocrine cells in the developing endocrine system of chick embryo small intestine with experimentally-induced atresia on day 12 and on day 16. Changes in enteroendocrine population were examined in gut specimens (excised proximal and distal to the atresia) from experimental embryos 19 days old and in control sham-operated chick embryos at the same age. Sections from proximal and distal bowel and control bowel were stained with Grimelius silver stain, a valuable histochemical method for detecting the argyrophil and argentophilic cells, and with an immunohistochemical procedure for detecting serotonin and neurotensin immunoreactive cells. In chick embryo proximal bowel, intestinal dilation differed in the various embryos. We found significantly higher enteroendocrine cell counts in proximal bowel than in distal and control bowel. The differences depended on the precociousness of surgery and the severity of dilation. Considering the major contribution of enteroendocrine cells to the peristaltic reflex, our data may help to explain the pathogenesis of motility disorders related to intestinal atresia.     

Neurohumoral control of gastrointestinal motility

Neurohumoral substances and their receptors play a major part in the complex regulation of gastrointestinal motility and have therefore been the predominant targets for drug development. The numerous receptors involved in motility are located mainly on smooth muscle cells and neuronal structures in the extrinsic and intrinsic parts of the enteric nervous system. Within this system, receptor agonists and antagonists interacts directly to modify excitatory or inhibitory signals. In view of this complexity it is not surprising that our knowledge about the mechanisms of actions of the various neurohormones and drugs affecting gut motility has been rather fragmented and incomplete. However, recently substantial progress has been achieved, and drug therapy for gut dysmotility is emerging, based primarily on neurohumoral receptors. This paper presents a selective review of the neurohumoral regulatory mechanisms of gastrointestinal motility. In this context, the physiology and pharmacology of the smooth muscle cells, gastrointestinal motility and dysmotility, the enteric nervous system, gastrointestinal reflexes, and serotonin is presented. Further investigation and understanding of the transmitters and receptors involved in especially the reflex activation of peristalsis is crucial for the development of novel therapies for motility disorders.     

Fucosylated but Not Sialylated Milk Oligosaccharides Diminish Colon Motor Contractions

Human milk oligosaccharides (HMO) are being studied by different groups exploring a broad range of potential beneficial effects to the breastfed infant. Many of these effects have been attributed to a growth promotion effect on certain gut organisms such as bifidobacteria. Additionally, evidence indicates that HMO are able to directly promote positive changes in gut epithelium and immune responses under certain conditions. This study utilizes a standardized ex vivo murine colon preparation to examine the effects of sialylated, fucosylated and other HMO on gut motor contractions. Only the fucosylated molecules, 2’FL and 3’FL, decreased contractility in a concentration dependent fashion. On the basis of IC₅₀ determinations 3’FL was greater than 2 times more effective than 2’FL. The HMO 3’SL and 6’SL, lacto-N-neotetraose (LNnT), and galactooligosaccharides (GOS) elicited no effects. Lactose was used as a negative control. Fucosylation seems to underlie this functional regulation of gut contractility by oligosaccharides, and L-fucose, while it was also capable of reducing contractility, was substantially less effective than 3’FL and 2’FL. These results suggest that specific HMO are unlikely to be having these effects via bifidogenesis, but though direct action on neuronally dependent gut migrating motor complexes is likely and fucosylation is important in providing this function, we cannot conclusively shown that this is not indirectly mediated. Furthermore they support the possibility that fucosylated sugars and fucose might be useful as therapeutic or preventative adjuncts in disorders of gut motility, and possibly also have beneficial central nervous system effects.     

Neuropharmacology of stress-induced mucosal inflammation: implications for inflammatory bowel disease and irritable bowel syndrome

Inflammatory bowel disease (IBD) and the irritable bowel syndrome (IBS) are common causes of medical consultation and the most frequent diagnosis raised by gastroenterologists. Recent years have witnessed considerable advances in the understanding of the mechanisms involved in the initiation and perpetuation of these chronic and recurrent disorders. However, particularly in IBS, the success of the "bench-to the-bedside medicine" has been rather poor since many affected individuals still experience significant bother and negative impact in their quality of life despite growing investigative and sanitary costs. Besides IBD, several subgroups of IBS patients have been lately identified as carriers of mucosal inflammation throughout the gut. Although multifactorial, life stress has emerged as a critical factor for mucosal inflammation in these conditions. Due to the clinical and biological heterogeneity of IBD and IBS patients, the simplistic hypothesis of a stress-related stepwise progression of gut inflammation may be useful to gain operative knowledge and render better and specific diagnostic markers and improved therapeutic options. Therefore, in this review, we have consciously admitted the possibility of linear evolution of gut inflammation, from the mucosa to the serosa, and assumed a bidirectional progression, from physiological to pathological inflammation. Thus, we have outlined the stress neurocircuitry implicated in the regulation of gut inflammation and the participating pathways (mechanisms, receptors and molecules) and provided with both, evidence and a theoretical-based approach to present and potential drugs that, alone or in combination, might help to prevent, control or regress the stress-induced inflammatory process at different stages.     

Proteinase-activated receptors (PARs) in infection and inflammation in the gut

Proteinases have been shown to act as signaling molecules that are able to send specific signals to cells through the activation of proteinase-activated receptors (PARs). Those receptors which are expressed in a wide variety of cells in the gastrointestinal tract are considered as "emergency" mechanisms, particularly involved in inflammatory responses of the gut. Depending on the cell types of the gut in which PARs are activated, their activation interacts with all aspects of the gut physiology: motility, barrier function, transports, innate immune response, sensory functions, and even proliferation. A growing body of evidences discussed here suggests that these receptors, and the proteinases that activate them, are important mediators of the innate immune response of the gut and could play a major role in chronic inflammatory states of the gut (inflammatory bowel diseases), or infectious diseases.     

Cholinergic responsiveness of intestinal muscle in the pregnant guinea pig

Clinical observations and limited animal experiments have suggested that gastrointestinal motility is suppressed during pregnancy. We therefore compared isometric contractions of colon and ileal circular muscle in response to carbachol (10(-8) to 10(-4) M). Data was analyzed by comparing mean maximal tension, dose-response curves, and EC50 values for tissue from the two groups of animals. Circular muscle from proximal colon, distal colon, and ileum in pregnant animals developed less tension in response to carbachol than did tissue from non-pregnant controls. Dose-response curves in the pregnant groups were depressed, when compared with non-pregnant groups, at concentrations of 10(-6) M and greater. Sensitivity of the muscle to cholinergic stimulation, as measured by EC50 values, was similar in the ileum and proximal colon but increased slightly (p less than 0.05), by a factor of approximately 2, for distal colonic muscle from pregnant animals. Assuming that circular muscle contractions are primarily responsible for mixing and propulsion in the gut, this reduction in responsiveness to excitatory cholinergic stimulation is consistent with the concept of pregnancy-related suppression of gastrointestinal motility.     

The gut microbiota in the metagenomics era: sometimes a friend, sometimes a foe

The normal intestinal microflora (microbiota) represents a complex, dynamic, and diverse collection of microorganisms, which usually inhabit the gastrointestinal tract. Normally, between this flora and the human host a mutually beneficial long-term symbiotic relationship is established, where the host contributes essential nutrients necessary for the survival of the microbiota and the latter fulfils multiple roles in host nutrition and development. Several achievements have recently converged to renew interest in studying the normal gut microbiota: the development of molecular methods of studying the microbial communities, the improved understanding of host-microbe interactions in health and disease, and the potential for therapeutic manipulation of the microbiota. We present recent data concerning the molecular technologies of studying the microbiota and new findings regarding the composition of the normal flora. We underline the beneficial activities of the gut flora on the human host. We emphasize the recent findings in the alterations of the microbiota in various medical conditions (celiac disease, irritable bowel syndrome, obesity, colorectal cancer, allergic disorders, and especially inflammatory bowel diseases). The results of these new studies suggest that changes of the microbiota could be linked to the etiopathogenesis of these diseases. These outstanding findings could be used for further diagnostic tools and/or therapy.     

Cajal间质细胞及其可塑性的研究进展

Cajal间质细胞(interstitial cells of Cajal,ICC)是一类主要分布于胃肠道的间质细胞,与平滑肌细胞以及肠神经细胞有着紧密的关系。ICC分布于整个胃肠道,是胃肠道起搏细胞,具有产生和传播慢波的功能,参与神经递质调节,在一些胃肠动力性疾病中表现为异常状态。近期,关于ICC的生理功能、损伤和恢复机制的研究取得了显著的进展。ICC网络存在动态平衡,为了维持ICC网络功能,ICC周期代谢需要被紧密的控制调节平衡ICC死亡和更替。研究表明,ICC具有高度的可塑性,在一些缺失ICC的疾病中ICC并不一定死亡,转分化、去分化和细胞凋亡可能是ICC丢失的机制。。本文主要对Cajal间质细胞及其可塑性的研究进展进行了综述。     

Gastrointestinal functional bowel disorders: new therapies

Present therapies for functional gastrointestinal disorders are symptomatic and mainly treat altered bowel habits. New therapies are focused on nerve-gut communication dysfunction: 5-HT3 antagonists and 5-HT4 agonists have demonstrated activity in clinical trials. Promising targets for upper gut dysmotility drugs are motilin and cholecystokinin A receptors. Tachykinins, calcitonin gene-related peptide or glutamate antagonists are the most relevant candidates for visceral pain.     

Modulation of electrical activity in gastrointestinal smooth muscle by peptides.

A rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery in gastrointestinal smooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of some gastrointestinal smooth muscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree of modulation of electrical activity by peptides varies depending upon the region of the gastrointestinal tract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channel activity in gastrointestinal smooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channel activity in gastrointestinal smooth muscle. This represents one of the challenging areas to be studied in the field of gastrointestinal smooth muscle. One disease in which a better appreciation of the regulation of ion channel activity could lead to therapeutic benefit is irritable bowel syndrome. A coupling of smooth muscle electrical activity to hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spike activity which triggers hypermotility [40]. It would follow that inhibition of calcium influx should reduce spiking and, therefore, hypermotility. In fact, the calcium channel blockers nifedipine and nicardipine have been shown to decrease colonic motility in irritable bowel syndrome patients [62-64]. As our understanding of gastrointestinal smooth muscle ion channels expands, development of a gastrointestinal selective calcium channel blocker may be possible. This class of agents would be effective in the treatment of irritable bowel syndrome and potentially other peptide-related spastic smooth muscle disorders.     

Ghrelin as a target for gastrointestinal motility disorders

The therapeutic potential of ghrelin and synthetic ghrelin receptor (GRLN-R) agonists for the treatment of gastrointestinal (GI) motility disorders is based on their ability to stimulate coordinated patterns of propulsive GI motility. This review focuses on the latest findings that support the therapeutic potential of GRLN-R agonists for the treatment of GI motility disorders. The review highlights the preclinical and clinical prokinetic effects of ghrelin and a series of novel ghrelin mimetics to exert prokinetic effects on the GI tract. We build upon a series of excellent reviews to critically discuss the evidence that supports the potential of GRLN-R agonists to normalize GI motility in patients with GI hypomotility disorders such as gastroparesis, post-operative ileus (POI), idiopathic chronic constipation and functional bowel disorders.     

New antiemetic drugs

Three major areas of medicine are identified in which there is a need for new antiemetic drugs. These are the nausea and vomiting arising from gastrointestinal motility disturbances (functional dyspepsia, diabetic neuropathy, classical migraine), the sickness evoked by abnormal motion, and the severe emesis experienced by cancer patients as a result of certain cytotoxic therapies. For gastrointestinal-related nausea, selective stimulants of gut motility are suggested to form the basis for a new type of antiemetic therapy. In motion sickness, there has been progress in the understanding of the illness, but little advance in the development of new drugs that selectively prevent this type of sickness. In cancer chemo- and radio-therapy, the discovery that selective 5-HT3 (5-HT, 5-hydroxytryptamine) receptor antagonists can prevent severe cytotoxic-evoked emesis now promises to radically change the type of antiemetic therapy given to these patients. This type of antiemetic compound and the pharmacology of the new 5-HT3 receptor antagonists are, therefore, discussed in detail.     

Intestinal epithelial cell signalling and chronic inflammation: From the proteome to specific molecular mechanisms

Advancing knowledge regarding the cellular mechanisms of intestinal inflammation has led to a better understanding of the disease pathology in patients with inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis. It has become clear from numerous studies that enteric bacteria are a critical component in the development and prevention/treatment of chronic intestinal inflammation. An emerging new paradigm suggests that changes in the homeostasis of bacteria- and host-derived signal transduction at the intestinal epithelial cell (IEC) level may lead to a break in barrier function and the development of adaptive immune disturbances. The functional loss of anti-inflammatory host-derived signals in the gut including the immunosuppressive cytokines Interleukin 10 (IL-10) and transforming growth factor (TGF)-beta are of high relevance to the pathogenesis of IBD. The development of analytical tools including two-dimensional (2D) high-resolution protein separation techniques and peptide mass fingerprinting via high-sensitivity mass-spectrometers (MS) allows the quantitative assessment of protein expression changes in disease-relevant cell types. By using these advanced methods, the characterization of the epithelial cell proteome from murine models of experimental colitis and human IBD patients identified novel disease-related mechanisms with respect to the regulation of the glucose-regulated endoplasmic reticulum stress response protein 78 (grp-78). In conclusion, the identification and functional analysis of differentially expressed proteins in purified intestinal target cell types will help to add important insights to the understanding of the molecular pathogenesis of these immune-mediated chronic intestinal disorders.     

Ontogeny of excitatory and inhibitory control of gastrointestinal motility in the African clawed frog, Xenopus laevis

The transparent body wall of Xenopus laevis larvae during the first developmental stages allows in vivo studies of gastrointestinal tract activity. The purpose of this study was to chart the ontogeny of gut motility in Xenopus larvae and to identify the most important control systems during the first developmental stages. Coordinated descending contraction waves first occurred in the gut at Nieuwkoop and Faber stage 43 [0.8 +/- 0.1 contractions/min (cpm)] and increased to 4.9 +/- 0.1 cpm at stage 47. The cholinergic receptor agonist carbachol (5-10 microM) increased contraction frequency already at stage 43, as did neurokinin A (NKA, 0.3-1 microM). The muscarinic antagonist atropine (100 microM) first affected contraction frequency at stage 45, which coincides with the onset of feeding. The tachykinin antagonist MEN-10,376 (6 microM) blocked NKA-induced contractions but not spontaneous motility. Both sodium nitroprusside [nitric oxide (NO) donor, 1-10 microM] and vasoactive intestinal peptide (VIP, 0.1-1 microM) inhibited contractions from the earliest stage onward. Blocking NO synthesis using NG-nitro-L-arginine methyl ester (100 microM) had no effect per se, but antagonized VIP evoked inhibition at stage 47. We conclude that gastrointestinal motility is well developed in the Xenopus laevis larvae before the onset of feeding. Functional muscarinic and tachykinin receptors are present already at the onset of motility, whereas a cholinergic tone develops around the onset of feeding. No endogenous tachykinin tone was found. Functional VIP receptors mediate inhibition at the onset of motility. NO seems to mediate the VIP effect at later stages.     

Gastric and duodenal motility in the cat: the role of central innervation assessed by transient vagal blockade

Experiments were performed on four cats to characterize fasting gastric and small bowel motility and to assess the role of extrinsic vagal innervation in the control of that motor activity. A multilumen manometry tube was positioned to record pressure changes from the proximal small bowel and stomach. Transient vagal nerve blockade was accomplished by cooling the cervical vagosympathetic nerve trunks, previously isolated in skin loops on each side of the neck. Two characteristic patterns of basal activity were documented in the stomach: (i) regular phasic contractions of variable amplitude in the body of the stomach; and (ii) infrequent, irregular contractions of high amplitude in the distal antrum. In the duodenum, two predominant activity patterns were noted: (i) periods of continuous irregular activity; and (ii) irregular clusters of contractions separated by quiescent intervals. No typical migrating motor complex activity was seen in the basal gastric or small bowel recordings. Bilateral vagal blockade did not consistently change the general pattern of gastric or small bowel activity, but did appear to reduce gastric contractile activity, as measured by motility indices. We conclude that extrinsic vagal innervation does not play a major role in the control of fasting feline gastric and duodenal motility.