Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon

BACKGROUND & AIMS: A variety of gastrointestinal motility disorders have been attributed to alterations of interstitial cells of Cajal and malformations of the enteric nervous system. This study evaluates both the distribution of interstitial cells of Cajal and the pathohistology of the enteric nervous system in 2 severe human colorectal motility disorders. METHODS: Colonic specimens obtained from patients with slow-transit constipation (n = 11), patients with megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were stained with antibodies against c-kit (marker for interstitial cells of Cajal) and protein gene product 9.5 (neuronal marker). The morphometric analysis of interstitial cells of Cajal included the separate registration of the number and process length within the different regions of the muscularis propria. The structural architecture of the enteric nervous system was assessed on microdissected whole-mount preparations. RESULTS: In patients with slow-transit constipation, the number of interstitial cells of Cajal was significantly decreased in all layers except the outer longitudinal muscle layer. The myenteric plexus showed a reduced ganglionic density and size (moderate hypoganglionosis) compared with the control group. Patients with megacolon were characterized by a substantial decrease in both the number and the process length of interstitial cells of Cajal. The myenteric plexus exhibited either complete aganglionosis or severe hypoganglionosis. CONCLUSIONS: The enteric nervous system and interstitial cells of Cajal are altered concomitantly in slow-transit constipation and megacolon and may play a crucial role in the pathophysiology of colorectal motility disorders.     

Understanding and controlling the enteric nervous system

The enteric nervous system or the 'Little Brain' of the gut controls gastrointestinal motility and secretion, and is involved in visceral sensation. In this chapter, new developments in understanding the function of the enteric nervous system are described. In particular, the interaction of this system with the interstitial cells of Cajal, the pacemaker cells of the gut, is highlighted. The importance of the interaction between the enteric nervous system and the immune system is discussed, especially in relation to functional bowel disorders and post-operative ileus. Evidence is also provided that neurones can change their function and phenotype, a phenomenon called neuronal plasticity, which contributes to the pathogenesis of visceral hypersensitivity. Finally, new developments in stem cell transplantation are described. All these new insights should lead to a better understanding of the enteric nervous system and hopefully to better ways of controlling it.     

Paraneoplastic dysmotility: loss of interstitial cells of Cajal

Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.     

Key elements determining the intestinal region-specific environment of enteric neurons in type 1 diabetes

Diabetes,as a metabolic disorder,is accompanied with several gastrointestinal(GI) symptoms,like abdominal pain,gastroparesis,diarrhoea or constipation.Serious and complex enteric nervous system damage is confirmed in the background of these diabetic motility complaints.The anatomical length of the GI tract,as well as genetic,developmental,structural and functional differences between its segments contribute to the distinct,intestinal region-specific effects of hyperglycemia.These observations su...     

肠神经系统在功能性胃肠病发病中的作用

肠神经系统对胃肠道运动、分泌和血液供应具有独立的调节作用,功能性胃肠病（FGIDs）的慢性症状如腹泻、便秘和疼痛与肠神经调控的胃肠道功能异常有关。某些FGIDs存在肠神经递质表达异常,甚至神经元退行性改变;肠神经系统与肠道Cajal间质细胞、胶质细胞和免疫细胞连接和功能的异常亦可能参与了FGIDs的发病;脑-肠轴功能紊乱是应激和感染后肠易激综合征的发病机制之一。肠神经系统在FGIDs的发病中具有重要作用,以肠神经为靶点为开发治疗FGIDs的有效药物开辟了广阔的前景。     

Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes

BACKGROUND & AIMS: Gastrointestinal complications of long-standing diabetes include nausea, vomiting, abdominal pain, diarrhea, and constipation. The pathophysiology underlying these symptoms is poorly understood. Recent evidence suggests an important role for interstitial cells of Cajal in controlling gastrointestinal motility. The aim of this study was to determine changes in interstitial cells of Cajal and enteric innervation in a patient with insulin-dependent diabetes. METHODS: A full thickness jejunal biopsy was obtained from a 38-year-old insulin-dependent diabetic with evidence for diabetic gastroenteropathy. Immunohistochemistry, confocal microscopy, and 3-dimensional reconstruction techniques were used to quantify changes in the volume of interstitial cells of Cajal and enteric innervation. RESULTS: Interstitial cells of Cajal were markedly decreased throughout the entire thickness of the jejunum. A decrease in neuronal nitric oxide synthase, vasoactive intestinal peptide, PACAP, and tyrosine hydroxylase immunopositive nerve fibers was observed in circular muscle layer while substance P immunoreactivity was increased. CONCLUSIONS: The data suggest that long-standing diabetes is associated with a decrease in interstitial cells of Cajal volume and a decrease in inhibitory innervation, associated with an increase in excitatory innervation. The changes in interstitial cells of Cajal volume and enteric nerves may underlie the pathophysiology of gastrointestinal complications associated with diabetes and suggest future therapeutic targets.     

The Importance of Interstitial Cells of Cajal in the Gastrointestinal Tract

Gastrointestinal (GI) motility function and its regulation is a complex process involving collaboration and communication of multiple cell types such as enteric neurons, interstitial cells of Cajal (ICC), and smooth muscle cells. Recent advances in GI research made a better understanding of ICC function and their role in the GI tract, and studies based on different types of techniques have shown that ICC, as an integral part of the GI neuromuscular apparatus, transduce inputs from enteric motor neurons, generate intrinsic electrical rhythmicity in phasic smooth muscles, and have a mechanical sensation ability. Absence or improper function of these cells has been linked to some GI tract disorders. This paper provides a general overview of ICC; their discovery, subtypes, function, locations in the GI tract, and some disorders associated with their loss or disease, and highlights some controversial issues with regard to the importance of ICC in the GI tract.     

肠道炎症和恢复期Cajal间质细胞变化的相关机制

摘要炎症性肠病（IBD）患者常出现肠道动力紊乱，动力紊乱与肠道炎症密切相关。Cajal间质细胞（ICC）作为起搏细胞和肠道神经支配的调节者对控制胃肠道动力起关键作用。越来越多的证据显示在健康状态下或动力疾病中存在大量ICC的修复或再生。因此，明确ICC在肠道炎症中的病理生理机制，并阐明炎症恢复阶段促进ICC生长发育的因素具有重要意义。     

Enteric Nervous System in the Small Intestine: Pathophysiology and Clinical Implications

The digestive system is endowed with its own, local nervous system, referred to as the enteric nervous system (ENS). Given the varied functions of small intestine, its ENS has developed individualized characteristics relating to motility, secretion, digestion, and inflammation. The ENS regulates the major enteric processes such as immune response, detecting nutrients, motility, microvascular circulation, intestinal barrier function, and epithelial secretion of fluids, ions, and bioactive peptides. Remarkable progress has been made in understanding the signaling pathways in this complex system and how they work. In this article, we focus on recent advances that have led to new insights into small intestinal ENS function and the development of new therapies.     

慢传输型便秘发病机制的研究

慢传输型便秘(STC)的发病机制主要与肠神经系统(ENS)、Cajal间质细胞(ICC)、平滑肌、神经递质等有关。研究发现STC结肠组织中ENS出现退行性变化,肌间神经丛空泡变性,ICC数量减少,形态改变,平滑肌退行性变,多种神经递质发生改变。本文就STC发病机制的研究作一综述。     

Intestinale Innervationsstörungen: Anatomische Grundlagen und Diagnostik

Histopathological insights into intestinal innervation disorders require the knowledge of the anatomical topography and structure of the enteric nervous system (ENS). The ENS of the human colon is composed of intramural nerve meshes located in different layers of the intestinal wall (plexus musculares, plexus myentericus, plexus submucosi, plexus mucosi). A differentiated visualization of the components of the ENS is achieved-by enzyme- and immunohistochemical methods. In comparison to cross-sections, wholemount preparations of the intestinal wall allow a two dimensional demonstration of the network-character of the nerve plexus and preserve the anatomical in-situ conditions. A complete histopathological diagnosis of the ENS requires full-thickness biopsies or resected specimens, as an assessment of the entire plexus layers is achieved only by this procedure. The establishment of reference values by means of morphometrical studies of ENS contributes to an objective and standardized histopathological diagnosis. Aganglionosis, hypoganglionosis, intestinal neuronal dysplasia and heterotopias are considered to be the most acknowledged forms of intestinal innervation disorders. In addition, degenerative changes of enteric nerve plexus, visceral neuropathies and a disturbed homeostasis of enteric neurotransmitters are described. Recently, a pathogenetical significance for functional intestinal motility disorders has been attributed to interstitial cells of Cajal (ICC). The ENS and ICC play a major role in mediating and coordinating gastrointestinal motility and therefore shoud be taken into account in clinical disorders of the intestinal motor function.     

Advances in diabetic gastroparesis

This review addresses the advances in our understanding of the epidemiology and mechanisms in diabetic gastroparesis and dyspepsia. The mechanisms discussed include: blood glucose levels at the time of presentation, "autovagotomy," and the intrinsic innervation (particularly the interstitial cells of Cajal and nitrergic nerves). In animal models of diabetic gastroparesis, there is evidence that homeostatic mechanisms are activated in the enteric nervous system to compensate for the loss of extrinsic innervation. Understanding these advances is key to the development of novel therapeutic strategies and for making rational choices in the management of diabetic gastroparesis and dyspepsia.     

Deficiency of interstitial cells of Cajal in the small intestine of patients with Crohn''s disease

OBJECTIVE: Interstitial cells of Cajal are critical for the generation of electrical slow waves that regulate the phasic contractile activity of the tunica muscularis of the GI tract. Under certain pathophysiological conditions loss of interstitial cells of Cajal may play a role in the generation of certain motility disorders. The aim of the present study was to determine if there is an abnormality in the density or distribution of interstitial cells of Cajal from patients with Crohn's disease. METHODS: Small intestines from control subjects and patients with Crohn's disease were examined using immunohistochemistry and antibodies against the Kit receptor, which is expressed in interstitial cells of Cajal within the tunica muscularis of the GI tract. The density and distribution of interstitial cells of Cajal were assessed in the longitudinal and circular muscle layers and in the myenteric and deep muscular plexus regions of Crohn's and control tissues. RESULTS: Tissues from Crohn's disease patients showed an almost complete abolition of interstitial cells of Cajal within the longitudinal and circular muscle layers and a significant reduction in numbers at the level of the myenteric and deep muscular plexuses. CONCLUSIONS: In tissues from Crohn's disease patients, the density of interstitial cells of Cajal was reduced throughout the tunica muscularis in comparison to control small intestines. The disturbance of intestinal motility that occurs in patients with Crohn's disease may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis.     

生长抑素对Oddi括约肌功能的影响

天然生长抑素(somatostatin,SST)是一种胃肠激素及神经肽,主要分布于神经和消化系统中,具有广泛的生物学效应. 消化系SST大多由胰腺和胃肠黏膜中的D细胞分泌,能抑制胃肠运动及多种激素分泌. SST调节作用由G蛋白偶联受体,即生长抑素受体(somatostatin receptor,SSTR)介导. Oddi括约肌(sphincter of Oddi,SO)位于十二指肠乳头周围,是一结构和功能相对独立的器官,其运动主要受神经、激素、Cajal间质细胞的调节. SST对SO的作用尚存在争议,本文就生长抑素对SO功能的影响进行综述.     

Stem Cell Therapy for GI Neuromuscular Disorders

The enteric nervous system is the intrinsic innervation of the gut. Several neuromuscular disorders affect the neurons and glia of the enteric nervous system adversely, resulting in disruptions in gastrointestinal motility and function. Pharmacological interventions to remedy gastrointestinal function do not address the underlying cause of dysmotility arising from lost, absent, or damaged enteric neuroglial circuitry. Cell-based therapies have gained traction in the past decade, following the discovery of several adult stem cell niches in the human body. Adult neural stem cells can be isolated from the postnatal and adult intestine using minimally invasive biopsies. These stem cells retain the ability to differentiate into several functional classes of enteric neurons and enteric glia. Upon identification of these cells, several groups have also established that transplantation of these cells into aganglionic or dysganglionic intestine rescues gastrointestinal motility and function. This chapter highlights key studies performed in the field of stem cell transplantation therapies that are targeted towards the remedy of gastrointestinal motility and function.     

针刺对功能性便秘ENS-ICC调节机制的研究进展

功能性便秘(functional constipation,FC)是临床常见病和多发病,其病因和发病机制尚不十分清楚,存在多种学说.实验研究表明,"泻药性结肠"动物模型结肠表现为肠神经系统神经丛超微结构、多种受体与ICC表达的异常.我们通过检索和分析近年来针刺治疗FC的实验研究文献,发现目前针刺对FC的调节机制的研究偏于单一化,多种机制之间的调控关系没有进行深入研究.今后的研究应侧重针刺对各机制之间相互关系的阐释以及对其关键机制的探讨,使针刺作用机制的研究进一步深入,从而更好地服务于临床.     

实验性脂肪肝大鼠肠道Cajal间质细胞的研究

背景：随着社会经济的飞速发展，脂肪肝的发病率呈逐年增高的趋势。目前关于脂肪肝对胃肠动力影响的研究仍较少，尤其是对并发症的影响因素及其相关机制。目的：观察实验性脂肪肝大鼠空肠Cajal间质细胞数量的变化，探讨其与胃肠动力的相关性。方法：35只Sprague—Dawley（SD）大鼠分为脂肪肝模型组和对照组，其中脂肪肝模型组25只，对照组10只。以高脂饲料喂养大鼠制备脂肪肝模型。造模12周后，以蓝色葡聚糖-2000灌胃，通过检测大鼠小肠推进率评估肠道动力。免疫组化染色检测空肠c—kit阳性Cajal间质细胞的变化。结果：脂肪肝模型制备成功。与对照组相比。脂肪肝模型组肠道动力显著减弱（P〈0．05）。空肠c—kit阳性Cajal间质细胞显著减少（P〈0．05）。结论：脂肪肝大鼠肠道动力减弱可能与空肠CaM间质细胞减少有关。     

Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system

The relationship between the development of the enteric nervous system and interstitial cells of Cajal (ICC) in the human small intestine was investigated in a full-term infant who presented with intestinal pseudo-obstruction. Immunohistochemistry revealed absence of enteric nerves and ganglia but abundant c-Kit immunoreactivity associated with Auerbach's plexus (ICC-AP). However, c-Kit immunoreactivity associated with the deep muscular plexus (ICC-DMP) and intermuscular ICC was absent. Electron microscopy showed ICC-AP with a normal ultrastructure; ICC-DMP were seen but were severely injured, suggesting degeneration. In vitro recording of intestinal muscle showed slow wave activity as well as response to cholinergic stimulation. Fluoroscopic examination of the small bowel showed a variety of motor patterns, including rhythmic, propagating contractions. In conclusion, total absence of enteric nerves was associated with absence of normal ICC-DMP. However, a normal musculature, including a network of ICC-AP, allowed for generation of rhythmic, propagating contractile activity, suggesting the presence of functional motor activity.     

A New Paradigm Shift in Gastroparesis Management

Gastroparesis, once regarded as a rare disease, is difficult to diagnose and challenging to treat; there were many breakthrough advances in the 2010s, shifting the paradigm of the understanding of this complex entity and its management. Similar to diabetes, its increasing prevalence reflects increased accessibility to diagnostic modalities and suggests that gastroparesis was underacknowledged in the past. Major developments in the three main aspects of the disease include the discovery of smooth muscle cells, interstitial cells of Cajal, PDGFRα⁺ cells syncytium, rather than interstitial cells of Cajal alone, as the main gastric pacemaker unit; the development of validated point-of-care diagnostic modalities such as a wireless motility capsule, the carbon 13-labeled breath test, and impedance planimetry; and the introduction of novel minimally invasive therapeutic options such as newer pharmacologic agents and gastric peroral endoscopic pyloromyotomy. All aspects of these advances will be discussed further in this review.     

Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out

In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors’ work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.