Assessing the interstitial cells of Cajal, cells of enteric nervous system and neurotransmitters in slow transit constipation, using immunohistochemistry for CD117, PGP9.5 and serotonin.
Geramizadeh Bita,Hayati Kamran,Rahsaz Marjan,Hosseini Seyed-Vahid
Hepato-gastroenterology
BACKGROUND/AIMS:Slow transit constipation is one of the common causes of chronic constipation, in which the intestinal diameter is normal, but its transit time is markedly increased. The underlying cause in this disease is not definitely understood. METHODOLOGY:In this study was investigated the difference in the quantity of pace maker cells, cells of enteric nervous system and serotonin positive cells in normal colon and colon of the patients with slow transit constipation by using immunohistochemistry for c-Kit, PGP 9.5 and serotonin. RESULTS:The number of c-Kit positive pacemaker cells in the muscular layer was significantly decreased in the patients with slow transit constipation. PGP 9.5 positive enteric nervous system cells were significantly decreased in the patients with slow transit constipation in inner circular layer. Number of serotonin positive cells in the patients with slow transit constipation was significantly increased. CONCLUSIONS:Slow transit constipation is most probably a true enteric neuropathy.
[Promotion of basic research in efficacy enhancement of chronic constipation].
Wang Li,Tong Weidong
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery
The incidence of chronic constipation increases year by year, but it is underestimated in affecting the health of patients. Clinical diagnosis and treatment of chronic intractable constipation is difficult, owing to the diversity of clinical manifestations and the unclear pathogenesis. The basic research is expected to identify the pathophysiological mechanism of chronic intractable constipation in the future, which can find out a ultimate solution approach and improve clinical efficacy. At present there are several basic research ways attracting our attention, including enteric nervous system (such as nerve cells, intestinal neurotransmitters, intestinal sensory nerve regulation mechanism), intestinal smooth muscle cells, Cajal interstitial cells and sacral neuromodulation and intestinal microecology. Although current basic researches are still very preliminary, but they have laid foundations of clinical drug development and application of new technology.
[Disorders of intestinal innervation as a possible cause for chronic constipation].
Wedel T,Roblick U,Gleiss J,Ott V,Eggers R,Kühnel W,Krammer H J
Zentralblatt fur Chirurgie
The gastrointestinal tract contains the largest amount of nerve cells apart from the central nervous system constituting together with glial cells the enteric nervous system (ENS). The morphology of the ENS is characterized by intramurally located ganglionated and non-ganglionated plexus of different structure. The diversity of neurotransmitters synthesized by the different nerve cell types as well as the complex neuronal circuits establish the basis for the mediation of a coordinated intestinal motility. Subsequently abnormalities of the ENS may cause severe constipation. The most acknowledged intestinal innervation disorder represents aganglionosis (Hirschsprung's disease) characterized by the absence of intramural nerve cells and the hypertrophy of nerve fiber bundles within the affected intestinal segment. Non-aganglionic intestinal innervation disorders include intestinal neuronal dysplasia (IND), hypoganglionosis and heterotopic ganglia. The pathogenesis of intestinal neuronal malformations is mainly attributed to development disorders of the ENS, in part caused by genetic defects. Furthermore, the ENS can sustain damage during the postnatal period by ischemic, inflammatory, autoimmunological processes or neurotoxic agents. The histopathological diagnosis of intestinal innervation disorders is achieved by enzyme- and immunohistochemical methods. The examination of the ENS can be carried out on mucosal, deep submucosal or full-thickness biopsies using serial transverse sections as well as on intestinal whole-mount preparations allowing a three-dimensional demonstration and assessment of the intramural plexus. Structural abnormalities of the myenteric and submucosal plexus and an abnormal content of neurotransmitters have been considered to be responsible for primary chronic constipation. However, until now no unified pathophysiological concept has been established due to the partly contradictory findings. Therefore, an important goal in patients with chronic constipation should be a detailed quantitative and qualitative assessment of the underlying neurohistopathology. The correlation of these data with functional parameters of intestinal motility may represent an useful tool for the differential diagnostic and therapeutic considerations.
The brain of the gut.
El Munshid H A
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association
One year before the close of the 19th century it was recognized that intestinal peristalsis was controlled by nerve plexuses in the wall of the gut independent of the central nervous system (CNS). This concept was developed further during the first quarter of the 20th century but was almost forgotten during the next 50 years until it was revived by the early 1970s. It is now recognized that the myenteric and submucous plexuses, referred to as the enteric nervous system (ENS), contain as many neurons as in the spinal cord. In addition to autonomy from the CNS, the ENS employs not only noradrenaline and acetylcholine but also serotonin (5-HT), ATP, peptides and nitric oxide as neurotransmitters, and controls gut movements, exocrine and endocrine secretions and the microcirculation, thus qualifying for being considered the brain of the gut. Reflexes involving the ENS may be entirely intrinsic such as that controlling peristalsis, between parts of the gut through prevertebral ganglia e.g. the enterogastric reflex, or between the gut and the CNS as examplified by the vago-vagal reflexes. Absent, defective or dysfunctional enteric neurons may result in achalasia, infantile hypertrophic pyloric stenosis, paralytic ileus, intestinal pseudo-obstruction, Hirschsprung's disease or idiopathic chronic constipation. Further, the ENS may be involved in the pathogenesis of secretory diarrhoea and inflammatory bowel disease. More research on the gut brain will deepen our understanding of the physiology and pathophysiology of the gastrointestinal tract.
[The enteric nervous system and interstitial cells of Cajal. Changes in chronic constipation in adults].
Wedel T,Böttner M,Krammer H J
Der Pathologe
Intestinal innervation disorders are part of the broad etiological spectrum of chronic constipation and need to be specifically addressed in differential diagnosis. The enteric nervous system constitutes the largest peripheral nervous system of its own ("brain in the gut"), and is involved in the mediation of intestinal motility. Morphologically different nerve cell types aggregate into intramural plexus layers and release a multitude of neurotransmitters. Malformations or lesions of the enteric nervous system may lead to a severely prolonged intestinal transit time resulting in chronic constipation resistant to conservative treatment. In contrast to the early manifestation of aganglionosis, non-aganglionic or acquired alterations to the intramural nerve plexus often remain unrecognised up to adulthood. Histopathological diagnosis is carried out by enzyme or immunohistochemical staining, either on sections or whole mount preparations, allowing an optimal visualization of the nerve plexus architecture. To diagnose hypoganglionosis, enteric ganglionitis or alterations in interstitial cells of Cajal, full-thickness biopsies are required. Interstitial cells of Cajal contribute significantly to the mediation of intestinal motility by generating "slow wave" activity. In adult patients with slow-transit constipation and megacolon, the intramuscular networks of the interstitial cells of Cajal show a significantly reduced density.
10.1007/s00292-007-0900-3
Muscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation.
Pustovit Ruslan V,Itomi Yasuo,Ringuet Mitchell,Diwakarla Shanti,Chai Xin-Yi,McQuade Rachel M,Tsukimi Yasuhiro,Furness John B
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
BACKGROUND:Because M1 muscarinic receptors are expressed by enteric neurons, we investigated whether positive allosteric modulators of these receptors (M1PAMs) would enhance colorectal propulsion and defecation in dogs, mice, and rats. METHODS:The potencies of the M1PAMs, T662 or T523, were investigated using M1 receptor-expressing CHO cells. Effectiveness of M1PAMs on defecation was investigated by oral administration in mice and rats, by recording propulsive contractions in anaesthetized rats and by recording high amplitude propagating contractions in dogs. KEY RESULTS:PAM EC50 values in M1 receptor-expressing CHO cells were 0.7-1.8 nmol/L for T662 and 8-10 nmol/L for T523. The compounds had 1000-fold lower potencies as agonists. In anesthetized rats, both compounds elicited propulsive colorectal contractions, and in dogs, mice, and rats, oral administration increased fecal output. No adverse effects were observed in conscious animals. M1PAMs triggered propagated high amplitude contractions and caused defecation in dogs. Nerve-mediated contractions were enhanced in the isolated mouse colon. M1PAMs were equi-effective in rats with or without the pelvic nerves being severed. In two models of constipation in mice, opiate-induced constipation and constipation of aging, defecation was induced and constipation was reversed. CONCLUSION AND INFERENCES:M1PAMs act at targets sites in the colorectum to enhance colorectal propulsion. They are effective across species, and they reverse experimentally induced constipation. Previous studies have shown that they are safe in human. Because they provide an enhancement of physiological control rather than being direct agonists, they are predicted to provide effective treatment for constipation.
10.1111/nmo.13692
Neurological disorders and small bowel dysmotility.
Current opinion in gastroenterology
PURPOSE OF REVIEW:Small bowel dysmotility is common in the context of neurological disorders. Overlooking it can have an adverse impact on patient's quality of life and neurological outcomes. This review focuses on describing the mechanisms and effects of enteric dysmotility in neurological patients and providing treatment options. RECENT FINDINGS:Small bowel dysmotility is prevalent among neurological patients. The definition and diagnosis of small bowel dysmotility is a challenge; however, up to two-thirds of neurological patients may experience associated symptoms. Small bowel dysmotility can affect the absorption of nutrients and medication, impacts on social and professional function and can result in malnutrition and its associated morbidity and mortality. SUMMARY:Small bowel dysmotility due to a neuropathy can result from acute or chronic disorders in the central and peripheral nervous system and includes the cerebral cortex, brain stem, spinal cord, parasympathetic (vagus) and sympathetic nerves and the myenteric and submucosal plexuses of the intestine. Generalized muscle disorders can also cause an enteral myopathy. Generally, the disorders may be degenerative or inflammatory. Both enteric neuropathy and myopathy may cause symptoms of abdominal pain, nausea/vomiting, bloating, constipation or diarrhoea and can cause malnutrition. The symptoms need to be addressed in order of importance to the patient and malnutrition prevented or treated.
10.1097/MOG.0000000000000836
Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon.
Wedel Thilo,Spiegler Juliane,Soellner Stefan,Roblick Uwe J,Schiedeck Thomas H K,Bruch Hans-Peter,Krammer Heinz-Juergen
Gastroenterology
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.
10.1053/gast.2002.36600
Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome.
Gershon Michael D
Journal of clinical gastroenterology
The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.
The autonomic nervous system: A potential link to the efficacy of acupuncture.
Frontiers in neuroscience
The autonomic nervous system (ANS) is a diffuse network that regulates physiological systems to maintain body homeostasis by integrating inputs from the internal and external environment, including the sympathetic, parasympathetic, and enteric nervous systems (ENS). Recent evidence suggests that ANS is one of the key neural pathways for acupuncture signal transduction, which has attracted worldwide attention in the acupuncture field. Here, we reviewed the basic and clinical research published in PubMed over the past 20 years on the effects of acupuncture on ANS regulation and homeostasis maintenance. It was found that acupuncture effectively alleviates ANS dysfunction-associated symptoms in its indications, such as migraine, depression, insomnia, functional dyspepsia, functional constipation. Acupuncture stimulation on some specific acupoints activates sensory nerve fibers, the spinal cord, and the brain. Using information integration and efferents from a complex network of autonomic nuclei of the brain, such as the insular cortex (IC), prefrontal cortex, anterior cingulate cortex (ACC), amygdala (AMG), hypothalamus, periaqueductal gray (PAG), nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), nucleus ambiguus (AMB), acupuncture alleviates visceral dysfunction, inflammation efferent autonomic nerves, and relieves pain and pain affect. The modulating pattern of sympathetic and parasympathetic nerves is associated with acupuncture stimulation on specific acupoints, intervention parameters, and disease models, and the relationships among them require further exploration. In conclusion, ANS is one of the therapeutic targets for acupuncture and mediates acupuncture's actions, which restores homeostasis. A systemic study is needed to determine the rules and mechanisms underlying the effects of acupoint stimulation on corresponding organs mediated by specific central nervous networks and the efferent ANS.
10.3389/fnins.2022.1038945
Gastrointestinal motility disorders in neurologic disease.
The Journal of clinical investigation
The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.
10.1172/JCI143771