Oligoneuronal Hypoganglionosis in Patients with Idiopathic Slow-Transit Constipation

PURPOSE: Several alterations of the enteric nervous system have been described as an underlying neuropathologic correlate in patients with idiopathic slow-transit constipation. To obtain comprehensive data on the structural components of the intramural nerve plexus, the colonic enteric nervous system was investigated in patients with slow-transit constipation and compared with controls by means of a quantitative morphometric analysis. METHODS: Resected specimens were obtained from ten patients with slow-transit constipation and ten controls (nonobstructive neoplasias) and processed for immunohistochemistry with the neuronal marker Protein Gene Product 9.5. The morphometric analysis was performed separately for the myenteric plexus and submucous plexus compartments and included the quantification of ganglia, neurons, glial cells, and nerve fibers. RESULTS: In patients with slow-transit constipation, the total ganglionic area and neuronal number per intestinal length as well as the mean neuron count per ganglion were significantly decreased within the myenteric plexus and external submucous plexus. The ratio of glial cells to neurons was significantly increased in myenteric ganglia but not in submucous ganglia. On statistical analysis, the histopathologic criteria (submucous giant ganglia and hypertrophic nerve fibers) of intestinal neuronal dysplasia previously described in patients with slow-transit constipation were not completely fulfilled. CONCLUSION: The colonic motor dysfunction in slow-transit constipation is associated with quantitative alterations of the enteric nervous system. The underlying defect is characterized morphologically by oligoneuronal hypoganglionosis. Because the neuropathologic alterations primarily affect the myenteric plexus and external submucous plexus, superficial submucous biopsies are not suitable to detect these innervational disorders.     

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.     

Irritable bowel syndrome and chronic constipation: Emerging drugs, devices, and surgical treatments

Irritable bowel syndrome (IBS) and chronic constipation (CC) are two of the most common functional disorders of the gut. CC and IBS are estimated to affect up to 20% and 27% of the North American population respectively. Although not life-threatening, CC and IBS can profoundly and negatively affect quality of life and are associated with a significant economic burden related to direct and indirect annual health-care costs. Possible etiologies for IBS and CC include alterations in visceral sensation and gastrointestinal motility. IBS may be caused by disturbances in brain-gut interactions affecting gastrointestinal motility and visceral sensitivity. Research efforts in CC have begun to identify abnormalities in myenteric neurons, alterations in neurotransmitters and their receptors, and incoordination of the muscles of the pelvic floor or anorectum. Both disorders may be influenced by genetic predisposition, environmental factors, and stress. In this article, the safety and efficacy of traditional and emerging therapies for CC and IBS are examined. In addition, their pathophysiology and symptoms are briefly reviewed.     

Toxoplasma gondii causes death and plastic alteration in the jejunal myenteric plexus

AIM:To assess the effects of ME-49 Toxoplasma gondii(T.gondii) strain infection on the myenteric plexus and external muscle of the jejunum in rats.METHODS:Thirty rats were distributed into two groups:the control group(CG)(n = 15) received 1 m L of saline solution orally, and the infected group(IG)(n=15)inoculated with 1 m L of saline solution containing500 oocysts of M-49 T.gondii strain orally.After 36 d of infection,the rats were euthanized.Infection with T.gondii was confirmed by blood samples collected from all rats at the beginning and end of the experiment.The jejunum of five animals was removed and submitted to routine histological processing(paraffin)for analysis of external muscle thickness.The remaining jejunum from the others animals was used to analyze the general population and the NADH-diaphorase,VIPergic and nitrergic subpopulations of myenteric neurons;and the enteric glial cells(S100-IR).RESULTS:Serological analysis showed that animals from the IG were infected with the parasite.Hypertrophy affecting jejunal muscle thickness was observed in the IG rats(77.02±42.71)in relation to the CG(51.40±12.34),P0.05.In addition,31.2%of the total number of myenteric neurons died(CG:39839.3±5362.3;IG:26766.6±2177.6;P0.05);hyperplasia of nitrergic myenteric neurons was observed(CG:7959.0±1290.4;IG:10893.0±1156.3;P0.05);general hypertrophy of the cell body in the remaining myenteric neurons was noted[CG:232.5(187.2-286.0);IG:248.2(204.4-293.0);P0.05];hypertrophy of the smallest varicosities containing VIP neurotransmitter was seen(CG:0.46±0.10;IG:0.80±0.16;P0.05)and a reduction of 25.3%in enteric glia cells(CG:12.64±1.27;IG:10.09±2.10;P0.05)was observed in the infected rats.CONCLUSION:It was concluded that infection with oocysts of ME-49 T.gondii strain caused quantitative and plastic alterations in the myenteric plexus of the jejunum in rats.     

Scintigraphic measurement of ileocaecal transit in irritable bowel syndrome and chronic idiopathic constipation.

This study investigated the hypothesis that some features of functional gastrointestinal disorders may be associated with abnormalities of ileocaecal transit by measuring ileocaecal transit using a scintigraphic technique in 43 patients with chronic constipation, 20 patients with irritable bowel syndrome (IBS), and 18 control subjects. Subjects ingested enteric coated capsules, which delivered 111-indium radionuclide to the distal ileum. Gammacamera images were acquired at hourly intervals until caecal filling was complete. Ileocaecal transit was defined as the time between peak scintigraphic activity in the terminal ileum and peak activity in the caecum. The mean (SD) ileocaecal transit of 103 (50) minutes in patients with IBS was significantly faster than that in control subjects (mean (SD) ileocaecal transit 174 (78) minutes, p < 0.002). There were no significant differences in ileocaecal transit between patients with chronic idiopathic constipation and the control subjects, or between patients with constipation predominant and diarrhoea predominant IBS. This study developed a practical scintigraphic method of measuring ileocaecal transit. The rapid ileocaecal transit in both the constipation and diarrhoea predominant forms of IBS suggests that bloating may not after all result from delayed ileal emptying.     

Stopping or reducing dietary fiber intake reduces constipation and its associated symptoms

AIM: To investigate the effect of reducing dietary fiber on patients with idiopathic constipation.METHODS: Sixty-three cases of idiopathic constipation presenting between May 2008 and May 2010 were enrolled into the study after colonoscopy excluded an organic cause of the constipation. Patients with previous colon surgery or a medical cause of their constipation were excluded. All patients were given an explanation on the role of fiber in the gastrointestinal tract. They were then asked to go on a no fiber diet for 2 wk. Thereafter, they were asked to reduce the amount of dietary fiber intake to a level that they found acceptable. Dietary fiber intake, symptoms of constipation, difficulty in evacuation of stools, anal bleeding, abdominal bloating or abdominal pain were recorded at 1 and 6 mo.RESULTS: The median age of the patients (16 male, 47 female) was 47 years (range, 20-80 years). At 6 mo, 41 patients remained on a no fiber diet, 16 on a reduced fiber diet, and 6 resumed their high fiber diet for religious or personal reasons. Patients who stopped or reduced dietary fiber had significant improvement in their symptoms while those who continued on a high fiber diet had no change. Of those who stopped fiber completely, the bowel frequency increased from one motion in 3.75 d (± 1.59 d) to one motion in 1.0 d (± 0.0 d) (P < 0.001); those with reduced fiber intake had increased bowel frequency from a mean of one motion per 4.19 d (± 2.09 d) to one motion per 1.9 d (± 1.21 d) on a reduced fiber diet (P < 0.001); those who remained on a high fiber diet continued to have a mean of one motion per 6.83 d (± 1.03 d) before and after consultation. For no fiber, reduced fiber and high fiber groups, respectively, symptoms of bloating were present in 0%, 31.3% and 100% (P < 0.001) and straining to pass stools occurred in 0%, 43.8% and 100% (P < 0.001).CONCLUSION: Idiopathic constipation and its associated symptoms can be effectively reduced by stopping or even lowering the intake of dietary fiber.     

Intestinal epithelial barrier and neuromuscular compartment in health and disease

A number of digestive and extra-digestive disorders, including inflammatory bowel diseases, irritable bowel syndrome, intestinal infections, metabolic syndrome and neuropsychiatric disorders, share a set of clinical features at gastrointestinal level, such as infrequent bowel movements, abdominal distension, constipation and secretory dysfunctions. Several lines of evidence indicate that morphological and molecular changes in intestinal epithelial barrier and enteric neuromuscular compartment contribute to alterations of both bowel motor and secretory functions in digestive and extra-digestive diseases. The present review has been conceived to provide a comprehensive and critical overview of the available knowledge on the morphological and molecular changes occurring in intestinal epithelial barrier and enteric neuromuscular compartment in both digestive and extra-digestive diseases. In addition, our intent was to highlight whether these morphological and molecular alterations could represent a common path(or share some common features) driving the pathophysiology of bowel motor dysfunctions and related symptoms associated with digestive and extra-digestive disorders. This assessment might help to identify novel targets of potential usefulness to develop original pharmacological approaches for the therapeutic management of such disturbances.     

Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding: A systematic review

BACKGROUNDAnemia is considered a public health issue and is often caused by iron deficiency. Iron-deficiency anemia (IDA) often originates from blood loss from lesions in the gastrointestinal tract in men and postmenopausal women, and its prevalence among patients with gastrointestinal bleeding has been estimated to be 61%. However, few guidelines regarding the appropriate investigation of patients with IDA due to gastrointestinal bleeding have been published.AIMTo review current evidence and guidelines concerning IDA management in gastrointestinal bleeding patients to develop recommendations for its diagnosis and therapy.METHODSFive gastroenterology experts formed the Digestive Bleeding and Anemia Workgroup and conducted a systematic literature search in PubMed and professional association websites. MEDLINE (via PubMed) searches combined medical subject headings (MeSH) terms and the keywords “gastrointestinal bleeding” with “iron-deficiency anemia” and “diagnosis” or “treatment” or “management” or “prognosis” or “prevalence” or “safety” or “iron” or “transfusion” or “quality of life”, or other terms to identify relevant articles reporting the management of IDA in patients over the age of 18 years with gastrointestinal bleeding; retrieved studies were published in English between January 2003 and April 2019. Worldwide professional association websites were searched for clinical practice guidelines. Reference lists from guidelines were reviewed to identify additional relevant articles. The recommendations were developed by consensus during two meetings and were supported by the published literature identified during the systematic search.RESULTSFrom 494 Literature citations found during the initial literature search, 17 original articles, one meta-analysis, and 13 clinical practice guidelines were analyzed. Based on the published evidence and clinical experience, the workgroup developed the following ten recommendations for the management of IDA in patients with gastrointestinal bleeding: (1) Evaluation of hemoglobin and iron status; (2) Laboratory testing; (3) Target treatment population identification; (4) Indications for erythrocyte transfusion; (5) Treatment targets for erythrocyte transfusion; (6) Indications for intravenous iron; (7) Dosages; (8) Monitoring; (9) Indications for intravenous ferric carboxymaltose treatment; and (10) Treatment targets and monitoring of patients. The workgroup also proposed a summary algorithm for the diagnosis and treatment of IDA in patients with acute or chronic gastrointestinal bleeding, which should be implemented during the hospital stay and follow-up visits after patient discharge.CONCLUSIONThese recommendations may serve as a starting point for clinicians to better diagnose and treat IDA in patients with gastrointestinal bleeding, which ultimately may improve health outcomes in these patients.     

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.     

Dermatoglyphic (fingerprint) evidence for a congenital syndrome of early onset constipation and abdominal pain

Chronic idiopathic constipation and abdominal pain are the most common gastrointestinal symptoms but their cause is rarely determined; therefore, they usually are called functional. To determine if congenital factors play a role in these disorders, we examined dermatoglyphic (fingerprint) patterns, a congenital marker, in 155 consecutive patients with gastrointestinal complaints. Sixty-four percent of patients with constipation and abdominal pain before age 10 yr had one or more digital arches, compared with 10% of patients without constipation and abdominal pain (p less than 0.001). Seventy percent of constipated patients with arches had the onset of symptoms before age 10 yr compared with 23% of constipated patients without arches (p less than 0.001) and 14% of patients with symptoms other than constipation (p less than 0.001). Compared with an age- and sex-matched sample of patients without arches, patients with arches had a higher prevalence of constipation and abdominal pain before age 10 (p = 0.003), were more likely (p less than 0.001) to have chronic intestinal pseudoobstruction (an organic disorder), and were less likely (p = 0.013) to have irritable bowel syndrome (a functional disorder). Identification of a congenital marker, digital arches, associated with early onset constipation and abdominal pain may help to differentiate a congenital organic syndrome from functional disorders such as the irritable bowel syndrome.     

Nitric oxide synthase and VIP distribution in enteric nervous system in idiopathic chronic constipation

Idiopathic chronic constipation has been correlated to neural abnormalities that consist of a reduced number of myenteric plexus neurons and a decreased concentration of VIP-positive nerve fibers within the circular muscle. Recent studies hypothesized the involvement of nitric oxide in motility disorders of the human gut. To date, no information is available on nitric oxide involvement in idiopathic chronic constipation. The density of VIP- and nitric oxide-producing neurons was evaluated by immunocytochemistry using anti-VIP and anti-nitric oxide synthase antibodies in five patients with idiopathic chronic constipation. A low total neuron density was found at the myenteric plexus. The density of VIP-positive neurons was low while that of nitric oxide synthase-positive neurons was high at both plexuses. Our data confirm that idiopathic slow-transit chronic constipation is due to abnormal neurogenic factors. The presence of numerous nitric oxide synthase-positive neurons, all along the colon and at both plexuses, supports the hypothesis that an excessive production of nitric oxide may cause the persistent inhibition of contractions.Supported by MURST University Funds.     

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。     

Irritable bowel syndrome: Relations with functional,mental, and somatoform disorders

This review describes the conceptual and clinical relations between irritable bowel syndrome (IBS), other functional, somatoform, and mental disorders, and points to appropriate future conceptualizations. IBS is considered to be a functional somatic syndrome (FSS) with a considerable symptom overlap with other FSSs like chronic fatigue syndrome or fibromyalgia syndrome. IBS patients show an increased prevalence of psychiatric symptoms and disorders, especially depression and anxiety. IBS is largely congruent with the concepts of somatoform and somatic symptom disorders. Roughly 50% of IBS patients complain of gastrointestinal symptoms only and have no psychiatric comorbidity. IBS concepts, treatment approaches, as well as health care structures should acknowledge its variability and multidimensionality by: (1) awareness of additional extraintestinal and psychobehavioral symptoms in patients with IBS; (2) general and collaborative care rather than specialist and separated care; and (3) implementation of “interface disorders” to abandon the dualistic classification of purely organic or purely mental disorders.     

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Besides the enormous medical and economic consequences, national disasters, such as the Wenchuan 8.0 earthquake, also pose a risk to the mental health of survivors. In this context, a better understanding is needed of how functional brain systems adapt to severe emotional stress. Previous animal studies have demonstrated the importance of limbic, paralimbic, striatal, and prefrontal structures in stress and fear responses. Human studies, which have focused primarily on patients with clinically established posttraumatic stress disorders, have reported abnormalities in similar brain structures. At present, little is known about potential alterations of brain function in trauma survivors shortly after traumatic events. Here, we show alteration of brain function in a cohort of healthy survivors within 25 days after the Wenchuan earthquake by a recently discovered method known as “resting-state” functional MRI. The current investigation demonstrates that regional activity in frontolimbic and striatal areas increased significantly and connectivity among limbic and striatal networks was attenuated in our participants who had recently experienced severe emotional trauma. Trauma victims also had a reduced temporal synchronization within the “default mode” of resting-state brain function, which has been characterized in humans and other species. Taken together, our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in posttraumatic stress disorders, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors.     

消化道Cajal间质细胞介导肠神经传递的研究进展

消化道Cajal间质细胞(ICC)与胃肠运动功能关系密切。ICC根据形态和功能主要分成三种类型。ICC超微结构与肠神经联系紧密,形态学和功能学研究证实ICC介导肠神经的胃肠道作用。     

Natural history and long-term clinical course of Crohn’s disease

Crohn’s disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract.Occasionally,so-called metastatic disease occurs in extra-intestinal sites.Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues.Genetic,epigenetic and environmental factors appear to play a role.Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance.The disorder occurs over a broad age spectrum,from early childhood to late adulthood.More than 80%are diagnosed before age 40 years usually with terminal ileal and colonic involvement.Pediatric-onset disease is more severe and more extensive,usually with a higher chance of upper gastrointestinal tract disease,compared to adult-onset disease.Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications(i.e.,fistula,abscess).Although prolonged remission may occur,discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process.Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis.Until now,treatment has focused on removing risk factors,particularly cigarette smoking,and improving symptoms.In clinical trials,clinical remission is largely defined as improved numerical and endoscopic indices for"mucosal healing"."Deep remission"is a conceptual,more"extended"goal that may or may not alter the long-term natural history of the disease in selected patients,albeit at a significant risk for treatment complications,including serious and unusual opportunistic infections.     

Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patient's symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.     

Autonome Neuropathie und mehr

In patients with diabetes almost all relevant regulatory systems and effector organs which are of importance for physiological functioning of gastrointestinal motility, secretion and sensitivity may be altered. Possible disturbances with negative effects on the gastrointestinal tract include autonomic neuropathy, enteric neuropathy with alterations of the myenteric and submucosal plexus, loss of interstitial cells of Cajal (ICC), altered secretion of insulin and other regulatory peptide hormones and diabetic myopathy of smooth muscles of the gastrointestinal canal. Moreover, almost all gastrointestinal functions are also impaired by hyperglycemia. In individual patients with gastrointestinal functional disturbances and corresponding complaints it is usually impossible to clarify the exact role of these mechanisms for the pathogenesis of symptoms; however, there is preliminary evidence that improved understanding may lead to new therapeutic options.     

Respiratory disorders during sleep in chronic obstructive pulmonary disease

Patients with COPD may show slow, progressive deteriorations in arterial blood gases during the night, particularly during rapid eye movement (REM) sleep. This is mainly due to hypoventilation, while a deterioration of ventilation/perfusion mismatch plays a minor role. The severity of gas exchanges alterations is proportional to the degree of impairment of diurnal pulmonary function tests, particularly of partial pressure of oxygen (PaO₂) and of carbon dioxide (PaCO₂) in arterial blood, but correlations between diurnal and nocturnal blood gas levels are rather loose. Subjects with diurnal PaO₂ of 60–70 mmHg are distinguished in “desaturators” and “nondesaturators” according to nocturnal oxyhemoglobin saturation behavior. The role of nocturnal hypoxemia as a determinant of alterations in sleep structure observed in COPD is dubious. Effects of the “desaturator” condition on pulmonary hemodynamics, evolution of diurnal blood gases, and life expectancy are also controversial. Conversely, it is generally accepted that occurrence of sleep apneas in COPD is associated with a worse evolution of the disease. Nocturnal polysomnographic monitoring in COPD is usually performed when coexistence of sleep apnea (“overlap syndrome”) is suspected, while in most other cases nocturnal oximetry may be enough. Nocturnal oxygen attenuates sleep desaturations among stable patients, without increases in PaCO₂ of clinical concern. Nocturnal treatment with positive pressure ventilators may give benefit to some stable hypercapnic subjects and patients with the overlap syndrome.     

The maturing architecture of the brain's default network

In recent years, the brain''s “default network,” a set of regions characterized by decreased neural activity during goal-oriented tasks, has generated a significant amount of interest, as well as controversy. Much of the discussion has focused on the relationship of these regions to a “default mode” of brain function. In early studies, investigators suggested that, the brain''s default mode supports “self-referential” or “introspective” mental activity. Subsequently, regions of the default network have been more specifically related to the “internal narrative,” the “autobiographical self,” “stimulus independent thought,” “mentalizing,” and most recently “self-projection.” However, the extant literature on the function of the default network is limited to adults, i.e., after the system has reached maturity. We hypothesized that further insight into the network''s functioning could be achieved by characterizing its development. In the current study, we used resting-state functional connectivity MRI (rs-fcMRI) to characterize the development of the brain''s default network. We found that the default regions are only sparsely functionally connected at early school age (7–9 years old); over development, these regions integrate into a cohesive, interconnected network.