Gastrointestinal motility disorders in patients with diabetes mellitus

Abstract. Disturbed gastric and small intestinal motility is an often overlooked clinical problem. Delayed gastric emptying of liquid and/or solid food in patients with type 1 and type 2 diabetes (gastroparesis diabeticorum) occurs in approximately 50% of the patients. Also, the interdigestive gastric and small intestinal motility is often affected. There is only a weak correlation between symptoms and objectively measurable motor disturbances. Patients with severe upper gastrointestinal symptoms usually have disturbed motility, but most patients with impaired motility are asymptomatic. Recent studies have clearly shown that, in addition to autonomic neuropathy, acute metabolic derangements are likely to contribute to disturbed motility. Elevated glucose levels impair gastric and small intestinal motility during fasting and after food intake. Hyperinsulinemia per se has effects similar to hyperglycaemia on the stomach and small bowel, and may be a mediator of the effects of hyperglycaemia in healthy subjects. The impact of insulin on motility in diabetic patients is still unclear. Treatment of the gastric motility disorder should include a stabilization of gastric emptying. Different therapeutic modes may be useful, e.g. application of prokinetic drugs and optimizing the metabolic situation.     

Targeting the abnormalities of gastroduodenal functions in functional dyspepsia.

The current definition of functional dyspepsia changes the previous concept of absence of organic disease to the presence of a functional alteration of the upper gastrointestinal tract. From a theoretical point of view, the alteration of any major gastrointestinal function may induce dyspeptic symptoms. However, both asymptomatic subjects with some gastrointestinal functional alteration and dyspeptic patients without a demonstrable dysfunction are not unusual. This may be explained at least in part by the more recent concept of visceral sensitivity. The potential role of acid secretion in the pathogenesis of functional dyspepsia as well as the positive effect of antisecretory drugs in a proportion of patients may be based on an increased gastric acid secretion and duodenal acid overload, a hypersensitivity to acid and/or the development of acid-mediated gastrointestinal motor abnormalities. Helicobacter pylori infection may play a role in this context. Both interdigestive and postprandial gastrointestinal motility, mainly a delayed gastric emptying and an altered intragastric distribution of nutrients, have been described to be disturbed in up to half of the patients with functional dyspepsia. This may also be an explanation for the high frequency of intestinal bacterial overgrowth in these patients. Most probably, visceral hypersensitivity should be present for motor alterations to induce symptoms. This is the basis for future development of new drugs in the management of this functional syndrome. The role of H. pylori in the pathogenesis of functional dyspepsia is a matter of discussion, but a proportion of patients benefit from eradication therapy and, therefore this therapeutic approach should be taken into account.     

Expression of CDC25 Phosphatases in Human Gastric Cancer

Background Gastric cancer may be considered the final step of a progressive imbalance between mucosal cell proliferation and apoptosis. CDC25 phosphatases comprise a multigene family, including CDC25A and CDC25B, that plays a crucial role in the control of cell cycle progression and has been linked to the development of human cancers. The role of CDC25 phosphatases in the pathogenesis of gastric cancers is, however, still largely unknown. Material and methods Immunohistochemical expression of CDC25A and CDC25B was investigated in matched normal and cancerous tissues from 70 patients with gastric cancer (52 intestinal and 18 diffuse type). Results In non-cancerous gastric tissues the expression of CDC25A and CDC25B was absent or weak. In gastric cancer tissues, the enhanced immunoreactivity of CDC25 phosphatases was independent of intestinal or diffuse type of gastric cancer. However, the intensity of immunostaining was related to the grade of differentiation of the tumors. Interestingly, c-myc expression was directly correlated with CDC25A and B expression. Conclusions The overexpression of CDC25A and B seems to be a common and very early event in the development of both intestinal and diffuse types of gastric cancer and may play an important role in gastric carcinogenesis.     

Functional dyspepsia: recent pathophysiological advances

Functional dyspepsia is a clinical syndrome defined by upper abdominal symptoms, without identifiable cause by conventional diagnostic evaluation. New diagnostic tests, such as gastrointestinal manometry and gastric emptying, may help in a better characterization of these patients by demonstrating specific motor abnormalities, such as postprandial antral hypomotility and delayed gastric emptying of solids, or less frequently, intestinal dysmotility patterns indicating a visceral neuropathy. Nevertheless, a substantial proportion of dyspeptic patients have normal motility patterns. Interestingly, recent studies have shown that a gastric hypersensitivity to distension may be the cause of the postprandial symptoms in functional dyspepsia. These data indicate that functional dyspepsia may include an heterogeneous group of patients with different underlying disturbances.     

The role of the intestinal tract as a source for transmission of nosocomial pathogens

The intestinal tract provides an important source for transmission of many nosocomial pathogens, including Enterococcus species, Clostridium difficile, Candida species, Enterobacteriaceae, and other gram-negative bacilli. Recent data suggest that the intestinal tracts of hospitalized patients may also be an important reservoir of Staphylococcus aureus. Although the clinical manifestations of these pathogens are diverse, a common pathogenesis is involved in their colonization of and dissemination from the intestinal tract. Of particular importance is the role that antibiotic selective pressure plays in promotion of colonization by antibiotic-resistant pathogens. Strategies to limit the spread of these pathogens must include efforts to improve adherence to standard infection control practices and promotion of good antimicrobial stewardship. New strategies that include application of novel technologies to the problem of pathogen transmission are needed, and additional research is needed to clarify the potential utility of selective decontamination of the digestive tract.     

脑源性神经营养因子在乳鼠结肠扩张刺激诱导的慢性内脏高敏感和肠道动力异常中的作用

背景：慢性内脏高敏感和肠道动力异常是肠易激综合征（IBS）的主要病理生理特征，但两者的形成机制至今尚未明确。目的：研究乳鼠结肠扩张刺激动物模型成年后内脏感觉和肠道动力的变化以及脑源性神经营养因子（BDNF）在其中所起的作用，从而探讨BDNF在IBS发病机制中的作用。方法：建立乳鼠结肠扩张动物模型，通过检测成年大鼠对结直肠扩张的行为学反应评估内脏感觉．通过检测全胃肠和小肠传输功能评估肠道动力。比较腹腔注射BDNF抗体后内脏感觉和肠道动力的变化情况。以逆转录聚合酶链反应（RT-PCR）、蛋白质印迹法、酶联免疫吸附测定（EUSA）检测各组回肠、结肠BDNF及其受体TrkB的表达。结果：模型组成年后内脏敏感性增高，肠道动力增强。应用BDNF抗体后模型组内脏敏感性降低，肠道动力减弱。除成年期模型组结肠TrkB mRNA表达外，其余各组BDNF和TrkB mRNA表达均显著高于对照组（P〈0．05）。乳鼠期和成年期模型组回肠、结肠BDNF和TrkB蛋白表达均显著高于对照组（P〈0．05）。结论：BDNF在慢性内脏高敏感和肠道动力的变化中起一定作用，参与了IBS的发生。     

REVIEW: Small Bowel Review: Normal Physiology Part 2

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practising gastroenterologist. Selected important clinical learning points include the following: (1) numerous peptides are being identified which stimulate the proliferation and functional response of the small intestine to disease or resection, and may in time find a clinical use; (2) under usual in vivo conditions, absorption of nutrients has little effect on the paracellular movement of water; (3) the permeability of the intestine is modified by the function of the tight junctions, and measuring intestinal permeability may be useful to reflect the presence of disease; (4) the release of serotonin is influenced by cholinergic, adrenergic, and nonadrenergic, noncholinergic mechanisms, and serotonin agonists and antagonists may play an important future role in the treatment of motility disorders; (5) the use of endothelin receptor antagonists may be useful for the treatment of intestinal anaphylaxis; (6) the alterations in intestinal pH and motility in patients with Crohn's disease may influence the action of pH- or time-dependent release medications; and (7) patients with irritable bowel syndrome may also have abnormalities in gastric and small intestinal motility.     

Unraveling the ties between irritable bowel syndrome and intestinal microbiota

Irritable bowel syndrome(IBS)is the most prevalent functional gastrointestinal disorder.It is a multifactoria disorder.Intestinal microbiota may cause the pathogenesis of IBS by contributing to abnormal gastrointestina motility,low-grade inflammation,visceral hypersensitivity,communication in the gut-brain axis,and so on.Previous attempts to identify the intestinal microbiota composition in IBS patients have yielded inconsistent and occasionally contradictory results.This inconsistency may be due to the differences in the molecular techniques employed,the sample collection and handling methods,use of single samples that are not linked to fluctuating symptoms,or other factors such as patients diets and phenotypic characterizations.Despite these difficulties,previous studies found that the intestina microbiota in some IBS patients was completely different from that in healthy controls,and there does appear to be a consistent theme of Firmicutes enrichment and reduced abundance of Bacteroides.Based on the differences in intestinal microbiota composition,many studies have addressed the roles of microbiotatargeted treatments,such as antibiotics and probiotics,in alleviating certain symptoms of IBS.This review summarizes the current knowledge of the associations between intestinal microbiota and IBS as well as the possible modes of action of intestinal microbiota in the pathogenesis of IBS.Improving the current level of understanding of host-microbiota interactions in IBS is important not only for determining the role of intestinal microbiota in IBS pathogenesis but also for therapeutic modulation of the microbiota.     

Reduced interstitial cells of Cajal and increased intraepithelial lymphocytes are associated with development of small intestinal bacterial overgrowth in post-infectious IBS mouse model

Objective: Intestinal dysmotility and immune activation are likely involved in the pathogenesis of small intestinal bacteria overgrowth (SIBO) in irritable bowel syndrome (IBS). We aimed at investigating the role of interstitial cells of Cajal (ICC) and intestinal inflammation in the development of SIBO using a post-infectious IBS (PI-IBS) mouse model.

Materials and methods: NIH mice were randomly infected with Trichinella spiralis. Visceral sensitivity and stool pattern were assessed at 8-weeks post-infection (PI). Intestinal bacteria counts from jejunum and ileum were measured by quantitative real-time PCR to evaluate the presence of SIBO. ICC density, intraepithelial lymphocytes (IELs) counts, and intestinal cytokine levels (IL1-β, IL-6, toll-like receptor-4 (TLR-4), IL-10) in the ileum were examined.

Results: PI-IBS mice demonstrated increased visceral sensitivity compared with the control group. One-third of the PI-IBS mice developed SIBO (SIBO+/PI-IBS) and was more likely to have abnormal stool form compared with SIBO negative PI-IBS (SIBO?/PI-IBS) mice but without difference in visceral sensitivity. SIBO+/PI-IBS mice had decreased ICC density and increased IELs counts in the ileum compared with SIBO?/PI-IBS mice. No difference in inflammatory cytokine expression levels were detected among the groups except for increased TLR-4 in PI-IBS mice compared with the control group.

Conclusions: Development of SIBO in PI-IBS mice was associated with reduced ICC density and increased IELs counts in the ileum. Our findings support the role of intestinal dysmotility and inflammation in the pathogenesis of SIBO in IBS and may provide potential therapeutic targets.     

DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction.

BACKGROUND: Hereditary forms of chronic idiopathic intestinal pseudo-obstruction (CIIP) are well described but the aetiology of most cases of sporadic CIIP is unknown. AIM: To determines whether herpes viruses can persist in the gastrointestinal tract, thereby implicating them in the pathogenesis of CIIP. METHODS: Twenty one specimens of small and large intestine from 13 patients with CIIP (eight visceral myopathy, three visceral neuropathy, two undifferentiated), and 12 patients operated on for colorectal cancer (controls) were examined for evidence of Herpesvirus DNA (cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex virus type 1, and varicella zoster virus) by nested polymerase chain reaction (PCR) and in situ DNA hybridisation (ISH) to localise signal to the muscularis propria or myenteric plexus. RESULTS: Screening with nested PCR produced three patients with positive results. One patient with an inflammatory visceral neuropathy had EBV detected in the small intestine by PCR, and ISH demonstrated localisation to neurones in the myenteric plexus. A patient with a visceral myopathy had EBV DNA in both the small and large intestine; and one patient with a visceral neuropathy had small intestine positive for CMV DNA (both negative by ISH). No control tissue was positive for any virus. CONCLUSIONS: In individual patients there appears to be evidence linking a viral aetiology to sporadic CIIP. The role of neurotropic viruses in acute and chronic motility disturbances needs further study.     

重视黏膜低度炎症在肠易激综合征发病机制中的作用

研究发现一些肠易激综合征（IBS）患者结肠和回肠黏膜中存在低度炎症，急性肠道感染、遗传因素、食物过敏、肠道菌群改变、社会心理因素等可能触发肠道低度炎症的发生，并使之持续存在。这种低度炎症可导致胃肠运动功能紊乱．激活内脏感觉系统，可能在IBS的发病机制中起一定作用，应予重视；     

Neuromuscular disease of the gastrointestinal tract

Gastrointestinal motility is the function of gastrointestinal smooth muscle. It is controlled by both the intrinsic and extrinsic nerves of the gastrointestinal tract and, to a lesser degree, the gastrointestinal hormones. Therefore, any abnormality of the above factors, theoretically, can cause gastrointestinal dysmotility. In a clinical situation, commonly seen is gastrointestinal dysmotility caused by either smooth muscle or intrinsic and extrinsic nerves dysfunction. Diseases that cause smooth muscle dysfunction include familial visceral myopathies, nonfamilial visceral myopathies, collagen disease, muscular dystrophies, amyloidosis, thyroid disease, and so on. Diseases that cause enteric nerve dysfunction include familial visceral neuropathies, nonfamilial visceral neuropathies, diabetes mellitus, Chagas' disease, ganglioneuromatosis of the intestine, visceral neuropathy of carcinomatosis, Parkinson's disease, and so on. The patients with neuromuscular disease of the gastrointestinal tract have a wide range of clinical manifestations regardless of the underlying cause. At one end of the spectrum, the patients may be asymptomatic, and at the other end of the spectrum, the patients may have functional obstruction of the gastrointestinal tract. Plain abdominal x-rays, upper gastrointestinal (UGI) and small bowel x-rays, enteroclysis, barium enema, and manometric studies are useful for the work-up of these patients. Enteroclysis is especially helpful in ruling out mechanical obstruction of the small intestine in patients with chronic intestinal pseudo-obstruction. Treatment is mainly symptomatic and supportive. There is no effective drug to improve gastrointestinal motility. Surgery may be helpful in selected cases of severe gastrointestinal dysmotility.     

Regulation of gastrointestinal functions by the ileocecal area]

The importance of the distal small intestine and the ileocecal region for the regulation of gastrointestinal functions in humans has not been investigated in depth until recently. A regulatory role is postulated because even in healthy subjects, undigested nutrients pass across the ileocecal junction after most meals (physiologic malabsorption). Nutrient exposure of the ileocecal region causes slowing of gastric emptying and small intestinal transit, and decrease in small intestinal motor activity; under certain experimental conditions, ileal nutrients induce conversion of intestinal motility from digestive to interdigestive patterns. In addition, the secretory activity of the proximal gastrointestinal tract is inhibited by the ileocecal region. Inhibition of gastric secretion and exocrine pancreatic secretion are well established responses to ileal nutrient exposure; inhibition of bile secretion likely occurs, but is not proven. The intermediary mechanisms of these effects have not been clarified; the most likely candidates include endorphins, peptide YY (PYY), and glucagon-like-peptide-1 (GLP-1). Overall, the available data support the concept that the ileocecal region participates in the physiologic control of gastrointestinal motor and secretory functions. Whether disturbances of these regulatory mechanisms participate in the pathophysiology of gastrointestinal disease has not been investigated.     

肠道菌群失调与肠易激综合征的研究进展

肠易激综合征（IBS）的发病机制复杂,可能与内脏感觉过敏、胃肠道动力异常、肠道菌群失调、小肠细菌过度生长、肠道感染、食物不耐受、免疫异常、社会心理因素以及脑一肠轴异常等有关。研究显示,肠道菌群失调可能与IBS症状的产生和持续有关。本文就肠道菌群失调与IBS的研究进展作一综述。     

Pathogenesis and therapy for idiopathic dyspepsia

Functional dyspepsia (FD) is one of the most common gastrointestinal disorders. This review summarizes recent progress in our understanding of the pathogenesis and therapy for FD. Although distinction among FD, irritable bowel syndrome, and reflux disease is difficult in population-based studies, separate entities can be recognized in patients who seek medical attention. The pathogenesis of FD remains unclear, but recent studies have demonstrated a role for acute gastrointestinal infection in triggering FD and in genetic polymorphisms of G-proteins in predisposing to FD. The role of abnormalities in gastric motor function, visceral hypersensitivity, and psychosocial factors in the pathophysiology of dyspeptic symptoms has been the topic of multiple studies. Treatment options for FD remain limited. Recent studies have focused on acid-suppressive drugs and on novel prokinetics. Progress in our understanding of the pathogenesis and pathophysiology of FD may lead to new or improved treatment modalities. Areas of major advances are the role of infection and genetic predisposition and studies on the role of abnormalities in gastric motility and sensitivity.     

Dyspepsia and its overlap with irritable bowel syndrome

Patients with functional dyspepsia and the irritable bowel syndrome are commonly seen in both primary care and gastroenterology subspecialty settings. Although functional dyspepsia and the irritable bowel syndrome can occur separately, recent research suggests that they often appear together as an overlap syndrome and thus may represent different portions of a unifying spectrum of disease. Despite their widespread prevalence, the pathogenesis of these disorders is not well established but may include impaired gastric emptying, gastric dysrhythmias, hypersensitivity (to acid exposure and to stretch), and Helicobacter pylori infection. Once other disorders in the differential diagnosis have been excluded, treatment of patients with functional dyspepsia, irritable bowel syndrome, and the overlap syndrome without alarm signs underscores current prevailing pathophysiologies and is generally empiric and symptom based. It is hoped that management of these disorders will become more targeted and efficacious as our understanding of them improves.     

Most Gastric Cancer Occurs on the Distal Side of the Endoscopic Atrophic Border

Background: The endoscopic atrophic border indicates the extent of atrophic gastritis. The aims of this study were to examine the relation of intestinal and diffuse types of gastric cancer to the atrophic border and to study the pathologic condition of the atrophic border. Methods: In 83 patients with gastric cancer the extent of atrophic gastritis was assessed macroscopically. In 46 patients gastric biopsy specimens were also taken, to compare the histologic features of gastritis proximal and distal to the atrophic border. Results: Eighty-five per cent of gastric cancers (including 93% of intestinal type) occurred on the distal side of the atrophic border. Early diffuse gastric cancer arose closer to the atrophic border than intestinal-type cancer and was more likely to be sited proximal to it. Histologically, the grade of polymorphonuclear cell infiltration (inflammatory activity) and Helicobacter pylori density were significantly greater on the proximal side (P < 0.05), whereas the grades of glandular atrophy and intestinal metaplasia were significantly greater distally (P < 0.001). Conclusions: The atrophic border delineates the area of atrophic gastritis and intestinal metaplasia, and it is within the distal part of the stomach that gastric cancer occurs most frequently. Endoscopists should observe the distal side particularly carefully to identify early gastric cancer. The relationship of the two histologic types of cancer to areas of intestinal metaplasia and 'active' inflammation may have implications for the pathogenesis of cancer and, if so, for the potential protective effect of H. pylori eradication.     

Digestive manifestations in systemic sclerosis

Gastrointestinal involvement occurs in most patients with systemic sclerosis. Pathology is characterized by vasculopathy, resulting in tissue ischemia, progressive dysfunction and fibrosis. In its diffuse and visceral pattern, digestive manifestations may involve most of the intestinal tract and are the most frequent before renal, cardiac and pulmonary involvement. Whatever the visceral extension, about 80% of patients have digestive manifestations including gastroesophageal reflux, abnormalities of intestinal motility leading to chronic intestinal pseudo-obstruction and small bowel bacterial overgrowth and malnutrition. Long-term treatment of reflux with high-dose proton pump inhibitors appears safe and effective for symptom relief and may prevent recurrence of esophagitis and stricture. Prokinetic agents effective in pseudoobstruction include metoclopramide, domperidone, octreotide, and erythromycin.     

Intestinal pseudoobstruction caused by diffuse lymphoid infiltration of the small intestine

Four young women presented with diarrhea, malabsorption, and intestinal pseudoobstruction. Intestinal biopsy specimens (both peroral and full-thickness) showed flat small intestinal mucosa, sparsity of crypts, and a widespread lymphoid infiltrate in the lamina propria, muscularis propria, and myenteric plexus. There was no neuron or nerve fiber loss or damage in the plexus; muscle cell absence in the vicinity of lymphoid cell infiltration in the muscularis propria probably accounted for the pathogenesis of pseudoobstruction. Immunochemical stains showed that the infiltrate was polyclonal, and none of the patients has developed lymphoma on clinical follow-up of 4-16 yr. Transient improvement in symptoms occurred after antibiotic therapy in 3 patients, and 1 patient had improvement after treatment with cyclophosphamide and prednisone; however, symptoms of pseudoobstruction persist in all. These cases illustrate yet another cause of intestinal pseudoobstruction which is histologically distinct from visceral myopathies and neuropathies. The pathogenesis of this illness may be related to that of diffuse immunoproliferative diseases seen in Third World countries.     

Disturbances in small bowel motility.

Recently, the small intestine has become the focus of investigation as a potential site of dysmotility in the irritable bowel syndrome (IBS). A number of motor abnormalities have been defined in some studies, and include 'clustered' contractions, exaggerated post-prandial motor response and disturbances in intestinal transit. The significance of these findings remains unclear. The interpretation of available studies is complicated by differences in subject selection, the direct influence of certain symptoms, such as diarrhoea and constipation, and the interference of compounding factors, such as stress and psychopathology. Dysmotility could also reflect autonomic dysfunction, disturbed CNS control and the response to heightened visceral sensation or central perception. While motor abnormalities may not explain all symptoms in IBS, sensorimotor interactions may be important in symptom pathogenesis and deserve further study.