Immunomodulation of enteric neural function in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which is characterised by symptoms such as bloating, altered bowel habit and visceral pain. It’s generally accepted that miscommunication between the brain and gut underlies the changes in motility, absorpto-secretory function and pain sensitivity associated with IBS. However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. Anecdotally, IBS patients have noted that periods of stress can result in symptom flares and many patients exhibit co-morbid stress-related mood disorders such as anxiety and depression. However, in addition to psychosocial stressors, infection-related stress has also been linked with the initiation, persistence and severity of symptom flares. Indeed, prior gastrointestinal infection is one of the strongest predictors of developing IBS. Despite a lack of overt morphological inflammation, the importance of immune factors in the pathophysiology of IBS is gaining acceptance. Subtle changes in the numbers of mucosal immune cell infiltrates and elevated levels of circulating pro-inflammatory cytokines have been reproducibly demonstrated in IBS populations. Moreover, these immune mediators directly affect neural signalling. An exciting new area of research is the role of luminal microbiota in the modulation of neuro-immune signalling, resulting in local changes in gastrointestinal function and alterations in central neural functioning. Progress in this area has begun to unravel some of the complexities of neuroimmune and neuroendocrine interactions and how these molecular exchanges contribute to GI dysfunction     

肠黏膜低度炎症与肠易激综合征

肠易激综合征(IBS)是一种常见的胃肠功能性疾病,但其发病机制仍未明确,可能与胃肠道动力异常、内脏高敏感性、肠道过度产气、肠道微生态环境改变及心理精神因素等有关。近年来研究认为肠道黏膜的低度炎症与IBS的发病关系密切,这一观点可能为IBS发病机制及治疗提供新的依据。     

大鼠肠易激综合征肠黏膜下神经丛可塑性的研究

目的探讨大鼠肠黏膜下神经丛内肠神经元及兴奋性神经递质在肠易激综合征(IBS)不同亚型发病中的意义及替加色罗干预的结果。方法成年雄性SD大鼠45只,均分为IBS伴腹泻组(IBS-D)、IBS伴便秘组(IBS-C)、替加色罗干预的IBS-D组、替加色罗干预的IBS-C组和空白对照组共5组。分别采用乙酸灌肠和冰水灌胃方法制成IBS-D和IBS-C大鼠模型,替加色罗干预的两组每日加用替加色罗2 mg/kg体质量灌胃7 d。用蛋白基因产物9.5(PGP9.5)的免疫组化方法及兴奋性神经递质乙酰胆碱的组化染色法检测各组大鼠肠黏膜下神经丛内肠神经元及兴奋性神经递质的变化。结果①肠黏膜下神经丛内肠神经元数目IBS-D模型组(13.19±0.93)和IBS-C组(13.17±1.93)显著低于对照组(18.36±1.71)(P值均<0.01);替加色罗干预的IBS-D组(15.48±1.56)高于IBS-D组,替加色罗干预的IBS-C组(14.82±1.61)高于IBS-C组(P值均<0.05)。②肠黏膜下神经丛内胆碱酯酶阳性的神经元数目IBS-C组(7.56±0.39)显著低于对照组(10.43±1.39)及IBS-D组(10.03±1.13)(P值均<0.01),IBS-D组与对照组差异无统计学意义(P>0.05)。替加色罗干预的IBS-C组(9.51±1.47)显著高于IBS-C组(P<0.01),与对照组差异无统计学意义(P>0.05)。结论肠黏膜下神经丛内肠神经元数量的减少可能是实验大鼠IBS-D模型和IBS-C模型发病的共同机制;IBS-C模型组大鼠胆碱酯酶阳性的神经元数目显著减少与其症状相关。     

肠易激综合征与炎症关系的研究现状

长期以来,肠易激综合征(IBS)被认为是一种慢性功能性肠道疾病.此文回顾性分析了感染后肠易激综合征(PI-IBS)中,起促炎作用的细胞因子(CK)和起抑炎作用的CK的变化,提出这两种CK的失衡促进了IBS的出现.     

The pathophysiology of irritable bowel syndrome: inflammation and motor disorder]

Irritable bowel syndrome (IBS) is one of the most common disorders and a heterogeneous condition in view of symptoms and underlying mechanisms. Though underlying causes of pathophysiologic changes remain unclear, low grade mucosal inflammation and abnormal intestinal motility are accepted mechanisms which alter gut function and generate symptoms of IBS. First, before 1980s, abnormal colonic and rectal motor functions were regarded as the main pathophysiology of IBS, but only 25-75% of IBS patients have apparent motor abnormalities which differ from the motor functions in normal controls. So, various gastrointestinal motility tests were not indicated for the diagnosis of IBS. The high-amplitude propagating contractions of colon in IBS patients may be related to the visceral pain perception. Second, the low grade mucosal inflammation may be involved in the pathophysiology of visceral hypersensitivity. Post infectious IBS (PI-IBS) occupied 6-17% of the total IBS and some previous prospective studies reported that 7-33% of acute bacterial enteritis patients developed IBS after 6-12 months of infection. The relative risk of IBS in the gastroenteritis cohort was 11.9 and the strongest risk factor is the duration of diarrhea. After enteritis event, the increased number of immunocytes, mast cells and large amount of lymphocytes infiltration were revealed in mucosa and enteric nervous system of the gut. Beside the inflammatory cells, enterochromaffin cells, cytokines and inducible nitric oxide may be related to the pathophysiologic mechanism of PI-IBS. Lastly, the abnormalities in the gastrointestinal autonomic nervous system can induce constipation or motor disorders, but further research should elucidate it.     

Effects of bacteria on the enteric nervous system: implications for the irritable bowel syndrome

A unified scenario emerges when it is considered that a major impact of stress on the intestinal tract is reflected by symptoms reminiscent of the diarrhea-predominant form of irritable bowel syndrome. Cramping abdominal pain, fecal urgency, and explosive watery diarrhea are hallmarks not only of diarrhea-predominant irritable bowel syndrome, but also of infectious enteritis, radiation-induced enteritis, and food allergy. The scenario starts with stress-induced compromise of the intestinal mucosal barrier and continues with microorganisms or other sensitizing agents crossing the barrier and being intercepted by enteric mast cells. Mast cells signal the presence of the agent to the enteric nervous system (ie, the brain-in-the-gut), which uses one of the specialized programs from its library of programs to remove the "threat." This is accomplished by stimulating mucosal secretion, which flushes the threatening agent into the lumen and maintains it in suspension. The secretory response then becomes linked to powerful propulsive motility, which propels the secretions together with the offending agent rapidly in the anal direction. Cramping abdominal pain accompanies the strong propulsive contractions. Urgency is experienced when arrival of the large bolus of liquid distends the recto-sigmoid region and reflexly opens the internal anal sphincter, with continence protection now provided only by central reflexes that contract the puborectalis and external anal sphincter muscles. Sensory information arriving in the brain from receptors in the rapidly distending recto-sigmoid accounts for the conscious sensation of urgency and might exacerbate the individual's emotional stress. The symptom of explosive watery diarrhea becomes self-explanatory in this scenario.     

Diet and the irritable bowel syndrome

Food intake plays a key role in triggering or perpetuating symptoms in patients with IBS. Evaluation of the impact of diet in the individual patient requires a precise dietary history and a 7-day prospective dietary analysis, which should include the quality and quantity of food consumed, chronologic sequence and nature of symptoms, and the frequency and consistency of bowel movements. The caloric density of the meal, total fat intake, the quantity and quality of lactose-containing foods, sorbitol, fructose, and the nature and quantity of soluble and insoluble fiber intake must be noted. Patients with reflux esophageal symptoms should eliminate foods that decrease LES pressure, such as chocolate, peppermint, alcohol, and coffee. Direct esophageal mucosal irritants such as tomatoes, citrus juices, sharp condiments, and alcohol should be limited. Gastric emptying is slowed with the ingestion of fats and soluble fiber. Small bowel motility is slowed by soluble fiber and fatty foods. Gaseous syndromes may be reduced by avoidance of smoking, chewing gum, excessive liquid intake, and carbonated drinks. The reduced intake of large amounts of lactose-containing foods, sorbitol, and fructose may limit postprandial bloating. Flatus production can be lowered by reducing fermentable carbohydrates such as beans, cabbage, lentils, brussel sprouts, and legumes. Soluble and insoluble fiber ingestion will reduce sigmoidal intraluminal pressures and overcome spastic constipation when given in progressive graded doses. Effective dietary manipulations remain a key factor in reducing symptoms in IBS.     

Post-infectious irritable bowel syndrome:Mechanistic insights into chronic disturbances following enteric infection

Irritable bowel syndrome(IBS)is a commonly encountered chronic functional gastrointestinal(GI)disorder.Approximately 10%of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery.The appearance of new IBS symptoms following an infectious event is defined as post-infectiousIBS.Indeed,with the World Health Organization estimating between 2 and 4 billion cases annually,infectious diarrheal disease represents an incredible international healthcare burden.Additionally,compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features.A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota,epithelial barrier integrity,effector cell functions,and innate and adaptive immune features,all proposed physiological manifestations that can underlie GI abnormalities in IBS.Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms,and illicit successful infections.Consequently,the impact of infectious events on host physiology can be multidimensional in terms of anatomical location,functional scope,and duration.This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease,but may also lead to the establishment of chronic GI dysfunction compatible with IBS.     

Comorbidity in irritable bowel syndrome

BACKGROUND: Comorbid nongastrointestinal symptoms account for two-thirds of excess health-care costs in irritable bowel syndrome (IBS). OBJECTIVES: To determine whether IBS patients are at greater risk for specific comorbid disorders versus showing a general tendency to overreport symptoms; whether patients with inflammatory bowel disease (IBD) show patterns of comorbidity similar to IBS; whether comorbidity is explained by psychiatric disease; and whether excess comorbidity occurs in all IBS patients. METHODS: All 3,153 patients in a health maintenance organization with a diagnosis of IBS in 1994-1995 were compared to 3,153 age- and gender-matched controls, and to 571 IBD patients. All diagnoses in a 4-yr period beginning 1 yr before their index visit were categorized as gastrointestinal, psychiatric, or nongastrointestinal somatic. Nongastrointestinal somatic diagnoses were further divided into symptom-based versus biological marker-based diagnoses. RESULTS: Forty-eight of 51 symptom-based and 16 of 25 biomarker-based diagnoses were significantly more common in IBS versus controls. However, there were no unique associations. Bacterial, viral, and fungal infections and stroke were among diagnoses made more frequently in IBS. IBD patients were similar to controls. Greater somatic comorbidity was associated with concurrent psychiatric diagnosis. Only 16% of IBS patients had abnormally high numbers of comorbid diagnoses. CONCLUSIONS: Comorbidity in IBS is due to a general amplification of symptom reporting and physician consultation rather than a few unique associations; this suggests biased symptom perception rather than shared pathophysiology. Comorbidity is influenced by, but is not explained by, psychiatric illness. Excess comorbidity is present in only a subset of IBS patients.     

Microbiota and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a multifactorial disease during which the pathophysiological role of the gut microbiota has been recently highlighted. In almost 20% of the patients, IBS is clearly a post-infectious IBS as a consequence of an acute bacterial gastroenteritis. Some papers have reported an abnormal colonic fermentation in IBS patients that could explain symptoms such as bloating and be one of the factors triggering visceral hypersensitivity. More recently, significant differences in the composition of both the luminal and mucosa-associated microbiota have been reported between both IBS patients and healthy controls and IBS subgroups while some arguments exist for a small intestinal overgrowth in a subset of IBS patients. All these arguments for a deleterious role of the gut microbiota lead to the actual discuss to consider new therapeutic options, including mainly pre- and probiotics and maybe antibiotics.     

肠易激综合征大鼠模型肠神经系统神经递质表达的初步研究

目的 利用我们以往建立的便秘型肠易激综合征(C-IBS)大鼠模型,对该模型中SP、VIP、GABA、Ach、NE在肠神经系统的分布及表达进行研究,探讨这些物质在IBS发病机制中的可能作用。方法 采用以往本研究小组建立的C-IBS大鼠模型,取模型组及正常对照组大鼠的回盲部、结肠标本,进行常规组织固定、包埋、切片。分别应用抗SP、VIP、GABA、乙酰胆碱酯酶(AchE)、酪氨酸羟化酶(TH)抗体进行免疫组织化学染色,结果应用彩色病理图像分析系统对阳性表达的面积、不透光率密度值进行半定量分析。结果 C-IBS大鼠模型回盲部、结肠肌层中SP表达的不透光率密度明显增高(P<0.05),阳性面积与正常对照组无显著差异(P>0.05);C-IBS大鼠模型回盲部、结肠肌层中VIP表达的阳性面积、不透光率密度均明显增高(P<0.05);C-IBS大鼠模型回盲部、结肠肌层中GABA表达的不透光率密度明显降低(P<0.05),阳性面积与正常对照组无显著差异(P>0.05);C-IBS大鼠模型回盲部、结肠肌层中AchE、TH表达的阳性面积、不透光率密度与正常对照组尤显著差异(P>0.05)。结论 C-IBS大鼠模型中肠神经系统SP、VIP、GABA表达具有改变,提示这些神经递质在肠道可能参与C-IBS的病理生理过程。     

Probiotics and irritable bowel syndrome

Irritable bowel syndrome(IBS)is common gastrointestinal problems.It is characterized by abdominal pain or discomfort,and is associated with changes in stool frequency and/or consistency.The etiopathogenesis of IBS may be multifactorial,as is the pathophysiology,which is attributed to alterations in gastrointestinal motility,visceral hypersensitivity,intestinal microbiota,gut epithelium and immune function,dysfunction of the brain-gut axis or certain psychosocial factors.Current therapeutic strategies are often unsatisfactory.There is now increasing evidence linking alterations in the gastrointestinal microbiota and IBS.Probiotics are living organisms which,when ingested in certain numbers,exert health benefits beyond inherent basic nutrition.Probiotics have numerous positive effects in the gastrointestinal tract.Recently,many studies have suggested that probiotics are effective in the treatment of IBS.The mechanisms of probiotics in IBS are very complex.The purpose of this review is to summarize the evidence and mechanisms for the use of probiotics in the treatment of IBS.     

褪黑激素与肠易激综合征

肠易激综合征是一种原因不明的慢性肠功能紊乱性疾病，其发病机制尚不清楚。其治疗方法也在不断改进中，褪黑激素对肠易激综合征的治疗有着积极的作用。     

Management of the irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT(3) antagonist, tegaserod, a partial 5-HT(4) agonist, kappa-opioid agonists, and neurokinin antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain-gut axis is key to the eventual development of effective therapies for IBS.     

Real-time PCR analysis of enteric pathogens from fecal samples of irritable bowel syndrome subjects

Background

Growing amount of scientific evidence suggests that microbes are involved in the pathophysiology of irritable bowel syndrome (IBS). The predominant fecal microbiota composition of IBS subjects has been widely studied with DNA-based techniques but less research has been focused on the intestinal pathogens in this disorder. Here, we optimized a highly sensitive panel of 12 quantitative real-time PCR (qPCR) assays to shed light on the putative presence of intestinal pathogens in IBS sufferers. The panel was used to screen fecal samples from 96 IBS subjects and 23 healthy controls.

Results

Fifteen IBS samples (17%) tested positive for Staphylococcus aureus with a thermonuclease (nuc) gene-targeting qPCR assay, whereas none of the healthy controls were positive for S. aureus (p < 0.05). The S. aureus -positive IBS samples were confirmed by sequencing of the PCR amplicons. Clostridium perfringens was detected from IBS and control groups with a similar frequency (13% and 17%, respectively) with α-toxin (plc) gene -targeting qPCR assay while none of the samples tested positive for the Cl. perfringens enterotoxin-encoding gene (cpe).

Conclusions

The qPCR panel consisting of 12 assays for an extensive set of pathogenic microorganisms provides an efficient alternative to the conventional detection of gastrointestinal pathogens and could accelerate the initiation of targeted antibiotic therapy reducing the risk of post-infectious IBS (PI-IBS). S. aureus has not been previously reported to be associated with the onset of IBS. Although we discovered significant differences in the prevalence of S. aureus between the study groups, its importance in giving rise to IBS symptoms requires further studies.