The possible role of gastrointestinal endocrine cells in the pathophysiology of irritable bowel syndrome

Introduction: The etiology of irritable bowel syndrome (IBS) is unknown, but several factors appear to play a role in its pathophysiology, including abnormalities of the gastrointestinal endocrine cells. The present review illuminates the possible role of gastrointestinal hormones in the pathophysiology of IBS and the possibility of utilizing the current knowledge in treating the disease.

Areas covered: Research into the intestinal endocrine cells and their possible role in the pathophysiology of IBS is discussed. Furthermore, the mechanisms underlying the abnormalities in the gastrointestinal endocrine cells in IBS patients are revealed.

Expert commentary: The abnormalities observed in the gastrointestinal endocrine cells in IBS patients explains their visceral hypersensitivity, gastrointestinal dysmotility, and abnormal intestinal secretion, as well as the interchangeability of symptoms over time. Clarifying the role of the intestinal stem cells in the pathophysiology of IBS may lead to new treatment methods for IBS.     

Recent developments in the pathophysiology of irritable bowel syndrome

Irritable bowel syndrome(IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients.     

Promising role of D-amino acids in irritable bowel syndrome

Irritable bowel syndrome (IBS) is an important health care concern. Alterations in the microbiota of the gut-brain axis may be linked to the pathophysiology of IBS. Some dietary intake could contribute to produce various metabolites including D-amino acids by the fermentation by the gut microbiota. D-amino acids are the enantiomeric counterparts of L-amino acids, in general, which could play key roles in cellular physiological processes against various oxidative stresses. Therefore, the presence of D-amino acids has been shown to be linked to the protection of several organs in the body. In particular, the gut microbiota could play significant roles in the stability of emotion via the action of D-amino acids. Here, we would like to shed light on the roles of D-amino acids, which could be used for the treatment of IBS.     

Fecal microbiota transplantation for managing irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder affecting 11.2% of the world adult population. The intestinal microbiome is thought to play a pivotal role in the pathophysiology of IBS. The composition of the fecal microbiome in IBS patients differs from that in healthy individuals, but the exact bacteria species involved in the development of IBS remain to be determined. There is also an imbalance between useful and harmful bacteria (dysbiosis) in the intestinal microbiome in patients with IBS. Consuming prebiotics, probiotics, or synbiotics has a limited effect on IBS symptoms. In contrast, fecal microbiome transplantation (FMT) in IBS patients reverses the dysbiosis to normobiosis and reduces the IBS symptoms in about 70% of patients, and is not associated with any serious adverse events.

Area covered: The available data on the microbiome and FMT in IBS regarding the efficacy of FMT in managing IBS were found using a PubMed search of these topics.

Expert commentary: FMT is a promising tool for managing irritable syndrome. It appears to be effective, easy, and inexpensive procedure. However, more controlled studies involving larger cohorts of IBS are needed before FMT can be used as a routine procedure in the clinic.     

Gut microbiota role in irritable bowel syndrome: New therapeutic strategies

In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome(IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial(Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful(Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required.     

Irritable bowel syndrome and endometriosis: New insights for old diseases

Irritable bowel syndrome and endometriosis are two diseases affecting a significant part of the female population, either together or individually, with remarkable consequences in the quality of life. Several studies suggest an epidemiological association between them.Their association may not be just an epidemiological phenomenon, but the manifestation of a pathophysiological correlation, which probably generates a mutual promotion phenomenon. In particular, both clinical entities share the presence of a chronic low-grade inflammatory state at the basis of the disease persistence.Recognizing this association is highly significant due to their prevalence and the common clinical manifestation occurring with a chronic abdominal pain. A further multi disciplinary approach is suggested in these patients’ management in order to achieve an adequate diagnostic work up and a targeted therapy.This paper analyses some common pathophysiological mechanisms, such as activation of mast cell line, neuronal inflammation, dysbiosis and impaired intestinal permeability. The aim was to investigate their presence in both IBS and endometriosis, and to show the complexity of their relationship in the generation and maintenance of chronic inflammation.     

Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for management

Irritable bowel syndrome (IBS) may, in part at least, result from a dysfunctional interaction between the indigenous flora and the intestinal mucosa which, in turn, leads to immune activation in the colonic mucosa. Some propose a role for bacterial overgrowth as a common causative factor in the pathogenesis of symptoms in IBS; other evidence points to more subtle qualitative changes in the colonic flora; both hypotheses remain to be confirmed but the likelihood that bacterial overgrowth will prove to be a major factor in IBS now seems remote. Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and, perhaps, localized, quantitative and/or qualitative changes in the colonic flora. How probiotics exert their effects remain to be defined but an anti-inflammatory effect seems likely. While this approach to the management of IBS is in its infancy, it is evident that manipulation of the flora, whether through the administration of antibiotics or probiotics, deserves further attention in IBS.     

Convergence of neuro-endocrine-immune pathways in the pathophysiology of irritable bowel syndrome

Disordered signalling between the brain and the gut are generally accepted to underlie the functional bowel disorder, irritable bowel syndrome (IBS). However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. This common gastrointestinal disorder is characterised by alterations in bowel habit such as diarrhoea and/or constipation, bloating and abdominal pain, and symptom exacerbation has been linked with periods of stress, both psychosocial and infection-related. Indeed, a high level of comorbidity exists between IBS and stress-related mood disorders such as anxiety and depression. Moreover, studies have observed alterations in autonomic output and neuro-endocrine signalling in IBS patients. Accumulating evidence indicates that a maladaptive stress response, probably mediated by the stress hormone, corticotropin-releasing factor contributes to the initiation, persistence and severity of symptom flares. Other risk factors for developing IBS include a positive family history, childhood trauma, dietary factors and prior gastrointestinal infection. An emerging role has been attributed to the importance of immune factors in the pathophysiology of IBS with evidence of altered cytokine profiles and increased levels of mucosal immune cells. These factors have also been shown to have direct effects on neural signalling. This review discusses how pathological changes in neural, immune and endocrine pathways, and communication between these systems, contribute to symptom flares in IBS.     

Recent advances in the diagnosis of irritable bowel syndrome

The symptom-based diagnosis of irritable bowel syndrome (IBS) has not been established in everyday clinical practice, and the diagnosis of this disorder remains one of exclusion. It has been demonstrated that the densities of duodenal chromogranin A, rectal peptide YY and somatostatin cells are good biomarkers for the diagnosis of sporadic IBS, and low-grade mucosal inflammation is a promising biomarker for the diagnosis of postinfectious IBS. Genetic markers are not useful as biomarkers for IBS since the potential risk genes have yet to be validated, and the intestinal microbiota cannot be used because of the lack of an association between a specific bacterial species and IBS. Furthermore, gastrointestinal dysmotility and visceral hypersensitivity tests produce results that are too nonconsistent and noncharacteristic to be used in the diagnosis of IBS. A combination of symptom-based assessment, exclusion of overlapping gastrointestinal diseases and positive biomarkers appears to be the best way to diagnose IBS.     

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.     

The gut microbiome and irritable bowel syndrome: State of art review

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract, the physiology of which is not very well understood. There are multiple factors and pathways involved in pathogenesis of this entity. Among all, dysmotility, dysregulation of the brain-gut axis, altered intestinal microbiota and visceral hypersensitivity play a major role. Over the last years, research has shown that the type of gut microbiome present in an individual plays a significant role in the pathophysiology of IBS. Multiple studies have consistently shown that subjects diagnosed with IBS have disruption in gut microbiota balance. It has been established that host immune system and its interaction with metabolic products of gut microbiota play an important role in the gastrointestinal tract. Therefore, probiotics, prebiotics and antibiotics have shown some promising results in managing IBS symptoms via modulating the interaction between the above. This paper discusses the various factors involved in pathophysiology of IBS, especially gut microbiota.     

Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients

AIM： To determine the composition of both fecal and duodenal mucosa-associated microbiota in irritable bowel syndrome （IBS） patients and healthy subjects using molecular-based techniques.
METHODS： Fecal and duodenal mucosa brush samples were obtained from 41 IBS patients and 26 healthy subjects. Fecal samples were analyzed for the composition of the total microbiota using fluorescent in situ hybridization （FISH） and both fecal and duodenal brush samples were analyzed for the composition of bifidobacteria using real-time polymerase chain reaction.
RESULTS： The FISH analysis of fecal samples revealed a 2-fold decrease in the level of bifidobacteria （4.2 ± 1.3 vs 8.3 ± 1.9, P 〈 0.01） in IBS patients compared to healthy subjects, whereas no major differences in other bacterial groups were observed. At the species level, Bifidobacterium catenulatum levels were significantly lower （6 ± 0.6 vs 19 ± 2.5, P 〈 0.001） in the IBS patients in both fecal and duodenal brush samples than in healthy subjects.
CONCLUSION： Decreased bifidobacteria levels in both fecal and duodenal brush samples of IBS patients compared to healthy subjects indicate a role for microbiotic composition in IBS pathophysiology.     

Methodological issues in the study of intestinal microbiota in irritable bowel syndrome

Irritable bowel syndrome (IBS) is an intestinal functional disorder with the highest prevalence in the industrialized world. The intestinal microbiota (IM) plays a role in the pathogenesis of IBS and is not merely a consequence of this disorder. Previous research efforts have not revealed unequivocal microbiological signatures of IBS, and the experimental results are contradictory. The experimental methodologies adopted to investigate the complex intestinal ecosystem drastically impact the quality and significance of the results. Therefore, to consider the methodological aspects of the research on IM in IBS, we reviewed 29 relevant original research articles identified through a PubMed search using three combinations of keywords: “irritable bowel syndrome + microflora”, “irritable bowel syndrome + microbiota” and “irritable bowel syndrome + microbiome”. For each study, we reviewed the quality and significance of the scientific evidence obtained with respect to the experimental method adopted. The data obtained from each study were compared with all considered publications to identify potential inconsistencies and explain contradictory results. The analytical revision of the studies referenced in the present review has contributed to the identification of microbial groups whose relative abundance significantly alters IBS, suggesting that these microbial groups could be IM signatures for this syndrome. The identification of microbial biomarkers in the IM can be advantageous for the development of new diagnostic tools and novel therapeutic strategies for the treatment of different subtypes of IBS.     

Interstitial cells of Cajal: a novel hypothesis for the pathophysiology of irritable bowel syndrome

Irritable bowl syndrome (IBS) affects a large proportion of the world's population, and accounts for a considerable number of visits to gastroenterologists and general practitioners. Despite its high prevalence, the precise mechanism of IBS has not been identified to date. The interstitial cells of Cajal (ICC) participate in the production of slow waves and the regulation of their propagation through the gastrointestinal system; thus, they are important components of gastrointestinal motility. The present review proposes that ICC play a central role in the pathophysiology of IBS. This hypothesis is based on many links between ICC and currently proposed mechanisms of IBS pathophysiology. It appears that ICC may be involved in almost all of the previously explained pathogenic mechanisms of IBS. If proven, this hypothesis may provide a key to solving the IBS mystery.     

结肠黏膜肥大细胞活化在肠易激综合征发病中的作用

目的　探讨结肠黏膜肥大细胞活化在肠易激综合征 (IBS)发病机制中的作用。方法　采用c Fos和类胰蛋白酶免疫组化双标方法 ,对应激和条件应激肠功能紊乱大鼠及符合罗马Ⅱ标准、连续就诊的发作期IBS患者 5 6例进行直肠乙状结肠交界处黏膜肥大细胞活化程度研究 ,并与对照大鼠和健康对照组及 2例无症状超过 6个月的IBS患者相比较 ,观察应激和条件应激大鼠在应激前 30min腹腔注射 (i.p .)肥大细胞稳定剂色甘酸二钠 2 0mg/kg对大鼠内脏敏感性的影响 ,通过Spearman等级相关分析评价IBS患者症状严重指数与肥大细胞活化分数的关系。结果　与对照组相比 ,应激 [(8.0± 0 .9)比(2 .5± 0 .8) ]和条件应激 [(7.8± 0 .8)比 (2 .5± 0 .8) ]大鼠结肠下段黏膜活化细胞明显增加 ,但肥大细胞总数无明显改变 ;色甘酸二钠显著降低应激大鼠 [(7.2± 1.2 )比 (3.8± 0 .8) ,P <0 .0 1]和条件应激大鼠[(6 .8± 0 .8)比 (3.8± 0 .8) ,P <0 .0 1]的内脏敏感性 ,对对照组大鼠却无影响。与 2 0例正常对照组相比 ,IBS发作期患者直肠乙状结肠交界处黏膜肥大细胞数目和活化细胞分数显著增加 [(85± 12 )比 (15± 6 ) ,P <0 .0 1],肥大细胞活化分数与症状严重程度指数显著相关 (r =0 .86 2 ,P <0 .0 1)。结论　肠道黏膜肥大细胞活化     

肥大细胞在肠易激综合征发病机制中的研究进展

肠易激综合征(irritable bowel syndrome,IBS)是以腹痛、腹部不适伴排便习惯改变和/或大便性状异常为特征的常见功能性胃肠病.IBS全球患病率为2%-15%.本病病因及发病机制尚不十分明确,目前认为多与胃肠动力异常、内脏高敏、感染与炎症、神经-内分泌失调、精神心理、食物过敏等多种因素有关.近年来提出的"神经-免疫-内分泌网络"理论在IBS发病机制中占有重要地位.研究发现,胃肠道的肥大细胞(mast cells,MCs)在IBS的发病中发挥着重要作用.本文拟以MCs在IBS中的发病机制的最新研究进展作一综述.     

Gut dysbiosis and irritable bowel syndrome: The potential role of probiotics

Objective

To discuss the role of gut dysbiosis in the development of irritable bowel syndrome (IBS) and the impact of probiotics as a potential therapeutic measure.

Possible therapeutic role of Ig E blockade in irritable bowel syndrome

Omalizumab is a humanized monoclonal antibody that binds to the high-affinity type-I Ig E Fc receptors on mast cells(MCs) and basophils, inhibiting the Ig E immune pathway. Irritable bowel syndrome(IBS) is the most common functional gastrointestinal disorder, and dysregulation of the immune system likely contributes to its etiology and/or symptomatology. Colonic biopsies from patients with IBS demonstrate considerable increase in the number of degranulating MCs releasing histamine in proximity to nerves, and this event may underlie the common IBS symptom of abdominal pain. Pharmacologic control of MC activation and mediator release is a current area of active interest in the field of IBS research. Recently, we and Pearson et al described 2 cases of patients with IBS with diarrhea(IBS-D) showing positive clinical response to omalizumab. In both cases, the female patients had severe, long-lasting IBS-D and achieved an almost complete resolution of IBS symptoms. Both patients were also able to discontinue all IBS medications after commencing the anti-Ig E therapy. For both patients, the omalizumab treatment showed a relatively rapid onset of action, resembling the efficacy observed in and previously reported for patients with chronic spontaneous urticaria. In this Editorial, we discuss the possible biological mechanisms that may underlie the clinical efficacy of omalizumab in IBS. We suggest that there is a need for a well-designed prospective study to investigate the therapeutic effects of anti-Ig E in IBS.     

Molecular basis of the irritable bowel syndrome

Irritable bowel syndrome(IBS)is a functional disorder characterized by abdominal pain,discomfort and bloating.The pathophysiology of IBS is poorly understood,but the presence of psychosocial basis is now known.There is an increasing number of publications supporting the role of genetics in IBS.Most of the variations are found in genes associated with the brain-gut axis,revealing the strong correlation of brain-gut axis and IBS.miRNAs,which play critical roles in physiological processes,are not well studied in IBS.However,so far there is found an involvement of alterations in miRNA expression or sequence,in IBS symptoms.IBS phenotype is affected by epigenetic alteration and environment.Changes in DNA and histone methylation are observed in patients who suffered childhood trauma or abuse,resulting in altered gene expression,such as the glucocorticoid receptor gene.Finally,diet is another factor associated with IBS,which may contribute to symptom onset.Certain foods may affect on bacterial metabolism and epigenetic modifications,predisposing to IBS.