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Increased mast cells in irritable bowel syndrome
Abstract
Mast cells (MC) release potent mediators which alter enteric nerve and smooth muscle function and may play a role in the pathogenesis of the irritable bowel syndrome (IBS). The aim of this study was to determine if MC were increased in the colon of IBS patients compared to controls. Biopsy specimens were obtained from the caecum, ascending colon, descending colon and rectum of 28 patients: 14 IBS (Rome criteria); seven normal; and seven inflammatory controls. Tissue was stained immunohistochemically using a monoclonal mouse antibody for human mast cell tryptase (AA1). Tissue area occupied by tryptase-positive MC (volume density of mast cells) was quantified by image analysis. The number of plasma cells, lymphocytes, eosinophils, neutrophils and macrophages were each graded semiquantitatively (0-4) in haematoxylin and eosin stained sections. Mast cell volume density was significantly (P < 0.05) higher in IBS (0.91 +/- 0.18; CI 0.79; 1.0) than normal controls (0.55 +/- 0.14; CI 0.40; 0.69) in the caecum but not at other sites. Apart from MC, there was no evidence of increased cellular infiltrate in the IBS group. MC were significantly increased in the caecum of IBS patients compared to controls. The multiple effects of the intestinal mast cell alone, or as a participant of a persistent inflammatory response, may be fundamental to the pathogenesis of IBS.
... MCs are related with major intestinal functions, such as epithelial secretion, epithelial permeability, blood flow, neuroimmune interactions and visceral sensation [56]. In fact, MCs hyperplasia and activation would lead to anomalous gastrointestinal sensitivity, motility and secretion, which in turn promote abdominal pain and/or discomfort, bloating and abnormal intestinal function [57]. In this sense, many therapies targeting mast cells have been explored in IBS patients and have shown good effectiveness to some extent [58,59]. ...
... sensation [56]. In fact, MCs hyperplasia and activation would lead to anomalous gastrointestinal sensitivity, motility and secretion, which in turn promote abdominal pain and/or discomfort, bloating and abnormal intestinal function [57]. In this sense, many therapies targeting mast cells have been explored in IBS patients and have shown good effectiveness to some extent [58,59]. ...
Limosilactobacillus fermentum CECT5716, a probiotic strain isolated from human milk, has reported beneficial effects on different gastrointestinal disorders. Moreover, it has shown its ability to restore altered immune responses, in association with microbiome modulation in different pathological conditions. Therefore, our aim was to assess the effects of a Limosilacbacillus fermentum CECT5716 in a rat experimental model of irritable bowel syndrome (IBS) that resembles human IBS. The experimental IBS was induced by deoxycholic acid (DCA) in rats and then, Limosilactobacillus fermentum CECT5716 (109 CFU/day/rat) was administered. Behavioral studies, hyperalgesia and intestinal hypersensitivity determinations were performed and the impact of the probiotic on the inflammatory and intestinal barrier integrity was evaluated. Additionally, the gut microbiota composition was analyzed. Limosilactobacillus fermentum CECT5716 attenuated the anxiety-like behavior as well as the visceral hypersensitivity and referred pain. Moreover, this probiotic ameliorated the gut inflammatory status, re-establishing the altered intestinal permeability, reducing the mast cell degranulation and re-establishing the gut dysbiosis in experimental IBS. Therefore, our results suggest a potential use of Limosilactobacillus fermentum CECT5716 in clinical practice for the management of IBS patients.
... 35,54,55 Previous evidence shows that there is an increased number of MC in the intestinal and colonic mucosa of IBS patients, [56][57][58][59][60] particularly in the ileum-caecum region and rectum. [61][62][63] In Katinios et al study, the results show an increase in intestinal permeability and MC counts in IBS patients. 60 In Piche et al research, MC infiltrates in the lamina propria of caecum specimens were associated with the severity of fatigue and depression in both IBS subtypes patients. ...
Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by the extracutaneous proliferation of clonal MC in the bone marrow or other extramedullary sites with or without cutaneous involvement. GastrointestinaI (GI) manifestations, consisting of abdominal pain, diarrhea and malabsorption with various degrees of severity, are frequent in patients with SM and can result from mediator release or direct MC infiltration of the GI tract. Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic and recurrent abdominal pain or discomfort associated with defecation or change in bowel habit. The interaction between immune system and neuropeptides and the enhancement of an inflammatory mucosal response with an increase in immune cells is a key feature of IBS. Previous evidence shows that there is an increased number of MC in the intestinal and colonic mucosa of IBS patients. MC are present in the GI and their activation has been associated to some pro-secretory neurotransmitters such as substance P and vasoactive intestinal peptide in the proximity of enteric nerves suggesting a bidirectional regulatory pathway with neurocrine control of MC activation. Research concerning the role of enteric MC in both SM and IBS is still scarce as well as their link to neuro-peptides. Likewise, more evidence is needed regarding MC and neuropeptides interaction in order to further comprehend the pathophysiology of the GI manifestations of SM and IBS, and the boundaries between these pathologies. In this review we hypothesize that GI symptoms SM and in IBS have similar mechanisms and mediators, with a special focus in the role of mucosal MC and neuropeptides.
... Whereas FD presents with symptoms thought to originate from the gastroduodenal region, IBS presents with lower GI complaints such as constipation, diarrhea and abdominal pain. Moreover, the inflammatory infiltrate in IBS predominantly consists of mast cells, initially reported in the terminal ileum (Weston et al., 1993) and cecum (O'Sullivan et al., 2000), but later also in other parts of the colon and even more proximally in the small intestine (Bashashati et al., 2018;Robles et al., 2019). However, the increased infiltration and degranulation of eosinophils in the colonic mucosa also suggested a role for eosinophils in IBS (Katinios et al., 2020;Salvo-Romero et al., 2020;Casado-Bedmar et al., 2021). ...
Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.
... The most consistently reported feature of IBS is increased mast cell numbers in both the SI and colon [34][35][36][37][38][39][40]. While some studies were unable to demonstrate altered mast cell numbers in the colon [41] likely due to methodological differences, sample sizes or selection bias, increased secretion of colonic tryptase and histamine [41][42][43] support a role for mast cells in IBS. ...
Background
Irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction (DGBI), presenting as chronic abdominal pain and altered defaecation. Symptoms are often food related. Much work in the field has focused on identifying physiological, immune and microbial abnormalities in the colon of patients; however, evidence of small intestinal immune activation and microbial imbalance has been reported in small studies. The significance of such findings has been largely underappreciated despite a growing body of work implicating small intestinal homeostatic imbalance in the pathogenesis of DGBIs.
Main text
Small intestinal mechanosensation is a characteristic feature of IBS. Furthermore, altered small intestinal barrier functions have been demonstrated in IBS patients with the diarrhoea-predominant subtype. Small intestinal bacterial overgrowth and increased populations of small intestinal mast cells are frequently associated with IBS, implicating microbial imbalance and low-grade inflammation in the pathogenesis of IBS. Furthermore, reports of localised food hypersensitivity responses in IBS patients implicate the small intestine as the site of immune-microbial-food interactions.
Conclusions
Given the association of IBS symptoms with food intake in a large proportion of patients and the emerging evidence of immune activation in these patients, the current literature suggests the pathogenesis of IBS is not limited to the colon but rather may involve dysfunction of the entire intestinal tract. It remains unclear if regional variation in IBS pathology explains the various symptom phenotypes and further work should consider the intestinal tract as a whole to answer this question.
... 47 Regional colon mast cell differences are found, being higher in the cecum in one report. 48 Small intestinal mast cells were higher in 10 of 11 studies from one meta-analysis and two systematic reviews. 44,45 There also are regional differences in small bowel distributions in IBS, being higher in the ileum than the duodenum and jejunum in one meta-analysis. ...
Abnormalities of mast cell structure or function may play prominent roles in irritable bowel syndrome (IBS) symptom genesis. Mast cells show close apposition to sensory nerves and release bioactive substances in response to varied stimuli including infection, stress, and other neuroendocrine factors. Most studies focus on patients who develop IBS after enteric infection or who report diarrhea‐predominant symptoms. Three topics underlying IBS pathogenesis have been emphasized in recent investigations. Visceral hypersensitivity to luminal stimulation is found in most IBS patients and may contribute to abdominal pain. Mast cell dysfunction also may disrupt epithelial barrier function which alters mucosal permeability potentially leading to altered bowel function and pain. Mast cell products including histamine, proteases, prostaglandins, and cytokines may participate in hypersensitivity and permeability defects, especially with diarrhea‐predominant IBS. Recent experimental evidence indicates that the pronociceptive effects of histamine and proteases are mediated by the generation of prostaglandins in the mast cell. Enteric microbiome interactions including increased mucosal bacterial translocation may activate mast cells to elicit inflammatory responses underlying some of these pathogenic effects. Therapies to alter mast cell activity (mast cell stabilizers) or function (histamine antagonists) have shown modest benefits in IBS. Future investigations will seek to define patient subsets with greater potential to respond to therapies that address visceral hypersensitivity, epithelial permeability defects, and microbiome alterations secondary to mast cell dysfunction in IBS.
Irritable bowel syndrome (IBS) is related to a problem in the gut-brain axis. This experimental research aimed to shed light on the potential therapeutic application of elderberry (EB), which can work on the axis and get better the IBS symptoms. There were three groups (36 Sprague-Dawley rats) in this experiment, including control, IBS, and IBS with EB diet (IBS + EB). Making use of intracolonic instillation of 1 ml of 4% acetic acid for 30 s, IBS was induced. 7 days later, the EB extract (2%) was added to the diets of all animals for 8 weeks. Some histological, behavioral, and stereological techniques were used to detect the effects of EB on the gut and brain tissues. The findings showed that the EB diet improved locomotion and decreased anxiety-like behavior in the rat models of IBS. Moreover, the diet dropped the expression of TNF-α and increased mucosal layer thickness and the number of goblet and mast cells in colon tissue samples. In the hippocampal samples, administration of EB prevented astrogliosis and astrocyte reactivity. Although hippocampal and cortical neurons decreased markedly in the IBS group, EB prevented the drop in the number of neurons. Although lots of research is needed to elucidate the effectiveness of EB in IBS and its exact molecular mechanism, the result of this study showed that EB as an antioxidant and immune-modulatory agent could be a promising research target to prevent the impairment in the gut-brain axis, and could ameliorative classic IBS symptoms.
Mast cells are residents of the tubular gastrointestinal (GI) tract, where they play an important role in host defense and other vital functions. Dysregulation of mast cells has been implicated in the pathogenesis of several neoplastic, inflammatory, and functional disorders, some of which may manifest with GI symptoms. Surgical pathologists must therefore confront when and how to evaluate GI biopsies for mast cells, and whether such decisions should be based on morphologic criteria, clinical context, or direct request from clinical colleagues. The pathologist's role in evaluation of mast cell infiltrates is best defined in the diagnosis of systemic mastocytosis, where the utility of morphologic assessment coupled with ancillary studies is well‐established. In contrast, in non‐neoplastic mast cell disorders such as mast cell activation syndrome, irritable bowel syndrome, or so‐called “mastocytic enterocolitis,” a role for histopathology, if any, is controversial. Despite this, pathologists have seen a sharp increase in requests for mast cell quantification in the latter setting, despite these requests not being supported by published evidence. Moreover, what constitutes a ‘normal’ number of mast cells in a luminal GI biopsy is not well‐established. As a result, there is considerable variation in how these requests are handled in practice. This review evaluates and summarizes the published evidence relating to mast cell evaluation in endoscopic GI biopsies in various clinical scenarios, with a goal of providing practical, evidence‐based guidance for the surgical pathologist when approached with requests for mast cell quantification in GI biopsies.
Most diseases are preventable, and they are related to what we eat. Moreover, most doctor visits are for lifestyle-based diseases, which means they can be prevented by adopting a healthy lifestyle. Treating the causes of illness rather than symptoms of the disease is not only safer and cheaper, but it can work better. In this context, the Special Issue on “Nutraceuticals in Immune System” for the journal Molecules was launched in January 2020. Soon after that, the world was ravaged by the COVID-19 pandemic causing a grave health threat. Paradoxically, the immune system can be both friend and foe of COVID-19. The COVID-19 manifests only mild to moderate symptoms for most infected people who recover without hospitalisation, demonstrating the proper functioning of the immune system in fighting such an infection. For some, however, the overactivation of the immune response causing “cytokine storm” has dire consequences, with severe respiratory failure leading to multiple organ failure, which could be fatal. In fact, most deaths from COVID-19 came from organ inflammation due to undesirable immune system responses. As such, the COVID-19 is a good case in point, demonstrating the importance of a healthy immune system.
Nutraceuticals are products derived from food sources with health benefits in addition to the basic nutritional values. Many of them can positively affect and enhance the immune system, which is particularly pertinent in the current turbulent times of COVID-19. Not surprisingly, nutraceutical sales rose dramatically during the pandemic period. However, much research is still needed to understand how natural products interact with the immune system to clarify their chemical compositions, mechanisms of action and effects on health and illnesses.
This Special Issue provided an open forum for researchers to share their research findings in the growing interest of nutraceuticals. We received an overwhelming response with a total of 33 submissions, of which only nine original research papers and ten reviews were accepted after rigorous peer-review. The included articles research into natural substances of interest in nutraceuticals ranging from herbal medicine to vitamins to microbiota-derived metabolites. The investigated immune-related responses include cancer, neurological diseases, gastroenterological disorders, inflammatory conditions, and infections.
We thank the publisher for this excellent opportunity to serve the research community. As academic editors for this Special Issue, it is our pleasure to review these insightful manuscripts first-hand. We thank all the authors for their contributions. The collected works represent our current understanding and latest findings of nutraceuticals in immune system, which we hope will continue to inspire knowledge quests into the field of nutraceuticals.
SerotoninSerotoninfunctionsSerotonergic paracrine targets as a neurotransmitterIntestinal mucosa in the enteric nervous systemEnteric nervous system (ENS). Aside from its neurotransmitter role, serotoninSerotonin also is a paracrine mediatorial signal in the digestive tract. It is a major paracrine signaling molecule in the integrated physiology of several classes of cells in the intestinal mucosaIntestinal mucosa. Paracrine action can be initiation or suppression of activity in populations of cells that make up divergent phenotypic classes. This underlies phenotypic plasticity in single classes and links single classes to other neighboring phenotypic classes, thereby forming a single and higher-order organization in which different categories of function are integrated to work in harmony as a single homeostatic entity at higher levels of physiological organization. Phenotypic classes of cells that are linked by serotonergic paracrine signaling at upper levels of functional organization in the small intestineIntestines are (1) enterochromaffin cellsEnterochromaffin cells (ECs); (2) enteric mast cellsEnteric mast cells; (3) spinal sensory afferents; (4) sympathetic postganglionic neurons; (5) enteric neuronsEnteric neurons.
Transmission electron microscopy was done using surgically resected specimens from 12 patients with Crohn's disease and three control subjects. Nonulcerated involved areas of ileum as well as proximal, grossly uninvolved resection margins were chosen for study. Specimens for transmission electron microscopy were prepared for viewing by a variety of techniques. Six hundred five Epon embedded blocks were studied by light microscopy, and 112 of these were viewed in the transmission electron microscope.
The evaluation of adverse reactions to foods involving abnormal immune responses to food allergens remains an important part of the practice of allergy and immunology. Approximately 5% of children younger than 3 years and 1.5% of the general population experience food allergic disorders, indicating that about 4 million Americans suffer from food allergies. The evaluation of adverse reactions to foods depends on a careful clinical history, diagnostic studies including appropriate skin testing or in vitro testing with food extracts, and/or endoscopy and biopsy. The mainstay of therapy remains avoidance of incriminated foods and education to deal with inadvertent exposures. Experience over the past decade suggests that the ready availability and early introduction of highly allergenic foods (eg, peanuts and nuts) into the diet will only increase the number of individuals suffering from hypersensitivity reactions to foods. Research has focused on the identification and characterization of allergenic proteins and the development of new therapeutic strategies, eg, plasmid DNA vaccines, to treat these disorders.
EDITOR,—Recent articles have discussed the management of the irritable bowel from several points of view. R C Spiller argues for a predominantly medical approach to treatment once the hurdles of reassurance and dietary advice have been negotiated,1 while Francis Creed emphasises the importance of psychological treatments for selected groups of patients.1 Michael J G Farthing explores the relations between the bowel, body, and brain and provides further advice about the importance of making an early, positive diagnosis and of avoiding overinvestigation.2 Perhaps the most important moment for a patient with the irritable bowel syndrome is the moment when he or she decides to make the first contact with general practice. We know from community based studies that the prevalence of the syndrome in the general population is roughly 20% but that only between a quarter and a third of patients consult general practitioners.3 Work in North America and Britain has shown that the severity and frequency of symptoms alone poorly predict the likelihood of consultation and that concerns that the symptoms represent a serious disease and specific worries about cancer explain much of the difference between those who do and do not consult.4 Patients who consult are more likely to have abnormal levels of anxiety and clinical depression than people with the syndrome in the community, in whom affective disorders are much less commonly seen. This means that we have to provide reassurance. Reassurance requires a direct confrontation of patients' anxieties about cancer and serious disease and an exploration of these beliefs if they are not immediately apparent. Unless this happens early in the course of the medicalisation of the syndrome, further attempts at reassurance, accompanied by repeated negative results of investigations, will probably serve simply to increase anxiety and apprehension about the symptoms and their underlying cause. The corollary is that initial treatment needs to embrace physical and psychological approaches, and a cognitive approach to symptoms is probably more likely to be successful than a search for “treatable” affective disorders. Gomborone et al recently documented the negative cognition of patients with the irritable bowel syndrome,5 and a randomised controlled trial of an early cognitive therapeutic intervention in the syndrome, starting as soon as possible after the first contact with general practice, seems worth while. References1.↵Spiller RC, Creed F. Irritable bowel or irritable mind? BMJ 1994;309: 1646-8. (17 December.)
Thirty-eight patients with particularly troublesome irritable bowel syndrome (IBS) were selected for trial on a 2-week exclusion diet. Eighteen patients improved dramatically and, with two exceptions, subsequently identified foods to which they were intolerant. Follow-up by postal questionnaire showed that at least 10 were still following their dietary restrictions 3–45 months later.
Twelve of the 16 food intolerant patients were intolerant to more than one food. Fifteen patients found their symptoms did not improve on the exclusion diet. Five patients refused to try or were unable to complete the exclusion diet. The use of an appropriate exclusion diet for selected patients with IBS is recommended.