Immune dysfunction in patients with functional gastrointestinal disorders

Abstract There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)‐5, IL‐10, IL‐13 and interferon γ (IFN‐γ)] and monocytic [IL‐10, IL‐12, tumour necrosis factor (TNF)‐α] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti‐CD28 or lipopolysaccharide (LPS) in controls (n = 32), irritable bowel syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non‐cardiac chest pain (NCCP) (n = 15). Serum IL‐6 and IL‐10 concentrations were compared, and the immunophenotype was assessed using fluorescent‐activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL‐5 and IL‐13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL‐12 and lymphocytic IL‐10 expression were reduced in IBS and FD, while IFN‐γ expression was also reduced in FD patients. Except for an increase in the numbers of CD3⁺CD45RA⁺CD45RO⁺ cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL‐10 levels and more CD3⁺CD45RA⁺CD45RO⁺ cells, while TNF‐α levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these disorders.     

The trials and tribulations of drug development for functional gastrointestinal disorders

Abstract  Functional gastrointestinal disorders (FGID) are common conditions seen in primary care and specialty practices but many affected individuals report a lack of satisfaction with available treatments. Despite the unmet need for more effective pharmacotherapy, drug development for these conditions can be challenging on many levels. This review will discuss the rationale and challenges of drug development for FGID. The reasons for engaging in drug development include that these conditions are highly prevalent, associated with a significant economic and healthcare burden, and associated with a lack of satisfaction with current therapies. The challenges include the lack of perception that FGID are legitimate disorders, the multidimensional and complex pathophysiology of FGID, the lack of a biological marker for diagnosis and treatment response, the heterogeneity of the patient population, the lack of consensus regarding the best outcome measures for clinical trials and the perceived increased risk–benefit ratio associated with drugs for FGID. Ongoing efforts are being taken to work towards a better understanding of pathophysiology, illness severity, patient-reported outcome measures, and benefit : risk assessment, and towards increasing education and communication amongst patients, clinicians, investigators, industry and regulatory agencies which will hopefully help optimize drug development strategies for FGID.     

Mechanisms of hypersensitivity in IBS and functional disorders

General introduction  The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.     

Functional gastrointestinal disorders and mast cells: implications for therapy

The pathophysiology of functional gastrointestinal disorders is poorly understood. Accepted common mechanisms include psychosocial factors, abnormal gastrointestinal motility and disturbed visceral sensory perception, but the underlying causes remain unclear. Mast cells (MCs) are immunocytes widely distributed throughout the gastrointestinal tract. Several stimuli (e.g. allergens, neuropeptides and stress) lead to MC activation with consequent mediator release (e.g. histamine, tryptase and prostanoids). The MC mediators interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. The intestinal mucosa of irritable bowel syndrome patients contains on average an increased number of MCs. These cells release an increased amount of mediators in close vicinity to mucosal innervation. The MC activation and their close proximity to nerve fibres is correlated with the severity of perceived abdominal painful sensations. These data provide a strong basis for considering MCs as important participants in visceral hypersensitivity and pain perception in irritable bowel syndrome. Inhibition of MC function may ameliorate irritable bowel symptoms. Novel drugs with an increased potential in the control of MC function (e.g., anti-IgE antibodies, the intracellular protein tyrosine kinase inhibitor Syk) and mediator release (e.g., second generation antihistamines, proteinase-activated receptor antagonists) may be useful pharmacological tools for these common disorders.     

High frequency of overlap between functional dyspepsia and overactive bladder

Background Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia. The association between irritable bowel syndrome (IBS) and bladder symptoms has been reported. This study is designed to investigate whether functional dyspepsia (FD), like IBS, is associated with OAB. Methods A web surveys containing questions about OAB, FD, IBS, and demographics were completed by 5494 public individuals (2302 men and 3192 women) who have no history of severe illness. The prevalence and overlap of OAB, FD, and IBS were examined. Key Results Among participants with FD, 20.5% could also be diagnosed with OAB (odds ratio [OR]: 2.85; 95% confidence interval [CI]: 2.21-3.67). Although concomitant FD and IBS were more strongly associated with OAB (OR: 4.34; 95% CI: 2.81-6.73), OAB was also highly prevalent among participants with FD but without IBS (OR: 3.09; 95% CI: 2.29-4.18). Among participants with FD, an overlapping OAB condition was more prevalent in those with both postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (OR: 3.75; 95% CI: 2.48-5.67) than in those with PDS or EPS alone. Among participants with OAB, the severity of bladder symptoms was greater in participants with dyspeptic symptoms than without them. Conclusions & Inferences Overactive bladder syndrome is common among FD patients, even if they do not have IBS. To improve FD patients' quality of life, it will be important to provide management for OAB.     

Unraveling functional abdominal bloating and distension: the role of thoraco-abdominal accommodation and a physical sign to aid its detection

Bloating and distension are common complaints in patients with irritable bowel syndrome of which the cause has remained elusive, although it has been shown that the obvious explanation of excessive gas is unlikely. The recent application of technologies such as the gas challenge technique, abdominal inductance plethysmography, CT scanning, as well as electromyography of the diaphragm and anterior abdominal wall, have allowed the situation to be slowly unraveled. It is now seems probable that the pathophysiology of bloating and distension are subtly different with the former having a sensory component whereas mechanical factors, such as disordered abdominal accommodation, contribute more to the latter.     

The challenge of cross-cultural, multi-national research: potential benefits in the functional gastrointestinal disorders

Abstract  The increasing interest in research in irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGIDs), taken together with the growing sophistication of communication technology, makes cross-cultural, multi-national research a feasible endeavour. The aim of this study is to encourage collaborative cross-cultural studies in FGIDs by discussing relevant methodological issues, and by suggesting potential areas in which cross-cultural research can make a significant contribution to the understanding of FGIDs and to patient care. To this end, methodological issues related to cross-cultural research and competences required for its conduct are presented together with a critique of published studies and recommendations for future research in the area. The term 'cross-cultural' research in FGIDs is usually applied to the results of prevalence studies, for example comparative studies of IBS prevalence in different countries and ethnic groups. The validity of these comparisons is impacted negatively by the lack of uniformity in research methods. In addition to prevalence studies, cross-cultural research can make a significant contribution in areas such as molecular biology, genetics, psychosocial factors, symptom presentation, extra-intestinal comorbidity, diagnosis and treatment, determinants of disease severity, healthcare utilization, and health-related quality of life, all issues that can be affected by culture, ethnicity and race. Well-designed and implemented cross-cultural studies can advance our knowledge in many FGID-related areas ranging from epidemiology through psychosocial factors, pathophysiological mechanisms and therapeutics. These studies, conducted by investigators with competence in cross-cultural research methodology, can advance our understanding of the FGIDs and contribute to improved patient care.     

Brain–gut connections in functional GI disorders: anatomic and physiologic relationships

Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the 'mind-body interaction' may largely arise in this region. Finally, the limbic system is also involved in the 'top down' modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of 'functional' disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.     

The “Biology‐First” Hypothesis: Functional disorders may begin and end with biology—A scoping review

While it is generally accepted that gastrointestinal infections can cause functional disturbances in the upper and lower gastrointestinal tract—known as postinfectious irritable bowel syndrome (PI‐IBS) and functional dyspepsia (PI‐FD)—it has still not been widely recognized that such an infection can also initiate functional non‐intestinal diseases, and that non‐intestinal infections can provoke both intestinal and non‐intestinal functional disturbances. We conducted a scoping review of the respective literature and—on the basis of these data—hypothesize that medically unexplained functional symptoms and syndromes following an infection may have a biological (genetic, endocrine, microbiological) origin, and that psychological and social factors, which may contribute to the disease “phenotype,” are secondary to this biological cause. If this holds true, then the search for psychological and social theories and factors to explain why one patient develops a chronic functional disorder while another does not is—at least for postinfectious states—misleading and detracts from exploring and identifying the true origins of these essentially biological disorders. The biopsychosocial model may, as the term implies, always begin with biology, also for functional (somatoform) disorders.     

Familial association of autonomic and gastrointestinal symptoms

Autonomic dysfunction occurs in the adult population with irritable bowel syndrome, but this association is not recognized in children. A mother and son with functional abdominal pain unresponsive to conventional treatment had complete resolution of symptoms with treatment directed at the autonomic dysfunction identified by testing. The authors recommend autonomic testing in patients with functional abdominal pain and suggest that autonomic dysfunction plays a direct and intrinsic role in the mechanism of these disorders and their symptoms.     

Life style in persons with functional gastrointestinal disorders--large-scale internet survey of lifestyle in Japan

Background Care of patients with functional gastrointestinal disorders (FGIDs) commonly includes offering guidance on diet, exercise, and other lifestyle factors, but there is little information available on the actual lifestyles of FGID sufferers. Methods An internet questionnaire survey of 15 000 adult members of the general public in Japan who were screened for functional dyspepsia (FD) and irritable bowel syndrome (IBS) using the Rome III adult FGID questionnaire was conducted. Key Results The prevalence of FD and IBS was 6.5% and 14.0%, respectively, and 3.0% of the subjects met the criteria for both FD and IBS. The prevalence of both FD and IBS was higher in women than in men. The lifestyles of 2 547 subjects who met the Rome III criteria for FD, IBS, or both were compared with the lifestyles of 1 000 control subjects who did not meet the criteria for FD or the criteria for IBS. Compared to the control subjects, a significantly lower percentage of subjects with FD, IBS, or both exercised frequently, and a significantly higher percentage thought that their sleep was insufficient, ate meals irregularly, did not have an appetite, did not like meat, thought that their vegetable consumption was insufficient, felt stress in their daily lives, and regarded themselves as being highly susceptible to stress. Conclusions & Inferences Persons with FGIDs are affected by impairment of sleep, eating habits, diet, exercise and other lifestyle factors, and feel excessive stress. This suggests that offering lifestyle guidance to FGID patients may be useful.     

Sleep disturbances are linked to both upper and lower gastrointestinal symptoms in the general population

Abstract  In tertiary referral patients, there is association between altered sleep patterns, functional bowel disorders and altered gut motor function. Body mass index (BMI) is also associated with gastrointestinal (GI) symptoms including diarrhoea, and with sleep disturbances. Our hypothesis is that sleep disturbances are associated with GI symptoms, and this is not explained by BMI. A 48-item-validated questionnaire was mailed to 6939 community participants in Olmsted County, MN. The survey included GI symptoms, sleep disturbance, daily lifestyle and quality of life (QOL). Independent contributions of sleep disturbance to individual symptoms were assessed using logistic regression adjusting for age, gender, lifestyle and mental health status. The association of an overall sleep score with an overall symptom score was examined and the ability of both scores to predict SF-12 physical and mental functioning scores assessed in multiple linear regression models. Among 3228 respondents, 874 (27%) reported trouble staying asleep. There was a significant correlation of overall sleep scores with overall GI symptom scores (partial r  = 0.28, P  < 0.001). Waking up once nightly at least four times a month was significantly associated with pain, nausea, dysphagia, diarrhoea, loose stools, urgency and a feeling of anal blockage. Trouble falling asleep was significantly associated with rectal urgency. Associations were independent of gender, age, lifestyle factors and BMI. Overall, sleep scores and GI symptom scores were both significant independent predictors of impaired QOL. In the community, reporting poor sleep is associated with upper and lower GI symptoms, but this is independent of BMI.