Molecular basis of functional gastrointestinal disorders

There are a number of abnormalities of gastrointestinal function, including sensory and motor dysfunction, which are believed to play a role in the manifestation of symptoms in patients with functional gastrointestinal disorders (FGID). In addition, there is a remarkable psychiatric comorbidity. Family and twin studies have provided strong evidence for a clustering of FGID in families and an increased concordance in monozygotic compared to dizygotic twins. This points towards the role of one or more hereditary (genetic) factors. Considering these disorders of function and the psychiatric comorbidity, polymorphisms of adrenergic, opioidergic or serotonergic receptors as well as G-protein beta3 (GNB3) subunit gene polymorphisms (C825T) and polymorphisms of 5-HT transporter genes are suitable causes. In addition, mediators or regulators of mucosal inflammation may trigger events that ultimately result in the manifestation of FGID. Thus, relevant polymorphisms of genes with immunmodulating and/or neuromodulating features (OPRM1, IL-4, IL-4R, TNFalpha) may also play a role in the manifestation of FGIDs.     

Functional and motility gastrointestinal disorders

As in previous years, a huge number of studies were presented at the Congress of the American Gastroenterology Association (Digestive Diseases Week [DDW]), some of which were better than others. The present article attempts to extract and summarize the most interesting findings reported. In general terms, certain technological advances have been consolidated, with full incorporation into clinical practice, such as impedancemetry and high-resolution manometry. New physiopathological data are coming to light that increasingly indicate the inextricable link between organic and psychological factors (the biopsychosocial model) in functional gastrointestinal disorders (FGID). Despite the high hopes that the Rome III criteria would improve the diagnosis of FGID and especially that of functional dyspepsia, their practical application has been fairly discouraging. Moreover, at least two studies have demonstrated that these criteria cannot be used to differentiate subtypes of functional dyspepsia and that there is wide overlap with gastroesophageal reflux disease. New data were presented on the role of genetic, microinflammatory and psychological factors in the etiopathogenesis of the two main FGID: functional dyspepsia and irritable bowel syndrome (IBS). The results on the safety and efficacy of acotiamide in functional dyspepsia and of linaclotide and prucalopride in idiopathic and IBS-associated constipation were also presented. Several studies, and even meta-analyses, have demonstrated the utility of biofeedback in the treatment of constipation. Even so, the efficacy of this therapy has been questioned due to certain methodological deficiencies in some studies. In DDW 2011, studies confirming the utility of biofeedback, whether hospital- or home-based were presented, in dyssynergy constipation. The present article also mentions certain features of special interest in the diagnosis and treatment of rumination syndrome, thoracic pain of possible esophageal origin and cannabinoid-induced hyperemesis syndrome.     

功能性胃肠病的遗传机制——相关基因研究

功能性胃肠病(FGID)有一定程度的家族聚集现象,在孪生人群中的FGID流行病学研究显示,单卵孪生的共同患病率高于异卵孪生。这些现象提示,遗传因素改变个体对FGID的易感性以及相似环境致病因素下FGID的临床表现异质性。此文综述FGID遗传易感性方面的研究进展。     

Trastornos funcionales digestivos post-infecciosos: del episodio agudo a la molestia crónica

Functional gastrointestinal disorders (FGID) form a major part of gastroenterology practice. Several studies have reported the development of post-infectious irritable bowel syndrome (PI-IBS) after acute gastroenteritis (AGE). Non-gastrointestinal (GI) infections may increase the risk of developing IBS. There are also data showing that a GI infection may trigger functional dyspepsia (PI-FD). The possible development of PI-IBS or PI-FD depends on factors related to both the infection and the host. Microinflammation has been found in patients with post-infectious FGID. Studies performed in animal models show that infection and acute inflammation permanently change gastrointestinal motility and sensitivity. The role of AGE in the development of FGID is important not only because this entity provides an excellent natural model for pathogenic study but also because it provides an opportunity for preventive action.     

Post-infectious functional gastrointestinal disorders: from the acute episode to chronicity

Functional gastrointestinal disorders (FGID) form a major part of gastroenterology practice. Several studies have reported the development of post-infectious irritable bowel syndrome (PI-IBS) after acute gastroenteritis (AGE). Non-gastrointestinal (GI) infections may increase the risk of developing IBS. There are also data showing that a GI infection may trigger functional dyspepsia (PI-FD). The possible development of PI-IBS or PI-FD depends on factors related to both the infection and the host. Microinflammation has been found in patients with post-infectious FGID. Studies performed in animal models show that infection and acute inflammation permanently change gastrointestinal motility and sensitivity. The role of AGE in the development of FGID is important not only because this entity provides an excellent natural model for pathogenic study but also because it provides an opportunity for preventive action.     

Gender, age, society, culture, and the patient's perspective in the functional gastrointestinal disorders

Patients with functional gastrointestinal disorders (FGID) often experience emotional distress, a perceived lack of validation, and an unsatisfactory experience with health care providers. A health care provider can provide the patient with a framework in which to understand and legitimize their symptoms, remove self-doubt or blame, and identify factors that contribute to symptoms that the patient can influence or control. This framework can be strengthened with the consideration of various important factors that impact FGID but are often overlooked. These include gender, age, society, culture, and the patient's perspective. There is evidence for sex- and gender-related differences in FGID, particularly irritable bowel syndrome (IBS). Whereas the majority of FGID, including IBS, bloating, constipation, chronic functional abdominal pain, and pelvic floor dysfunction, are more prevalent in women than men, functional esophageal and gastroduodenal disorders do not appear to vary by gender. Limited studies suggest that sex differences in visceral perception, cardioautonomic responses, gastrointestinal motility, and brain activation patterns to visceral stimuli exist in IBS. Gender differences in social factors, psychological symptoms, and response to psychological treatments have not been adequately studied. However, there appears to be a greater clinical response to serotonergic agents developed for IBS in women compared to men. The impact of social and cultural factors on the meaning, expression, and course of FGID are important. The prevalence of IBS appears to be lower in non-Western than Western countries. Although further studies are needed, the existing literature suggests that they are important to consider from both research and clinical perspectives.     

Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders

BACKGROUND: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (alpha(2)) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores. METHODS: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for alpha(2) adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score. RESULTS: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: alpha(2C) Del 322-325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and alpha(2A) -1291 (C-->G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the alpha(2C) Del 322-325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores. CONCLUSION: Functionally distinct alpha(2A) and alpha(2C) adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.     

Epidemiology of the functional gastrointestinal disorders diagnosed according to Rome II criteria: an Australian population-based study

BACKGROUND: Population-based studies of the prevalence of all functional gastrointestinal disorders (FGID) using the Rome II criteria are lacking. It is also not certain whether subjects who meet the Rome II criteria for an FGID are different in terms of demographic and psychological characteristics from those subjects meeting exclusively the more restrictive Rome I criteria. AIM: To determine whether using the more restrictive Rome I criteria would result in a more biologically determined group of FGID than when the Rome II is applied. METHODS: Subjects included individuals aged 18 years and older (n = 1,225) from the Penrith population who were initially surveyed with the Penrith District Health Survey in 1997. Subjects were sent a self-report questionnaire that contained items on gastrointestinal symptoms applying the Rome II criteria. Subjects were also assessed on psychological and personality factors and on physical and mental functioning. RESULTS: A total of 36.1% (n = 275) of respondents was diagnosed with an FGID according to Rome II criteria. The five most prevalent FGID were functional heartburn (10.4%), irritable bowel syndrome (8.9%), functional incontinence (7.6%), proctalgia fugax (6.5%) and functional chest pain (5.1%). Subjects meeting Rome II only criteria for FGID scored significantly higher on measures of psychological caseness and emotionality than Rome I only subjects, and these were independently associated with meeting Rome I only versus Rome II only criteria for FGID. CONCLUSION: The Rome II criteria FGID are common and do not appear to identify a vastly different group of FGID sufferers compared with the earlier Rome I criteria.     

Central nervous system involvement in functional gastrointestinal disorders

Although functional gastrointestinal disorders (FGID) are common, their pathophysiology remains incompletely understood. It is generally accepted that dysfunction of the bidirectional pathways between the gastrointestinal tract and the central nervous system (the 'brain-gut axis') at any level can cause FGID symptoms. In this review article, we focus on the role of the central nervous system in the brain-gut axis. First, we describe the functional anatomy of the brain-gut axis. Second, we focus on the results from brain-imaging studies both in healthy volunteers and in FGID patients. These new investigational techniques made identification of brain regions critically involved in processing of visceral afferent information possible. Differences in central nervous system response to visceral stimuli between controls and FGID patients will be highlighted. Third, we will address the issue of high comorbidity with psychiatric disorders. Some hypotheses about common pathophysiological substrates will be discussed.     

5-羟色胺7受体与功能性胃肠病

5-羟色胺及其受体广泛分布于胃肠道.5-羟色胺7受体有多种生理功能,对胃肠运动和感觉的调控有重要作用.对5-羟色胺7受体的分子结构、组织分布、生理功能已进行了相关研究,并日益受到重视.深入开展5-羟色胺7受体在消化道的生理功能和功能性胃肠病中的病理机制的研究,有助于进一步阐明功能性胃肠病的发病机制及开发新的有效治疗药物.     

Genetics of community-acquired pneumonia

The variable clinical presentation of community-acquired pneumonia (CAP) suggests a genetic predisposition. Specific mutations or polymorphisms in host response genes such as pattern recognition molecules (PRMs), inflammatory molecules, and the coagulation system are likely to play a role in this variable response to CAP. Mannose-binding lectin polymorphisms appear to play a more dominant role in CAP than other PRMs, such as the Toll-like receptors (TLRs). The role of tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) polymorphisms remain unclear despite extensive study whereas interleukin (IL)-10 and IL-1 receptor antagonist polymorphisms appear to play an important role in the anti-inflammatory response. Coagulation gene polymorphisms are likely important as well. The real value of these genetic studies in CAP and other severe infections will be when the management of an individual patient can be optimized by therapy based on the individual's genotype for molecules important in outcome.     

Control of human host immunity to mycobacteria

Infection with Mycobacterium tuberculosis results in disease in 5-10% of exposed individuals, whereas the remainder controls infection effectively. Similar inter-individual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis and other chronic infectious diseases, including viral infections. Although the outcome of infection is influenced by many factors, it is clear that genetic host factors play an important role in controlling disease susceptibility to intracellular pathogens. Knowledge of the genes involved and their downstream cellular pathways will provide new insights for the design of improved and rationalized strategies to enhance host-resistance, e.g. by vaccination. In addition, this knowledge will aid in identifying better biomarkers of protection and disease, which are essential tools for the monitoring of vaccination and other intervention trials. The recent identification of patients with deleterious mutations in genes that encode major proteins in the type-1 cytokine (IL-12/IL23-IFN-gamma) axis, that suffered from severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria (NTM) or M. bovis Bacille Calmette-Guerin (BCG)) or Salmonella species has revealed the major role of this system in innate and adaptive immunity to mycobacteria and salmonellae. Clinical tuberculosis has now been described in a number of patients with IL-12/IL23-IFN-gamma system defects. Moreover, unusual mycobacterial infections were reported in several patients with genetic defects in NEMO, a key regulatory molecule in the NFkappaB pathway. These new findings will be discussed since they provide further insights into the role of type-1 cytokines in immunity to mycobacteria, including M. tuberculosis.     

Contribution of ghrelin to functional gastrointestinal disorders' pathogenesis

Functional gastrointestinal disorders(FGID) are heterogeneous disorders with a variety of clinical manifestations, primarily defined by signs and symptoms rather than a definite underlying cause. Their pathophysiology remains obscure and, although it is expected to differ according to the specific FGID, disruptions in the brain-gut axis are now thought to be a common denominator in their pathogenesis. The hormone ghrelin is an important component of this axis,exerting a wide repertoire of physiological actions, including regulation of gastrointestinal motility and protection of mucosal tissue. Ghrelin's gene shows genetic polymorphism, while its protein product undergoes complex regulation and metabolism in the human body. Numerous studies have studied ghrelin's relation to the emergence of FGIDs, its potential value as an index of disease severity and as a predictive marker for symptom relief during attempted treatment. Despite the mixed results currently available in scientific literature, the plethora of statistically significant findings shows that disruptions in ghrelin genetics and expression are plausibly related to FGID pathogenesis. The aim of this paper is to review current literature studying these associations, in an effort to uncover certain patterns of alterations in both genetics and expression, which could delineate its true contribution to FGID emergence, either as a causative agent or as a pathogenetic intermediate.     

消化道错构瘤性息肉的最新研究进展

错构瘤息肉综合征（Hamartomatous Polyposis Syndromes, HPS）是一种罕见的遗传性疾病,HPS包括幼年性息肉综合征（juvenile polyposis syndrome, JPS）、PTEN错构瘤综合征(PTEN-hamartoma tumor syndrome)、Peutz-Jeghers综合征(Peutz-Jeghers syndrome, PJS)以及遗传性混合息肉综合征。HPS以消化道错构瘤息肉为特征,其临床表现包括黑便、直肠出血、贫血等消化道症状以及皮肤异常、发育迟缓等消化道外症状。HPS的诊断目前主要依靠患者的临床表现,但由于HPS十分罕见,并且临床表现复杂多样,HPS的诊断一直存在困难。近年来,得益于基因检测技术的快速发展,很多基因被证实与HPS的发生发展关系密切,这为HPS的监测、诊断和治疗带来了新的可能。本篇文章将从HPS的临床表现、基因表型、病理特征、治疗策略以及预防监测方面展开论述。     

The role of mannose-binding lectin in systemic lupus erythematosus

Susceptibility to systemic lupus erythematosus (SLE) is associated with genetic, hormonal, immunological, and environmental factors. Many genes have been related with the appearance of SLE, including several loci that code different complement components and their receptors. Some genetic deficiencies of complement molecules are strongly associated with SLE, probably because these deficiencies could cause decreased clearance of apoptotic cell material. As a consequence of the apoptotic material accumulation, high levels of autoantigens can be presented inappropriately to the immune system in an inflammatory context, resulting in an imbalance on the mechanisms of immunological tolerance, immune system activation, and autoantibody production. Recent studies proposed a role to the mannose-binding lectin (MBL) in the SLE physiopathogenesis. This protein activates the complement system, and the presence of several polymorphisms at the promoter and coding regions of the MBL-2 gene determines alterations at the plasma levels of MBL. Some of these polymorphisms have been associated with SLE susceptibility, as well as with clinical and laboratory typical features of this disease, cardiovascular events, and infections. Besides, it has been described that the presence of anti-MBL autoantibodies in sera of SLE patients can influence MBL plasma levels and its functional activity.     

Diet and functional gastrointestinal disorders: a population-based case-control study

BACKGROUND: Diet has been implicated to play a role in functional gastrointestinal disorders (FGID) in clinic-based studies. No population-based data comparing food and nutrient consumption between individuals with FGID and without gastrointestinal symptoms are available. OBJECTIVES: The purpose of this study was to compare the dietary consumption of specific food items and nutrients between individuals with FGID and without symptoms in a population-based sample. METHODS: A validated self-report Bowel Disease Questionnaire was mailed to an age- and gender-stratified random sample of participants aged 20-50 yr from Olmsted County, Minnesota. All patients who reported either FGID symptoms (irritable bowel or dyspepsia) or no gastrointestinal symptoms were invited to undergo a blinded physician interview and physical exam and to complete a validated Harvard Food Frequency Questionnaire. Wilcoxon rank sum tests and logistic regression were used for statistical analysis. RESULTS: In total, 222 of the 260 eligible (85%) subjects participated and 218 provided diet data: 99 were FGID cases and 119 were healthy controls. Cases and controls consumed similar number of servings per week of wheat-containing foods, lactose-containing foods, caffeinated drinks, and fructose-sweetened beverages. Cases were slightly more likely to consume >or=7 servings per week of norepinephrine- and epinephrine-containing foods (57%vs 45%, p= 0.10), but not serotonin- or tryptophan-containing foods. No differences were observed for amount of intake of calories, fiber, protein, iron, calcium, niacin, and vitamins C, D, E, niacin, B(1), B(2), B(6), and B(12). Cases reported consuming more fat (median, 33%vs 31%) and less carbohydrates (median, 49%vs 52%) than controls. CONCLUSIONS: No differences were seen in the consumption of frequently suspected "culprit" foods between community residents with and without FGID symptoms. While symptoms may be due to food sensitivity rather than altered diet composition, the role of fat and perhaps norepinephrine and epinephrine in foods in gut symptoms needs to be studied further.     

What Does Pain or Discomfort in Irritable Bowel Syndrome Mean?

Despite many studies on pain of functional gastrointestinal disorders (FGID), the pain mechanism of FGID is not well understood, and pain treatment of FGID is not established. Following our former functional dyspepsia (FD) study, we proposed two subgroups of patients with irritable bowel syndrome (IBS), pain and discomfort (not pain). The duration of disease of discomfort IBS patients was longer than that of pain IBS patients (P < 0.05) The rate of anxiety disorder of pain IBS patients tended to be higher than that of discomfort IBS patients (P = 0.07172). Fifteen (15.2%) of 99 pain IBS patients and 1 (3.4%) of 29 discomfort IBS patients overlapped FD (P < 0.1). We expected that a common psychosocial mechanism would influence both pain dyspepsia patients and pain IBS patients, however, there were some differences between these FGID patients with pain. Anxiety in IBS patients with lower gastrointestinal pain seems to be important in their treatment.     

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

BACKGROUND & AIMS: Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1 beta and its endogenous receptor antagonist are associated with risk of Helicobacter pylori-related gastric cancer. The aim of this study was to evaluate the role of proinflammatory cytokine gene polymorphisms in gastric and esophageal cancers defined by anatomic subsite. METHODS: We assessed polymorphisms of the IL-1 gene cluster and 4 other cytokine genes in a population-based case-control study of upper gastrointestinal cancers, including gastric cardia (n = 126) and noncardia adenocarcinoma (n = 188), esophageal squamous cell carcinoma (n = 53), and adenocarcinoma (n = 108), and frequency-matched controls (n = 212). ORs for the different cancers were computed from logistic regression models adjusted for potential confounding factors. RESULTS: Proinflammatory genotypes of tumor necrosis factor alpha and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1B(o) IL-1 receptor antagonist, tumor necrosis factor A, and IL-10 conferred greater risk, with ORs (and 95% confidence intervals) of 2.8 (1.6-5.1) for one, 5.4 (2.7-10.6) for 2, and 27.3 (7.4-99.8) for 3 or 4 high-risk genotypes. In contrast, these polymorphisms were not consistently related to the risks of esophageal or gastric cardia cancers. Polymorphisms in IL-4 and IL-6 were not associated with any of the cancers studied. CONCLUSIONS: A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.     

The role of genetic factors in development of atrial fibrillation

The review is devoted to problems of pathogenesis of atrial fibrillation and role of genetic factors in its development. Significance of genetic factors for origination of atrial fibrillation has been proved by aggregation of the disease in families. This review contains consideration of main candidate genes possibly related to development of the disease and detailed contemplation of value of polymorphisms of potassium and other ion channels. Data on candidate genes common for arterial hypertension and atrial fibrillation which encode components of renin-angiotensin system, NO-synthase, beta-adrenoreceptors are also presented. Probable role of genes encoding components of synthesis and transport of lipids, markers and mediators of inflammation is considered as well.     

Post-cholecystectomy symptoms were caused by persistence of a functional gastrointestinal disorder

AIM: To classify gallstone disease as a basis for assessment of post-cholecystectomy symptoms.METHODS: One hundred and fifty three patients with a clinical and ultrasonographic diagnosis of gallstones filled out a structured questionnaire on abdominal pain symptoms and functional gastrointestinal disorder (FGID) before and at six months after cholecystectomy. Symptom frequency groups (SFG) were categorized according to frequency of pain attacks. According to certain pain characteristics in gallstone patients, a gallstone symptom score was accorded on a scale from one to ten. A visual analogue scale was used to quantify pain. Operative specimens were examined for size and magnitude of stone contents as well as presence of bacteria. Follow-up took place after six months with either a consultation or via a mailed questionnaire. Results were compared with those obtained pre-operatively to describe and analyze symptomatic outcome.RESULTS: SFG groups were categorized as severe (24.2%), moderate (38.6%), and mild (22.2%) attack frequency, and a chronic pain condition (15%). Pain was cured or improved in about 90% of patients and two-thirds of patients obtained complete symptom relief. Patients with the most frequent pain episodes were less likely to obtain symptom relief. FGID was present in 88% of patients pre-operatively and in 57% post-operatively (P = 0.244). Those that became asymptomatic or improved with regard to pain also had most relief from FGID (P = 0.001). No pre-operative FGID meant almost complete cure.CONCLUSION: Only one third of patients with FGID experienced postoperative relief, indicating that FGID was a dominant cause of post-cholecystectomy symptoms.