Functional Gut Disorders Research Articles

Evaluation of Lower Functional Gut Disorders

There is an element of the art of medicine in the diagnosis of functional lower gut disorders. Functional disorders are believed to be problems of normal gut function; by definition, they imply or require a lack of organic disease. With advanced understanding and reliable definitions of irritable bowel syndrome (IBS) in particular, the concept that these disorders are purely a diagnosis of exclusion is outdated. Their cardinal symptoms, however, such as abdominal pain, diarrhea or constipation, have huge lists of potential organic causes. The key is to know how much investigation is needed before making the diagnosis. Many factors will influence this process, from both the patient and practitioner viewpoints.

Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors

Histamine is a major mast cell mediator of immunoneural signalling in the gut and mast cells play a role in the pathophysiology of functional and inflammatory bowel diseases. Histamine receptors are therefore promising drug targets to treat gut disorders. We aimed to study the so far unknown effect of histamine on neural activity in the human enteric nervous system (ENS) and to identify the pharmacology of histamine response. We used fast imaging techniques in combination with the potentiometric dye di-8-ANEPPS to monitor directly membrane potential changes and thereby neuronal excitability in the human submucous plexus from surgical specimens of 110 patients (2137 neurones, 273 ganglia). Local microejection of histamine resulted in action potential discharge in 37% of neurones. This excitatory effect was mimicked by the H(1) agonist HTMT-dimaleat, H(2) agonist dimaprit, H(3) agonist (R)-(-)-alpha-methylhistamine and H(4) agonist 4-methylhistamine. The excitatory actions of the agonists were specifically and selectively blocked by the H(1), H(2), H(3) or H(4) receptor antagonists pyrilamine, ranitidine, clobenpropit or J1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120), respectively. Clobenproprit reduced the excitatory response to histamine. Unlike in the guinea-pig ENS (R)-(-)-alpha-methylhistamine had no presynaptic actions in human submucous plexus. Application of agonists revealed receptor clustering which was as follows: 29% H(1)/H(3), 27% H(2), 20% H(1)/H(2)/H(3), 10% H(3), 7% H(1)/H(2) and 7% H(2)/H(3). Histamine excites human enteric neurones and this effect involves all four histamine receptors; most striking was the identification of an excitatory H(3) mediated component and the discovery of H(4) mediated neuronal excitation. These data may form the basis of identification of new targets to treat inflammatory and functional gut disorders.

Intestinal gas in plain abdominal radiographs does not correlate with symptoms after lactulose challenge

Intestinal gas production and abdominal discomfort can be triggered by the ingestion of carbohydrates such as lactulose. Using plain abdominal radiographs, we studied whether subjective complaints after a lactulose breath test would be quantitatively related to intestinal gas volumes. Abdominal symptoms after the breath test were quantified by a written questionnaire and gas volumes were scored in plain abdominal radiographs, in 50 consecutive patients with unexplained, irritable bowel syndrome-like symptoms. Breath excretion of hydrogen and methane was determined in all patients. Forty-two (84%) of the patients claimed that their post-breath test symptoms were a true replicate of their customary discomfort. Total symptom scores (sum of scores for pain/discomfort, borborygmi, bloating, diarrhea, constipation) or any specific symptom score were not significantly correlated to gas volume scores (r=-0.04; P=0.8 for total symptom score). The 13 (26%) methane producers had significantly higher mean gas volume scores compared with nonproducers (0.38 vs. 0.24; P=0.0008), but fewer symptoms (total symptom score 11.9 vs. 18.2; P=0.17). Intestinal gas volume, as scored in plain abdominal radiographs, is not correlated with abdominal discomfort after lactulose challenge. Intestinal gas may not be the major cause of abdominal discomfort following carbohydrate ingestion in patients with functional gut disorders.

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.

Review article: fructose malabsorption and the bigger picture

Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine. The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking. It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.

Postinfectious irritable bowel syndrome may occur after non‐gastrointestinal and intestinal infection

Postinfectious functional gastrointestinal disorders (FGIDs) may not be specific to gastroenteritis. This pilot study aimed to ascertain the 3- and 6-month incidence of functional gut disorders in people with non-gastrointestinal (GI) infection, gastroenteritis and healthy controls. This was a prospective study of three cohorts recruited from hospital (non-GI infections) and the community (others). FGIDs were diagnosed using self-completed Rome II modular questionnaires administered at baseline, 3 and 6 months. Thirty-six subjects with non-GI infection, 219 healthy subjects and 108 with bacterial gastroenteritis participated. No difference in incidence of FGID was detected between the GI and non-GI infection cohorts. Any FGID was more frequent in people who had a non-GI infection than in controls at both 3 [odds ratio: 4.34 (95% CI: 3.60-16.45)] and 6 months [4.76 (4.42-27.92)]. Irritable bowel syndrome (IBS) alone was more frequent in people with non-GI infections than in controls at 3 months (6.12 [1.30-29.12]) but did not quite reach statistical significance at 6 months (4.58 [0.79-26.46]). Our findings were unexpected. Postinfectious FGIDs may be related to non-GI and GI infection, although not all potential biases were controlled in study design. Further studies need to explore these preliminary findings and, if confirmed, the underlying mechanisms.

Functional Bowel Disorders

Employing a consensus approach, our working team critically considered the available evidence and multinational expert criticism, revised the Rome II diagnostic criteria for the functional bowel disorders, and updated diagnosis and treatment recommendations. Diagnosis of a functional bowel disorder (FBD) requires characteristic symptoms during the last 3 months and onset > or =6 months ago. Alarm symptoms suggest the possibility of structural disease, but do not necessarily negate a diagnosis of an FBD. Irritable bowel syndrome (IBS), functional bloating, functional constipation, and functional diarrhea are best identified by symptom-based approaches. Subtyping of IBS is controversial, and we suggest it be based on stool form, which can be aided by use of the Bristol Stool Form Scale. Diagnostic testing should be guided by the patient's age, primary symptom characteristics, and other clinical and laboratory features. Treatment of FBDs is based on an individualized evaluation, explanation, and reassurance. Alterations in diet, drug treatment aimed at predominant symptoms, and psychotherapy may be beneficial.

Development of irritable bowel syndrome may be associated with a parental history of bowel problems

Sirs, We read with special interest the review article by Kang1 on the cross-cultural epidemiological comparisons for irritable bowel syndrome (IBS). The author pointed out that there was a gender difference in the prevalence of IBS, health care utilization and stool frequency among different ethnic and/or cultural populations. Unfortunately, data from Japan were not cited on the review. We have reported the epidemiological data for IBS using Rome II diagnostic criteria2 from 417 Japanese subjects in the community.3 In this study, 14.2% (15.5% of females and 12.9% of males) were diagnosed as IBS and there was no difference in gender ratio. Only 22.0% of subjects with IBS had met a doctor for IBS-related symptoms.2 Our results for Japanese supported the statement of the review article in which female predominance was not seen using Rome I or II criteria in eastern population.1 We were also concerned about another factor affecting prevalence of IBS among the countries. A total of 417 subjects from the community sample in Sendai, Japan, and 56 patients with IBS in the gastrointestine (GI) clinic were asked whether their parents had a history of chronic or recurring abdominal pain/discomfort with abnormal bowel habit (parental history). Significantly more IBS patients (33.9%) and IBS nonconsulters (26.1%) had a parental history, compared to control subjects who were not diagnosed as IBS in the community (12.6%). The parental history was an independent risk factor for IBS diagnosis after adjusting for trait anxiety, depression and perceived stress. These results supported the results from the twin study in the USA4 and Australia.5 Furthermore, IBS patients with parental history had significantly higher scores of major symptoms for IBS (7-point scales); abdominal pain, abdominal discomfort, changes in bowel movement with abdominal pain/discomfort and softer stools with abdominal pain/discomfort than those without the history. Our results suggest that the parental history of bowel problems may affect the severity of IBS symptoms. Thus, this aggregation of IBS within families – namely, genetics and social learning through modelling the illness behaviour of parents – may be one of the risk factors for development and reinforcement of IBS symptoms. In fact, it has been reported that children of mothers with IBS have more somatic as well as GI symptoms, disability days and clinical visits.6 The recent genetic studies on the serotonin transporter (SERT) gene-linked polymorphic region (5-HTTLPR) revealed that IBS is not equivalent to SERT dysfunction but SERT dysfunction may contribute to behavioural and functional gut disorders.7 In the further research on epidemiological studies for IBS, such genetic and environmental (e.g. diet, belief and social habit) factors should be taken into account.

Brain Response to Visceral Aversive Conditioning: A Functional Magnetic Resonance Imaging Study

Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.

Intestinal perception: mechanisms and assessment

Physiological stimuli in the gut induce regulatory reflexes to accomplish the digestive process, but are normally not perceived. However, under some circumstances, gut stimuli may activate perception pathways and induce conscious sensations. Experimental evidence gathered during the past decade suggests that patients with functional gut disorders and unexplained abdominal symptoms may have a sensory dysfunction of the gut, so that physiological stimuli would induce symptoms. Assessment of visceral sensitivity is still poorly developed, but in analogy to somatosensory testing, differential stimulation of visceral afferents may be achieved by a combination of stimulation techniques, which may help to characterize sensory dysfunctions. Visceral afferent input is modulated by a series of mechanisms at different levels of the brain-gut axis, and conceivably, a dysfunction of these regulatory mechanisms could cause hyperalgesia. The sensory dysfunction in functional patients seems to be associated with altered reflex activity, and both mechanisms may interact to produce the symptoms. Evidence of a gut sensory-reflex dysfunction as a common pathophysiological mechanism in different functional gastrointestinal disorders would suggest that they are different forms of the same process, and that the clinical manifestations depend on the specific pathways affected.

Opioids and the gut: pharmacology and current clinical experience.

This article reviews the pharmacology and physiology of opiate receptors and the current and potential uses of opioid agonists and antagonists in clinical gastroenterology. Mu-receptors are involved in motor and sensory functions, and their modulation is established for treatment of diarrhea. Mu-antagonists have potential to reverse endogenous (e.g., postoperative ileus) or iatrogenic dysmotility (e.g., opioid bowel dysfunction). Modulation of the function of kappa-receptors may be a novel approach to control visceral pain in functional gut disorders. Results of formal testing of novel opioid modulators are keenly awaited.

Chronic diarrhea: a review on pathophysiology and management for the clinical gastroenterologist

The objectives of this article are to provide a review for general gastroenterologists of the fluid fluxes in the normal human gut and the pathophysiological mechanisms that lead to chronic diarrhea, and to propose a practical approach to management. Most clinical disorders presenting as chronic diarrhea involve more than one physiological mechanism. The role of motility and functional disorders that result in chronic diarrhea will be emphasized, given the high prevalence of these conditions. There is a growing understanding of the roles of neurotransmitters and hormones in the development of functional gut disorders and intestinal motility and secretion; modulation of these mechanisms also provides a means for novel therapy.

Gastrointestinal motility and the brain‐gut axis

The role of the brain‐gut axis in gastrointestinal motility is discussed according to the specific organs of the gastrointestinal tract. Not only clinical studies but basic animal research are reviewed. Although the mechanism of functional gut disorders remains to be clarified, recent data suggest that there is evidence that the brain‐gut axis has significant effects on gastrointestinal motility. The major role of endoscopy in the diagnosis of functional gastrointestinal disorders is to exclude organic gastrointestinal disorders. In the esophagus, the lower esophageal sphincter and a gamma‐aminobutyric acid B mechanism are considered to play important roles in gastroesophageal reflux disease. In the stomach, corticotropin‐releasing factor, neuropeptide Y and other substances might be involved in the pathogenesis of non‐ulcer dyspepsia. In the small intestine, corticotropin‐releasing factor, gamma‐aminobutyric acid B and other substances are considered to modulate intestinal transit via central mechanisms. In the colon, it is known that psychiatric factors are related to the onset and clinical course of irritable bowel syndrome. Serotonin, corticotropin‐releasing factor, gamma‐aminobutyric acid, orphanin FQ and neuropeptide Y have been reported as putative neurotransmitters. More efforts in basic science studies and animal and human studies of physiology of the gastointestinal tract are still required. These efforts will elucidate further mechanisms to clarify the etiology of motility disorders and encourage the investigation of new therapies in this field.

Gastrointestinal perception: pathophysiological implications.

Physiological gut stimuli during the digestive process are not normally perceived. However, gut stimuli activate a variety of afferent pathways and in some circumstances may induce conscious sensations. Experimental evidence gathered during the past decade suggests that patients with functional gut disorders and unexplained abdominal symptoms may have a sensory dysfunction of the gut, so that physiological stimuli would induce symptoms. Assessment of visceral sensitivity is still poorly developed, but in analogy to somatosensory testing, differential stimulation of visceral afferents may be achieved by a combination of stimulation techniques, which may help to characterize sensory dysfunctions. Visceral afferent input is modulated by a series of mechanisms at different levels of the brain gut axis, and conceivably, a dysfunction of these regulatory mechanisms could cause hyperalgesia. The sensory dysfunction in functional patients seems associated to altered reflex activity, and both mechanisms may interact to produce the symptoms. Evidence of a gut sensory-reflex dysfunction as a common pathophysiological mechanism in different functional gastrointestinal disorders, would suggest that they are different forms of the same process, and that the clinical manifestations depend on the specific pathways affected.

Relationship between psychological state and level of activity of extrinsic gut innervation in patients with a functional gut disorder

BACKGROUNDAnxiety and depression are known to be associated with alterations in central autonomic activity, and this may manifest as a functional gut disturbance. However, the final expression of motility disturbance...

Drug treatment options for irritable bowel syndrome: managing for success.

Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.

Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function.

Visceral sensation and motility are important in functional gut disorders and are partly controlled by adrenergic innervation. To characterize the alpha2-adrenergic control of motor and sensory function of descending colon and rectum. In 32 healthy volunteers, we assessed compliance, fasting and postprandial tone, and sensations of gas, urgency and pain during phasic distentions. Each subject received one agent at clinically approved doses: clonidine (0.05, 0.1, 0.2 or 0.3 mg p.o. ); or the alpha2 antagonist yohimbine (0.0125 mg, 0.05 mg, 0.125 mg or 0.2 mg intravenously and infusion over 2.5 h). Clonidine increased colonic and rectal compliance, and reduced tone, pain, gas sensation and rectal urgency. Clonidine showed large pairwise differences in sensation and motility between 0.05 and 0.1 mg doses, which did not interfere with the colon's motor response to feeding. Conversely, yohimbine dose-dependently altered the compliance curve, increased tone and sensations of gas, pain and urgency. Drug effects in the colon were more marked at low distensions; alpha2 modulation of rectal sensation was observed at all levels of distension. alpha2-adrenergic mechanisms modulate colorectal sensations and motility; at doses as low as 0.05 mg, clonidine reduced colorectal sensation while the tone response to feeding was preserved. These studies provide insight into the potential use of alpha2 agents in disease states.

Duodenal acid infusion causes esophageal hypersensitivity: Role of central sensitization in functional gut disorders

Duodenal acid infusion causes esophageal hypersensitivity: Role of central sensitization in functional gut disorders

Review article: cardiac adverse effects of gastrointestinal prokinetics.

Gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recently, several studies have shown that cisapride (a partial 5-HT4 receptor agonist) can induce dose-dependent cardiac adverse effects, including lengthening of the electrocardiographic QT interval, syncopal episodes and ventricular dysrhythmias. Until recently, it was not clear whether these effects were dependent on 5-HT4 receptor activation or related to peculiar characteristics in the molecular structure of single agents within the benzamide class. Experimental evidence now favours the second hypothesis: cisapride possesses Class III antiarrhythmic properties and prolongs the action potential duration through blockade of distinct voltage-dependent K+ channels, thus delaying cardiac repolarization and prolonging the QT interval. Patients at risk of cardiac adverse effects are children, subjects with idiopathic, congenital or acquired long QT syndrome and, in particular, those receiving concomitant medication with Class III antiarrhythmic agents, some H1-receptor antagonists (e.g. terfenadine), or drugs such as azole antifungals (e.g. ketoconazole, itraconazole, miconazole and fluconazole) and macrolide antibacterials (e.g. erythromycin, clarithrod-mycin and troleandomycin), which can inhibit cisapride metabolism by interfering with the CYP3A4 isoenzyme.

Rectogastric reflex-induced gastric hypersensitivity to mechanical distention and meal ingestion: A possible model for dyspepsia with functional lower gut disorders

Rectogastric reflex-induced gastric hypersensitivity to mechanical distention and meal ingestion: A possible model for dyspepsia with functional lower gut disorders