Evolving concepts in functional gastrointestinal disorders: promising directions for novel pharmaceutical treatments

In recent years there has been an increasing appreciation of the complexity of functional gastrointestinal disorders. These represent a spectrum of conditions which may affect any part of the gastrointestinal tract in which there appears to be dysregulation of visceral function and afferent sensation and a strong association with emotional factors and stress. There is a clear psychological dimension, with up to 60% of irritable bowel syndrome (IBS) patients reported to have psychological co-morbidities and altered pain perception is also common in comparison with control populations. The role of the enteric nervous system, the sensory pathways and the brain as well as the influence of the latter on sympathetic and parasympathetic outflow have likewise attracted increasing interest and have led to exciting new methods to study their complex interactions. The concept of low-grade inflammation, such as might occur after infection, acting as a trigger for neuromuscular dysfunction has also led to the broad integrative hypotheses that help to explain the biopsychosocial dimensions seen in functional gastrointestinal disease. The multi-component model places a major emphasis on neurogastroenterology and enteric and neuro-immune interactions where new approaches to pharmacotherapy lie. Drugs may affect motility, visceral sensation and other aspects of gut function such as secretion or absorption. More particularly, however, has been the search for and attempts to influence important mediators of these primary gut functions. Such targets include serotonin and selected 5-HT receptors, which are involved in gut motility, visceral sensation and other aspects of gut function, CCK receptors which are involved in the mediation of pain in the gut and nociception in the CNS, opioid receptors involved in pain in the brain, spinal cord and periphery, muscarinic M3-receptors, substance P and neurokinin A and B receptors which are involved in motor adaptation and pain transmission in association with inflammation, gabba receptors involved in nociception and cannabinoid receptors which are involved in the control of acetyl choline release in the gut. With a better understanding of the structures and pathways involved in visceral perception and hyperalgesia, in the CNS, spinal cord and the gut and new pharmacological tools we will be better able to elucidate the neuropharmacology of visceral perception and its relationship to gut dysfunction. It is likely that there will be multiple therapeutic options based on the spectrum of abnormalities capable of causing the spectrum of symptoms of functional gastrointestinal disorders in any individual patient.     

Functional dyspepsia： Are psychosocial factors of relevance？

The pathogenesis of Functional Dyspepsia (FD) remains unclear, appears diverse and is thus inadequately understood. Akin to other functional gastrointestinal disorders, research has demonstrated an association between this common diagnosis and psychosocial factors and psychiatric morbidity. Conceptualising the relevance of these factors within the syndrome of FD requires application of the biopsychosocial model of disease. Using this paradigm, dysregulation of the reciprocal communication between the brain and the gut is central to symptom generation, interpretation and exacerbation. Appreciation and understanding of the neurobiological correlates of various psychological states is also relevant. The view that psychosocial factors exert their influence in FD predominantly through motivation of health care seeking also persists. This appears too one-dimensional an assertion in light of the evidence available supporting a more intrinsic aetiological link. Evolving understanding of pathogenic mechanisms and the heterogeneous nature of the syndrome will facilitate effective management. Co-morbid psychiatric illness warrants treatment with conventional therapies. Acknowledging the relevance of psychosocial variables in FD, the degree of which is subject to variation, has implications for assessment and management. Available evidence suggests psychological therapies may benefit FD patients particularly those with chronic symptoms. The rationale for use of psychotropic medications in FD is apparent but the evidence base to support the use of antidepressant pharmacotherapy is to date limited.     

Fundamentals of neurogastroenterology: basic science

The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs.     

New technologies to investigate the brain-gut axis

Functional gastrointestinal disorders are commonly encountered in clinical practice, and pain is their commonest presenting symptom. In addition, patients with these disorders often demonstrate a heightened sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity that is likely to be important in their pathophysiology. Knowledge of how the brain processes sensory information from visceral structures is still in its infancy. However, our understanding has been propelled by technological imaging advances such as functional Magnetic Resonance Imaging, Positron Emission Tomography, Magnetoencephalography, and Electroencephalography （EEG）. Numerous human studies have non-invasively demonstrated the complexity involved in functional pain processing, and highlighted a number of subcortical and cortical regions involved. This review will focus on the neurophysiological pathways （primary afferents, spinal and supraspinal transmission）, brainimaging techniques and the influence of endogenous and psychological processes in healthy controls and patients suffering from functional gastrointestinal disorders. Special attention will be paid to the newer EEG source analysis techniques. Understanding the phenotypic differences that determine an individual＇s response to injurious stimuli could be the key to understanding why some patients develop pain and hyperalgesia in response to inflammation/injury while others do not. For future studies, an integrated approach is required incorporating an individual＇s psychological, autonomic, neuroendocrine, neurophysiological, and genetic profile to define phenotypic traits that may be at greater risk of developing sensitised states in response to gut inflammation or injury.     

Cerebral processing of auditory stimuli in patients with irritable bowel syndrome

AIM: To determine by brain functional magnetic resonance imaging (fMRI) whether cerebral processing of non-visceral stimuli is altered in irritable bowel syndrome (IBS) patients compared with healthy subjects. To circumvent spinal viscerosomatic convergence mechanisms, we used auditory stimulation, and to identify a possible influence of psychological factors the stimuli differed in their emotional quality. METHODS: In 8 IBS patients and 8 controls, fMRI measurements were performed using a block design of 4 auditory stimuli of different emotional quality (pleasant sounds of chimes, unpleasant peep (2000 Hz), neutral words, and emotional words). A gradient echo T2*-weighted sequence was used for the functional scans. Statistical maps were constructed using the general linear model. RESULTS: To emotional auditory stimuli, IBS patients relative to controls responded with stronger deactiva-tions in a greater variety of emotional processing regions, while the response patterns, unlike in controls, did not differentiate between distressing or pleasant sounds. To neutral auditory stimuli, by contrast, only IBS patients responded with large significant activations. CONCLUSION: Altered cerebral response patterns to auditory stimuli in emotional stimulus-processing regions suggest that altered sensory processing in IBS may not be specific for visceral sensation, but might reflect generalized changes in emotional sensitivity and affective reactivity, possibly associated with the psychological comorbidity often found in IBS patients.     

Cognitive behavioral approach to understanding irritable bowel syndrome

Irritable bowel syndrome(IBS)is considered a biopsychosocial disorder,whose onset and precipitation are a consequence of interaction among multiple factors which include motility disturbances,abnormalities of gastrointestinal sensation,gut inflammation and infection,altered processing of afferent sensory information,psychological distress,and affective disturbances.Several models have been proposed in order to describe and explain IBS,each of them focusing on specific aspects or mechanisms of the disorder.This review attempts to present and discuss different determinants of IBS and its symptoms,from a cognitive behavioral therapy framework,distinguishing between the developmental predispositions and precipitants of the disorder,and its perpetuating cognitive,behavioral,affective and physiological factors.The main focus in understanding IBS will be placed on the numerouspsychosocial factors,such as personality traits,early experiences,affective disturbances,altered attention and cognitions,avoidance behavior,stress,coping and social support.In conclusion,a symptom perpetuation model is proposed.     

Altered neuro-endocrine–immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model

The interaction between the brain and the gut as a pathological mechanism of functional gastrointestinal disorders has been recently recognized in the pathophysiology of the irritable bowel syndrome. Communication between central nervous system and enteric nervous system is two-directional: the brain can influence the function of the enteric nervous system and the gut can influence the brain via vagal and sympathetic afferents. In patients with irritable bowel syndrome, symptoms may be caused by alterations either primarily in the central nervous system (top-down model), or in the gut (bottom-up model), or in a combination of both. The brain–gut axis may be stimulated by various stressors either directed to the central nervous system (exteroreceptive stress) or to the gut (interoceptive stress). Particularly, clinical evidence suggest that in complex and multifactorial diseases such as irritable bowel syndrome, psychological disorders represent significant factors in the pathogenesis and course of the syndrome. Neuroimaging techniques have shown functional differences between central process in healthy subjects and patients with irritable bowel syndrome. Moreover, a high prevalence of psychological/psychiatric disorders have been reported in IBS patients compared to controls. Several data also suggest an alteration of neuro-endocrine and autonomic output to the periphery in these patients. This review will examine and discuss the complex interplay of neuro-endocrine–immune pathways, closely associated with neuropsychiatric disorders.     

Is there a causal link between psychological disorders and functional gastrointestinal disorders?

Psychological disorders, most notably anxiety and depressive disorders, somatization and catastrophizing, often precede or exacerbate functional gastrointestinal disorder (FGID) symptoms and correlate with symptom severity and health outcomes. Mounting evidence shows that psychological distress alters gut immunity, in particular mast cell activation, leading to a potentiation of sensory nerves and aberrant visceral pain perception. On the other hand, psychological stressors modulate the processing of incoming sensory signals by the brain, thereby contributing to FGID symptom development. A better understanding of the molecular mechanisms underlying stress-induced changes in the immune system or brain processing is crucial for the development of novel beneficial therapeutic strategies.     

磁共振成像技术在分析肠易激综合征患者脑功能中的应用

目的应用脑部功能性磁共振成像(fMRI)技术探究肠易激综合征(IBS)的病理生理机制中大脑功能区变化,并评价精神心理因素在其发病中的意义。方法收集31例IBS患者和20位正常对照者在不同容量直肠气囊刺激下获得的fMRI图像,并应用医院焦虑抑郁量表(HADS)进行精神心理因素评分,对结果进行统计学分析。结果 IBS患者的fMRI图像在不同容量地刺激下存在差异,并且脑部激活区域随着直肠气囊扩张容量的增加而不断扩大,激活区域的显示也越来越明显;而在正常对照者中的差异无统计学意义。结论 IBS患者的内脏敏感性与大脑皮质的活动性相关,但需要更大的样本量验证。而IBS患者内脏敏感性的程度是否与精神心理因素有必然的联系,还有待进一步的研究及验证。     

Visceral hypersensitivity in irritable bowel syndrome

Altered central processing, abnormal gastrointestinal motility and visceral hypersensitivity may be possible major pathophysiology of irritable bowel syndrome (IBS). These factors affect each other and are probably associated with development of IBS symptoms. It has been confirmed that lower pain threshold to colonic distention was observed in most of patients with IBS than healthy subjects. We have investigated pain perception of the descending colon among different subtypes of IBS. There was no difference in pain threshold to colonic distention between IBS with diarrhea and constipation. Some brain regions such as the anterior cingulate cortex (ACC) may play a major role for generating pain and/or pain-related emotion in humans. IBS patients showed greater activation in the perigenual ACC during painful rectal distention compared with healthy subjects. Inflammation, stress and the combination of both stimuli can induce significant increase in visceral sensitivity in animal models. Serotonin (5-HT) can modulate visceral perception. It has been thought that 5-HT(3) receptors may play an important role for conveying visceral sensation from the gut. Corticotropin-releasing hormone (CRH) may also modulate visceral pain hypersensitivity in IBS. CRH receptor-1 antagonist significantly prevented an increase in gut sensitivity in rats. It has been demonstrated that non-specific CRH receptor antagonist α-helical CRH significantly reduced abdominal pain score during gut stimulus in patients with IBS. In conclusion, visceral hypersensitivity is common in IBS patients and probably plays a major role in development of the symptoms and both central and peripheral factors may enhance the pain sensitivity.     

功能性消化不良中的幽门螺杆菌感染与精神心理因素

功能性消化不良(FD)是一类胃肠运动和内脏感觉异常性疾病,目前倾向于认为其是多因素所致的综合征。幽门螺杆菌感染可导致FD的形成;FD患者不同的表现可引起不同程度的精神心理改变,而精神心理疾病亦可引起FD。本文就FD中幽门螺杆菌感染与精神心理因素的研究进展作一综述。     

功能性消化不良研究的新观念

功能性消化不良是一种常见的功能性胃肠道疾病,造成功能性消化不良的病因目前尚未完全阐明,本文对感染因素、精神心理因素、遗传易感性和胃肠激素与功能性消化不良发病的关系做一综述。     

Functional gastrointestinal disorders and gut-brain axis: What does the future hold?

Despite their high prevalence, lack of understanding of the exact pathophysiology of the functional gastrointestinal disorders has restricted us to symptomatic diagnostic tools and therapies. Complex mechanisms underlying the disturbances in the bidirectional communication between the gastrointestinal tract and the brain have a vital role in the pathogenesis and are key to our understanding of the disease phenomenon. Although we have come a long way in our understanding of these complex disorders with the help of studies on animals especially rodents, there need to be more studies in humans, especially to identify the therapeutic targets. This review study looks at the anatomical features of the gut-brain axis in order to discuss the different factors and underlying molecular mechanisms that may have a role in the pathogenesis of functional gastrointestinal disorders. These molecules and their receptors can be targeted in future for further studies and possible therapeutic interventions. The article also discusses the potential role of artificial intelligence and machine learning and its possible role in our understanding of these scientifically challenging disorders.     

Conscious perception of gut activity

Regional disturbances of motility in the gastrointestinal tract have been proposed as likely pathogenetic mechanisms for a number of functional gut diseases. However, not all patients with functional gut symptoms exhibit detectable dysmotility. Some investigators have therefore postulated that visceral hypersensitivity to regional luminal stimuli underlies symptoms. The results of emerging research suggest that a pathogenic role of visceral hypersensitivity in functional gut disorders is plausible but that the issue is extremely complex, in view of the interactions between neural control of gut motility, conscious perception of gut signals, and modulation at spinal and brain centers.     

Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation

Asthma, like many inflammatory disorders, is affected by psychological stress, suggesting that reciprocal modulation may occur between peripheral factors regulating inflammation and central neural circuitry underlying emotion and stress reactivity. Despite suggestions that emotional factors may modulate processes of inflammation in asthma and, conversely, that peripheral inflammatory signals influence the brain, the neural circuitry involved remains elusive. Here we show, using functional magnetic resonance imaging, that activity in the anterior cingulate cortex and insula to asthma-relevant emotional, compared with valence-neutral stimuli, is associated with markers of inflammation and airway obstruction in asthmatic subjects exposed to antigen. This activation accounts for > or =40% of the variance in the peripheral markers and suggests a neural basis for emotion-induced modulation of airway disease in asthma. The anterior cingulate cortex and insula have been implicated in the affective evaluation of sensory stimulation, regulation of homeostatic responses, and visceral perception. In individuals with asthma and other stress-related conditions, these brain regions may be hyperresponsive to disease-specific emotional and afferent physiological signals, which may contribute to the dysregulation of peripheral processes, such as inflammation.     

Funktionelle Dyspepsie

In patients presenting with symptoms centered in the upper abdomen, functional dyspepsia (FD) is the most frequent diagnosis after exclusion of specific organic diseases by adequate diagnosis including endoscopy. FD is included in the overall clinical picture of functional gastrointestinal disease and is associated with one-third or more of patients with irritable bowel syndrome. The new Rome IV criteria propose two distinct entities of FD: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) according to predominant symptom grouping. In addition, the two entities frequently overlap with other functional gastrointestinal diseases. Important progress has been made in our understanding of underlying etiologies and mechanisms in FD. They include—beyond established disorders in gastroduodenal motility and visceral sensitivity—environmental and dietary factors, exposure to infectious and noninfectious inflammatory reactions, and to a minor extent also genetic factors. An essential aspect addresses the brain–gut axis and a new dimension is introduced by its interaction with the gastrointestinal microbiome. These advances will need to be taken into account in our diagnostic approach in the search for distinct structural and biochemical abnormalities that are not considered in routine clinical practice yet. Our advanced understanding of mechanisms will also be reflected by future developments of new targeted medications. Recommendations for lifestyle, nutrition, and medications including acid inhibitors, prokinetics, phytopharmaceuticals, antidepressants, and empirically microbiota modulators for the treatment of FD are currently available.     

Mechanisms Underlying Visceral Hypersensitivity in Irritable Bowel Syndrome

Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%–90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms.     

Cognitive modulation of the cerebral processing of human oesophageal sensation using functional magnetic resonance imaging

BACKGROUND: While cortical processing of visceral sensation has been described, the role that cognitive factors play in modulating this processing remains unclear. AIM: To investigate how selective and divided attention modulate the cerebral processing of oesophageal sensation. METHODS: In seven healthy volunteers (six males, mean age 33 years; ranging from 24 to 41 years old) from the general community, phasic visual and oesophageal (non-painful balloon distension) stimuli were presented simultaneously. During the selective attention task, subjects were instructed to press a button either to a change in frequency of oesophageal or visual stimuli. During a divided attention task, subjects received simultaneous visual and oesophageal stimuli and were instructed to press a button in response to a change in frequency of both stimuli. RESULTS: Selectively focussing attention on oesophageal stimuli activated the visceral sensory and cognitive neural networks (primary and secondary sensory cortices and anterior cingulate cortex respectively) while selective attention to visual stimuli primarily activated the visual cortex. When attention was divided between the two sensory modalities, more brain regions in the sensory and cognitive domains were utilised to process oesophageal stimuli in comparison to those employed to process visual stimuli (p=0.003). CONCLUSION: Selective and divided attention to visceral stimuli recruits more neural resources in both the sensory and cognitive domains than attention to visual stimuli. We provide neurobiological evidence that demonstrates the biological importance placed on visceral sensations and demonstrate the influence of cognitive factors such as attention on the cerebral processing of visceral sensation.     

The microbiota-gut-brain axis in functional gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs) are highly prevalent and pose a significant burden on health care and society, and impact patients’ quality of life. FGIDs comprise a heterogeneous group of disorders, with unclear underlying pathophysiology. They are considered to result from the interaction of altered gut physiology and psychological factors via the gut-brain axis, where brain and gut symptoms are reciprocally influencing each other’s expression. Intestinal microbiota, as a part of the gut-brain axis, plays a central role in FGIDs. Patients with Irritable Bowel Syndrome, a prototype of FGIDs, display altered composition of the gut microbiota compared with healthy controls and benefit, at the gastrointestinal and psychological levels, from the use of probiotics and antibiotics. This review aims to recapitulate the available literature on FGIDs and microbiota-gut-brain axis.     

Cerebral cortical registration of subliminal visceral stimulation

BACKGROUND & AIMS: Although brain registration of subliminal somatic stimulations such as masked visual stimuli and their influence on electrical and hemodynamic measures of cerebral activity have been reported previously, there have been no reports on cerebral cortical registration of subliminal visceral stimulation. Because studies evaluating the consequences of subliminal somatic stimulation have shown that subliminal stimulation can effect behavior, it is conceivable that such subliminal messages from the intestine could potentially influence intestinal sensory/motor function or effect the perception/interpretation of sensory signals originating from the gut. METHODS: We studied the cerebral cortical functional magnetic resonance imaging (fMRI) response to subliminal, liminal, and supraliminal rectal distention in healthy volunteers. RESULTS: Study findings indicate that subliminal afferent signals originating from the gut are registered in the cerebral cortex without reaching the level of awareness. Locations of cortical activity caused by intestinal subliminal stimulation are similar to those of liminal and supraliminal stimulation but their intensity and volume are significantly lower (P < 0.05). CONCLUSIONS: Subliminal afferent signals originating from the gut are registered in the cerebral cortex and induce changes in measures of brain activity, such as hemodynamic changes detectable by fMRI.