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.     

The intestinal microbiome,probiotics and prebiotics in neurogastroenterology

The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These findings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the field of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro- and prebiotics.     

The Brain-Gut-Microbiotal Axis: A framework for understanding functional GI illness and their therapeutic interventions

Functional gastrointestinal disorders (FGIDs), characterized by chronic abdominal complaints without a structural or biochemical cause, are common diseases that are frequently encountered by specialists in internal medicine. Collectively, irritable bowel syndrome (IBS) and functional dyspepsia are estimated to affect up to 22% of the population, and are often associated with additional somatic and pain complaints, all without an obvious structural source [1,2]. An appreciation of the current understanding of the mechanistic basis for these disorders is key to developing treatment goals and optimization of patient management strategies. In recent years, the brain-gut axis increasingly has been recognized as a central factor in the experience of functional abdominal pain disorders, including the most recent Rome IV guidelines which identify FGIDs as disorders of gut-brain interaction [3]. The brain-gut axis (BGA), simply defined, is a complex network of bidirectional communication between the central and enteric nervous systems. This axis broadly includes all the systems involved with communication between the GI tract and central nervous system (CNS), with principle inputs into this network occurring between the CNS, enteric nervous system (ENS), and autonomic nervous systems (ANS), but also includes interfaces with numerous other factors, including endocrine hormones and immune effector cells as well as interactions with the gut microbiota. Perturbances to this system have been found to play a critical role in the development of visceral hypersensitivity, bowel dysregulation, and mood. This review will summarize the principle processes involved in the neurologic and biologic function of the brain-gut axis, our current understanding of its role in functional GI disorders, and potential targets for therapeutic intervention.     

Brain-gut-microbiota axis in Parkinson's disease

Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.     

Overview of functional gastrointestinal disorders: dysfunction of the brain-gut axis

Functional gastrointestinal disorders are common and incompletely understood. The gut is controlled by a complex interaction of sensory and motor neurons in the local enteric nervous system. Inputs from the central nervous system modify gut function, whereas inputs from the gut to the brain mediate symptoms. Dysfunction at one or more sites in the brain-gut axis is likely to produce the various functional gastrointestinal syndromes. Therapies likewise can be directed at one or more levels.     

Plasticity in the enteric nervous system

Enteric ganglia can maintain integrated functions, such as the peristaltic reflex, in the absence of input from the central nervous system, which has a modulatory role. Several clinical and experimental observations suggest that homeostatic control of gut function in a changing environment may be achieved through adaptive changes occurring in the enteric ganglia. A distinctive feature of enteric ganglia, which may be crucial during the development of adaptive responses, is the vicinity of the final effector cells, which are an important source of mediators regulating cell growth. The aim of this review is to focus on the possible mechanisms underlying neuronal plasticity in the enteric nervous system and to consider approaches to the study of plasticity in this model. These include investigations of neuronal connectivity during development, adaptive mechanisms that maintain function after suppression of a specific neural input, and the possible occurrence of activity-dependent modifications of synaptic efficacy, which are thought to be important in storage of information in the brain. One of the applied aspects of the study of plasticity in the enteric nervous system is that knowledge of the underlying mechanisms may eventually enable us to develop strategies to correct neuronal alterations described in several diseases.     

Alterations of sensori-motor functions of the digestive tract in the pathophysiology of irritable bowel syndrome

Pathophysiology of irritable bowel syndrome (IBS) is based upon multiple factors that have been organised in a comprehensive model centred around the brain-gut axis. The brain-gut axis encompasses nerve pathways linking the enteric and the central nervous systems and contains a large proportion of afferent fibres. Functionally and anatomically, visceral nerves are divided in to two categories: the parasympathetic pathways distributing to the upper gut through the vagi and to the hindgut, through the pelvic and pudendal nerves, and the sympathetic pathways, arising form the spinal cord and distributing to the midgut via the paravertebral ganglia. Several abnormalities of gut sensori-motor function have been described in patients with IBS. Abnormal motility patterns have been described at the intestinal and colonic levels. Changes in colonic motility are mainly related to bowel disturbances linked to IBS but do not correlate with pain. More recently, visceral hypersensitivity has been recognised as a main characteristic of patients with IBS. It is defined by an exaggerated perception of luminal distension of various segments of the gut and related to peripheral changes in the processing of visceral sensations as well as modulation of perception by centrally acting factors including mood and stress. Viscero-visceral reflexes link the two edges of the brain-gut axis and may account for the origin of symptoms in some pathological conditions. Recent advances in the understanding of the role of myenteric plexus allowed recognition of several neurotransmitters involved at the level of both the afferent and efferent pathways. Targeting the receptors of these neurotransmitters is a promising way for development of new treatments for IBS.     

Role of gut microbiota via the gut-liver-brain axis in digestive diseases

The gut-brain axis is a bidirectional information interaction system between the central nervous system(CNS) and the gastrointestinal tract, in which gut microbiota plays a key role. The gut microbiota forms a complex network with the enteric nervous system, the autonomic nervous system, and the neuroendocrine and neuroimmunity of the CNS, which is called the microbiota-gut-brain axis. Due to the close anatomical and functional interaction of the gut-liver axis, the microbiota-gut-liver-brain axis has attracted increased attention in recent years. The microbiota-gut-liver-brain axis mediates the occurrence and development of many diseases, and it offers a direction for the research of disease treatment. In this review, we mainly discuss the role of the gut microbiota in the irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and hepatic encephalopathy via the gut-liver-brain axis, and the focus is to clarify the potential mechanisms and treatment of digestive diseases based on the further understanding of the microbiota-gut-liver-brain axis.     

Is irritable bowel syndrome an organic disorder?

Irritable bowel syndrome(IBS)is a common gastrointestinal disorder that is generally considered to be functional because there appears to be no associated anatomical defect.Stress and psychological factors are thought to play an important role in IBS.The gut neuroendocrine system(NES),which regulates all functions of the gastrointestinal tract,consists of endocrine cells that are scattered among the epithelial cells of the mucosa,and the enteric nervous system.Although it is capable of operating independently from the centra nervous system(CNS),the gut NES is connected to and modulated by the CNS.This review presents evidence for the presence of an anatomical defect in IBS patients,namely in the gastrointestinal endocrine cells.These cells have specialized microvilli that project into the lumen and function as sensors for the luminal content and respond to luminal stimuli by releasing hormones into the lamina propria,which starts a chain reaction that progresses throughout the entire NES.The changes in the gastrointestinal endocrine cells observed in IBS patients are highly consistent with the other abnormalities reported in IBS patients,such as visceral hypersensitivity,dysmotility,and abnormal secretion.     

CD4+ T-cell modulation of visceral nociception in mice

BACKGROUND & AIMS: Although inflammatory and immune cells are present in the gut in the absence of pathology, their presence does not result in sensitization of sensory nerves, implying the existence of a local antinociceptive influence. We hypothesized that a component of the immune system exerts an antinociceptive influence, thus enabling the gut to function in the absence of undue pain or discomfort. METHODS: Visceromotor responses to colorectal distention were measured in mice with severe combined immune deficiency (SCID) and their wild-type controls. RESULTS: SCID mice exhibited significantly lower pain thresholds. Transfer of CD4(+) T, but not B lymphocytes, normalized visceral pain in these mice. The restoration of normal visceral nociception following T-cell reconstitution in SCID mice was blocked by naloxone methiodide. Using an enzyme immunoassay and immunohistochemistry for beta-endorphin, we showed that in vitro stimulation of T lymphocytes induced the synthesis and release of beta-endorphin and that transfer of T cells into SCID mice increased the expression of beta-endorphin in the enteric nervous system. CONCLUSIONS: These findings indicate that the immune system is a critical determinant of visceral nociception and that T lymphocytes provide an important opioid-mediated antinociceptive influence in the gut.     

The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system

The enteric nervous system (ENS) coordinates the major functions of the gastrointestinal tract. Its development takes place within a constantly changing environment which, after birth, culminates in the establishment of a complex gut microbiota. How such changes affect ENS development and its subsequent function throughout life is an emerging field of study that holds great interest but which is inadequately explored thus far. In this addendum, we discuss our recent findings showing that a component of the ENS, the enteric glial cell network that resides in the gut lamina propria, develops after birth and parallels the evolution of the gut microbiota. Importantly, this network was found to be malleable throughout life by incorporating new cells that arrive from the area of the gut wall in a process of directional movement which was controlled by the lumen gut microbiota. Finally, we postulate on the roles of the intestinal epithelium and the immune system as potential intermediaries between gut microbiota and ENS responses.     

Psychosocial factors and visceral hypersensitivity in irritable bowel syndrome]

Most studies provide strong support for an etiologic role of stressful life events in irritable bowel syndrome (IBS). Consistent with the observations in both patients and doctors that psychosocial disturbances seem to precede the onset or exacerbation of gut symptoms, researches have consistently found high levels of emotional distress in a proportion of patients with IBS and other functional gastrointestinal disorders. Moreover, a variety of other potentially psychiatric diseases such as anxiety, depression, and sleep disorder also coexist frequently with IBS. In recent literatures, some studies have shown altered mechanoelastic properties such as colonic tone, compliance, and accommodation. The demonstrated differences in colonic compliance and accommodation suggest peripheral neuromuscular substrate contributing to the pathogenesis of IBS. However, until now, attention has focused on the disturbances of visceral hypersensitivity rather than on gastrointestinal motor function as a hallmark of IBS pathophysiology. But not all IBS patients show decreased rectosigmoid pain thresholds. Recent advances in brain imaging have allowed investigators to measure changes in regional cerebral blood flow during stimulation. Those methods have extended our understanding of brain function and brain-gut interaction. IBS is characterized by hypersensitivity to visceral sensation and augmented response to stress. Studies on the disorders of sensori-motor function have also contributed to understand the knowledge of neurotransmitters involved in the function of the enteric nervous system and to identify targets for the development of new treatments for IBS.     

The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system

The enteric nervous system (ENS) coordinates the major functions of the gastrointestinal tract. Its development takes place within a constantly changing environment which, after birth, culminates in the establishment of a complex gut microbiota. How such changes affect ENS development and its subsequent function throughout life is an emerging field of study that holds great interest but which is inadequately explored thus far. In this addendum, we discuss our recent findings showing that a component of the ENS, the enteric glial cell network that resides in the gut lamina propria, develops after birth and parallels the evolution of the gut microbiota. Importantly, this network was found to be malleable throughout life by incorporating new cells that arrive from the area of the gut wall in a process of directional movement which was controlled by the lumen gut microbiota. Finally, we postulate on the roles of the intestinal epithelium and the immune system as potential intermediaries between gut microbiota and ENS responses.     

Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases

Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease(IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell's function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.     

Stem Cell Therapy for GI Neuromuscular Disorders

The enteric nervous system is the intrinsic innervation of the gut. Several neuromuscular disorders affect the neurons and glia of the enteric nervous system adversely, resulting in disruptions in gastrointestinal motility and function. Pharmacological interventions to remedy gastrointestinal function do not address the underlying cause of dysmotility arising from lost, absent, or damaged enteric neuroglial circuitry. Cell-based therapies have gained traction in the past decade, following the discovery of several adult stem cell niches in the human body. Adult neural stem cells can be isolated from the postnatal and adult intestine using minimally invasive biopsies. These stem cells retain the ability to differentiate into several functional classes of enteric neurons and enteric glia. Upon identification of these cells, several groups have also established that transplantation of these cells into aganglionic or dysganglionic intestine rescues gastrointestinal motility and function. This chapter highlights key studies performed in the field of stem cell transplantation therapies that are targeted towards the remedy of gastrointestinal motility and function.     

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.     

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.     

Clinical endocrinology and metabolism. Receptors for gut peptides

Most gut peptides exert their effects through G protein-coupled receptors, a family of about 700 membrane proteins, 87 of which are presently known to have peptide ligands. Three additional gut peptide receptors are not G protein-coupled receptors but regulate intracellular cyclic GMP accumulation. The aim of this review is to illustrate how the sequencing of the human genome and other recent advances in genomics has contributed to our understanding of the role of peptides and their receptors in gastrointestinal function. Recent discoveries include the identification of receptors for the peptides motilin and neuromedin U, and new physiological ligands for the PTH2 receptor, the CRF(2) receptor and the growth hormone secretagogue receptor. Knockout mice lacking specific peptide receptors or their ligands provide informative animal models in which to determine the functions of the numerous peptide-receptor systems in the gut and to predict which of them may be the most fruitful for drug development. Some peptide-receptor signalling systems may be more important in disease states than they are in normal physiology. For example, substance P, galanin, bradykinin and opioids play important roles in visceral pain and inflammation. Other peptides may have developmental roles: for example, disruption of endothelin-3 signalling prevents the normal development of the enteric nervous system and contributes to the pathogenesis of Hirschsprung disease.     

Biopsychosocial issues in irritable bowel syndrome

Irritable bowel syndrome is a biopsychosocial disorder that results from dysregulation of central and enteric nervous system function. It manifests as dysmotility and/or visceral hypersensitivity, and is modified by psychosocial processes. The interaction of the biopsychosocial factors determines the experience of the illness. An understanding of the biopsychosocial model of illness requires a shift from concepts traditionally taught in Western medical schools (biomedical reductionism and dualism) to that of multicausality, where biologic and psychologic factors interact to determine the disease and its experience or illness.     

Psychosocial determinants of irritable bowel syndrome

From a pure motor disorder of the bowel, in the past few years, irritable bowel syndrome (IBS) has become a multifactorial disease that implies visceral hypersensitivity, alterations at the level of nervous and humoral communications between the enteric nervous system and the central nervous system, alteration of the gut microflora, an increased intestinal permeability and minimum intestinal inflammation. Psychological and social factors can interfere with the communication between the central and enteric nervous systems, and there is proof that they are involved in the onset of IBS and influence the response to treatment and outcome. There is evidence that abuse history and stressful life events are involved in the onset of functional gastrointestinal disorders. In order to explain clustering of IBS in families, genetic factors and social learning mechanisms have been proposed. The psychological features, such as anxiety, depression as well as the comorbid psychiatric disorders, health beliefs and coping of patients with IBS are discussed in relation to the symptoms and outcome.