Gut Axis Research Articles

Education and Hypnosis for Treatment of Functional Gastrointestinal Disorders (FGIDs) in Pediatrics

FGIDs in children and adolescents (ROME III classification) have a significant impact on the daily functioning and quality of life. Often it is the pain that is one of the main contributors to the burden of functional dyspepsia, functional abdominal pain (syndrome), and irritable bowel syndrome. Current knowledge confirms that a number of integrated networks at cortical and subcortical sites are responsible for the experience of pain. From the work of Mayer and Tillisch (2011), mainly based on structural and functional magnetic resonance imaging and positron emission tomography, it has become clear that abdominal pain syndromes are disorders of the bi-directional mind–brain–gut interactions. In this multi-factorial bio-psycho-social model we recognize the importance of neurobiological processes in the mind–brain–gut interactions, leading to alterations in motility, sensation, and immune functions. Medical treatment often offers little or no relief. Until now pharmaceutical research has not succeeded in developing safe new drugs with an effect on the brain–gut axis. More recent published research shows the rationale for the use of medical hypnosis in FGID. In this article the author will illustrate her specific approach in a pediatric gastroenterology clinic with children and adolescents with FGIDs. Being a pediatric gastroenterologist, the author emphasizes the importance of a clear diagnosis, explains the rationale for educating the patient and his or her parents on the multi-factorial bio-psycho-social model and the concepts of chronic pain, discusses the specific settings and pitfalls for hypnosis treatment in children, and last but not least, provides some examples of hypnotic sessions used with FGIDs.

Acupoint Specificity on Colorectal Hypersensitivity Alleviated by Acupuncture and the Correlation with the Brain-Gut Axis.

This project was focused on the study of the effect of the different acupoints on visceral hypersensitivity and the correlation with the brain-gut axis. By using a mouse model of zymosan-induced colorectal hypersensitivity, and observing the response of hypersensitivity model to colorectal distension stimulation in acupuncture at different acupoints, we selected the specific acupoints. With immunohistochemical staining method, we observed c-fos expression, distribution and changes after acupuncture on sensory pathway, including colorectum, spinal dorsal horn and different regions of brain center in the model with colorectal distension stimulation, and evaluated the acupuncture effect on brain-gut axis. The results revealed that the effectiveness of acupuncture for alleviating visceral hypersensitivity was different at individual acupoint, meaning Tianshu (ST25), Zusanli (ST36) and Shangjuxu (ST37)>Quchi (LI11) and Dachangshu (BL25)>Ciliao (BL32). C-fos expression was concentrated in anterior cingulate cortex, hypothalamus, spinal dorsal horn and colorectum in model of zymosan-induced colorectal hypersensitivity and it was down-regulated after acupuncture. The results demonstrates that the acupoint specificity presents in acupuncture for relieving visceral hypersensitivity and the effects are more predominated at the acupoints on stomach meridian innervated by the same or adjacent spinal ganglion segments. The model of zymosan-induced colorectal hypersensitivity can be the animal model simulating brain-gut interaction.

930 Is Rectal Hyposensitivity Caused by Bidirectional Gut and Brain Axis Dysfunction?

930 Is Rectal Hyposensitivity Caused by Bidirectional Gut and Brain Axis Dysfunction?

Irritable bowel syndrome

Abstract Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain associated with a change in frequency and form of stool. IBS is common, with a population prevalence of around 10%, and causes a reduction in quality of life. Its pathophysiology remains incompletely understood, although abnormal communications within the brain–gut axis are considered to be important. IBS can be subclassified according to predominant bowel habit and/or pain. Treatments are directed towards improving symptoms and are multifaceted. Dietary and lifestyle modification, pharmacotherapy and psychological interventions can be useful in managing the disorder.

Early-life stress selectively affects gastrointestinal but not behavioral responses in a genetic model of brain-gut axis dysfunction.

Early-life stress and a genetic predisposition to display an anxiety- and depressive-like phenotype are associated with behavioral and gastrointestinal (GI) dysfunction. Animals exposed to early-life stress, and those genetically predisposed to display anxiety or depressive behaviors, have proven useful tools in which to study stress-related GI disorders, such as irritable bowel syndrome (IBS). IBS is a heterogeneous disorder, and likely a consequence of both genetic and environmental factors. However, the combined effects of early-life stress and a genetic predisposition to display anxiety- and depression-like behaviors on GI function have not been investigated. We assessed the effect of maternal separation (MS) on behavioral and GI responses in WKY animals relative to a normo-anxious reference strain. Both non-separated (NS) WKY and WKY-MS animals displayed anxiety-like responses in the open-field test and depressive-like behaviors in the forced swim test relative to Sprague-Dawley rats. However, MS had no further influence on anxiety- and depressive-like behaviors exhibited by this stress-prone rat strain. Similarly, corticosterone levels measured after the OFT were insensitive to MS in WKY animals. However, WKY-MS displayed significantly increased colonic visceral hypersensitivity, fecal output, and altered colonic cholinergic sensitivity. Our data suggest that early-life stress, on the background of a genetic predisposition to display an anxiety- and depressive-like phenotype, selectively influences GI function rather than stress-related behaviors. Thus, our findings highlight the importance of genetic predisposition on the outcome of early-life adversity on GI function.

Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss.

The prevalence of obesity has increased worldwide, and approximately 25%–35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain–gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.

P.5.f.005 Acute tryptophan depletion modulates kynurenine production: a challenging component of cognitive impairment in brain–gut axis disorders

P.5.f.005 Acute tryptophan depletion modulates kynurenine production: a challenging component of cognitive impairment in brain–gut axis disorders

Gut microbiota, the pharmabiotics they produce and host health.

A healthy gut microbiota plays many crucial functions in the host, being involved in the correct development and functioning of the immune system, assisting in the digestion of certain foods and in the production of health-beneficial bioactive metabolites or 'pharmabiotics'. These include bioactive lipids (including SCFA and conjugated linoleic acid) antimicrobials and exopolysaccharides in addition to nutrients, including vitamins B and K. Alterations in the composition of the gut microbiota and reductions in microbial diversity are highlighted in many disease states, possibly rendering the host susceptible to infection and consequently negatively affecting innate immune function. Evidence is also emerging of microbially produced molecules with neuroactive functions that can have influences across the brain-gut axis. For example, γ-aminobutyric acid, serotonin, catecholamines and acetylcholine may modulate neural signalling within the enteric nervous system, when released in the intestinal lumen and consequently signal brain function and behaviour. Dietary supplementation with probiotics and prebiotics are the most widely used dietary adjuncts to modulate the gut microbiota. Furthermore, evidence is emerging of the interactions between administered microbes and dietary substrates, leading to the production of pharmabiotics, which may directly or indirectly positively influence human health.

Alterations of intestinal barrier and microbiota in chronic kidney disease.

Recent studies have highlighted the close relationship between the kidney and the gastrointestinal (GI) tract--frequently referred to as the kidney--gut axis--in patients with chronic kidney disease (CKD). In this regard, two important pathophysiological concepts have evolved: (i) production and accumulation of toxic end-products derived from increased bacterial fermentation of protein and other nitrogen-containing substances in the GI tract, (ii) translocation of endotoxins and live bacteria from gut lumen into the bloodstream, due to damage of the intestinal epithelial barrier and quantitative/qualitative alterations of the intestinal microbiota associated with the uraemic milieu. In both cases, these gut-centred alterations may have relevant systemic consequences in CKD patients, since they are able to trigger chronic inflammation, increase cardiovascular risk and worsen uraemic toxicity. The present review is thus focused on the kidney-gut axis in CKD, with special attention to the alterations of the intestinal barrier and the local microbiota (i.e. the collection of microorganisms living in a symbiotic coexistence with their host in the intestinal lumen) and their relationships to inflammation and uraemic toxicity in CKD. Moreover, we will summarize the most important clinical data suggesting the potential for nutritional modulation of gut-related inflammation and intestinal production of noxious by-products contributing to uraemic toxicity in CKD patients.

Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats

Disruption of bacterial colonization during the early postnatal period is increasingly being linked to adverse health outcomes. Indeed, there is a growing appreciation that the gut microbiota plays a role in neurodevelopment. However, there is a paucity of information on the consequences of early-life manipulations of the gut microbiota on behavior.To this end we administered an antibiotic (vancomycin) from postnatal days 4–13 to male rat pups and assessed behavioral and physiological measures across all aspects of the brain–gut axis. In addition, we sought to confirm and expand the effects of early-life antibiotic treatment using a different antibiotic strategy (a cocktail of pimaricin, bacitracin, neomycin; orally) during the same time period in both female and male rat pups.Vancomycin significantly altered the microbiota, which was restored to control levels by 8weeks of age. Notably, vancomycin-treated animals displayed visceral hypersensitivity in adulthood without any significant effect on anxiety responses as assessed in the elevated plus maze or open field tests. Moreover, cognitive performance in the Morris water maze was not affected by early-life dysbiosis. Immune and stress-related physiological responses were equally unaffected. The early-life antibiotic-induced visceral hypersensitivity was also observed in male rats given the antibiotic cocktail. Both treatments did not alter visceral pain perception in female rats. Changes in visceral pain perception in males were paralleled by distinct decreases in the transient receptor potential cation channel subfamily V member 1, the α-2A adrenergic receptor and cholecystokinin B receptor.In conclusion, a temporary disruption of the gut microbiota in early-life results in very specific and long-lasting changes in visceral sensitivity in male rats, a hallmark of stress-related functional disorders of the brain–gut axis such as irritable bowel disorder.

Inflammatory bowel disease and irritable bowel syndrome: similarities and differences.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here. Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain-gut axis dysfunction in IBD, implication of TNFSF gene in Crohn's disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission. IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients.

122 Modulation of cystic fibrosis gut inflammation – a pivotal role of the lung gut axis?

122 Modulation of cystic fibrosis gut inflammation – a pivotal role of the lung gut axis?

Brain and Gut Interactions in Irritable Bowel Syndrome: New Paradigms and New Understandings

Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits. Visceral hypersensitivity is believed to be a key underlying mechanism that causes pain. There is evidence that interactions within the brain and gut axis (BGA), that involves both the afferent-ascending and the efferent-descending pathways, as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex, and hippocampus, are deranged in IBS showing both the activation and inactivation. Clinical manifestations of IBS such as pain, altered gut motility, and psychological dysfunction may each be explained, in part, through the changes in the BGA, but there is conflicting information, and its precise role is not fully understood. A better understanding of the BGA may shed more knowledge regarding the pathophysiology of IBS that in turn may lead to the discovery of novel therapies for this common disorder.

P.3.027 Acute tryptophan depletion modulates kynurenine production: A challenging component of cognitive impairment in brain–gut axis disorders

P.3.027 Acute tryptophan depletion modulates kynurenine production: A challenging component of cognitive impairment in brain–gut axis disorders

Value of evoked potential in study of functional bowel disorders

In recent years, the development of neurogastroenterology and the application of neurophysiologic examinations have gradually revealed the association of gastrointestinal activity with cortical activity through the efferent and afferent pathways. The state of nerve conduction pathway between the brain and gastrointestinal tract is closely related with specific functions of the anus and rectum. Scholars have put forward the "brain gut axis" and "brain gut interaction" theories to explain the bidirectional interactionbetween the gastrointestinal tract and central nervous system. Evoked potentials have an important role in the diagnosis and research of electrophysiological changes in various parts of the neural system, which provides practical information for the study of the brain-gut pathway, promotes the diagnosis and understanding of diseases related to the brain-gut axis abnormalities, and provides the basis for developing new treatment methods. In this paper, we summarize the roles of various evoked potential techniques in the study of functional bowel disorders.

Zingerone regulates intestinal transit, attenuates behavioral and oxidative perturbations in irritable bowel disorder in rats

Stress can lead to the manifestation of functional gastrointestinal disorders, the most prominent being irritable bowel disorder. The present study investigated the impact zingerone in ameliorating chronic water stress induced irritable bowel disorder, brain gut axis dysfunction and dysregulation of the intestinal barrier due to oxidative stress. Rats were randomly allocated to groups and subjected to chronic water stress for a period of 21 days for 1h and the fecal pellet output was measured. At the end of chronic stress, behavioral assessment for anxiety like behavior was recorded and plasma corticosterone levels were measured 60min after water stress. The colonic transit was determined, levels of oxidative and antioxidant biomarkers were measured in the colon homogenate. Myeloperoxidase activity was determined as an indirect index of neutrophil infiltration. Chronic water stress increased the rate of colonic transit, fecal output, induced behavioral changes, and decreased antioxidant levels. An increase in lipid peroxide levels, catalase and corticosterone was observed. Mast cell infiltration was evident in the stressed group. Zingerone significantly reduced colonic transit, fecal output, neutrophil infiltration, and lipid peroxide formation. The levels of catalase were not altered; however, a marginal increase in the levels of glutathione peroxidase was observed. Zingerone significantly enhanced the levels of superoxide dismutase, glutathione and decreased the levels of corticosterone. Zingerone produced marked improvement in stress induced irritable bowel disorder which could be attributed to the powerful antioxidant nature, direct effect on the intestinal smooth muscle and adaptogenic nature.

P.4.a.004 Novel object recognition memory and contextual fear extinction is impaired in a chronic stress mouse model of brain–gut axis dysfunction

P.4.a.004 Novel object recognition memory and contextual fear extinction is impaired in a chronic stress mouse model of brain–gut axis dysfunction

Interleukin 13 and Serotonin: Linking the Immune and Endocrine Systems in Murine Models of Intestinal Inflammation

ObjectiveInfiltration of activated immune cells and increased cytokine production define the immunophenotype of gastrointestinal (GI) inflammation. In addition, intestinal inflammation is accompanied by alteration in the numbers of serotonin (5-hydroxytryptamine; 5-HT) synthesizing enterochromaffin (EC) cells and in 5-HT amount. It has been established that EC cells express interleukin (IL)-13 receptor, additionally IL-13 has been implicated in the pathogenesis of ulcerative colitis. In this study, we investigated the role of IL-13 mediated 5-HT signaling in pathogenesis of colitis.MethodologyColitis was induced in IL-13 deficient (IL-13−/−) and wild-type (WT) mice with dextran sulfate sodium (DSS) and dinitrobenzene sulfonic acid (DNBS), as well as in IL-13−/− mice given recombinant mouse IL-13 (rmIL-13) and 5-hydroxytryptamine (5-HTP), the direct precursor of 5-HT.Principal Findings and ConclusionElevated colonic IL-13 levels were observed in WT mice receiving DSS in comparison to control. IL-13−/− mice administered DSS exhibited significantly reduced severity of colitis compared to WT mice as reflected by macroscopic and histological damage assessments. Following DSS administration, significantly lower pro-inflammatory cytokine production and fewer infiltrating macrophages were observed in IL-13−/− mice compared to WT. The reduced severity of colitis observed in IL-13−/− mice was also accompanied by down-regulation of EC cell numbers and colonic 5-HT content. In addition, increasing colonic 5-HT content by administration of rmIL-13 or 5-HTP exacerbated severity of DSS colitis in IL-13−/− mice. IL-13−/− mice also exhibited reduced severity of DNBS-induced colitis. These results demonstrate that IL-13 plays a critical role in the pathogenesis of experimental colitis and 5-HT is an important mediator of IL-13 driven intestinal inflammation. This study revealed important information on immune-endocrine axis in gut in relation to inflammation which may ultimately lead to better strategy in managing various intestinal inflammatory conditions including inflammatory bowel disease.

PTU-121 Normal Values and Reproducibility of the Real Time Beat-To-Beat Index of Cardiac Vagal Tone in Healthy Humans

IntroductionThe vagus nerve is the primary neuroanatomical substrate within the brain gut axis (1). In humans, surrogate measures of vagal tone are most commonly evaluated using heart rate variability (HRV)...

Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder.