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• W2778077278 abstract "In June 2016, the National Institutes of Health hosted a workshop on functional bowel disorders (FBDs), particularly irritable bowel syndrome, with the objective of elucidating gaps in current knowledge and recommending strategies to address these gaps. The workshop aimed to provide a roadmap to help strategically guide research efforts during the next decade. Attendees were a diverse group of internationally recognized leaders in basic and clinical FBD research. This document summarizes the results of their deliberations, including the following general conclusions and recommendations. First, the high prevalence, economic burden, and impact on quality of life associated with FBDs necessitate an urgent need for improved understanding of FBDs. Second, preclinical discoveries are at a point that they can be realistically translated into novel diagnostic tests and treatments. Third, FBDs are broadly accepted as bidirectional disorders of the brain−gut axis, differentially affecting individuals throughout life. Research must integrate each component of the brain−gut axis and the influence of biological sex, early-life stressors, and genetic and epigenetic factors in individual patients. Fourth, research priorities to improve diagnostic and management paradigms include enhancement of the provider−patient relationship, longitudinal studies to identify risk and protective factors of FBDs, identification of biomarkers and endophenotypes in symptom severity and treatment response, and incorporation of emerging “-omics” discoveries. These paradigms can be applied by well-trained clinicians who are familiar with multimodal treatments. Fifth, essential components of a successful program will include the generation of a large, validated, broadly accessible database that is rigorously phenotyped; a parallel, linkable biorepository; dedicated resources to support peer-reviewed, hypothesis-driven research; access to dedicated bioinformatics expertise; and oversight by funding agencies to review priorities, progress, and potential synergies with relevant stakeholders. In June 2016, the National Institutes of Health hosted a workshop on functional bowel disorders (FBDs), particularly irritable bowel syndrome, with the objective of elucidating gaps in current knowledge and recommending strategies to address these gaps. The workshop aimed to provide a roadmap to help strategically guide research efforts during the next decade. Attendees were a diverse group of internationally recognized leaders in basic and clinical FBD research. This document summarizes the results of their deliberations, including the following general conclusions and recommendations. First, the high prevalence, economic burden, and impact on quality of life associated with FBDs necessitate an urgent need for improved understanding of FBDs. Second, preclinical discoveries are at a point that they can be realistically translated into novel diagnostic tests and treatments. Third, FBDs are broadly accepted as bidirectional disorders of the brain−gut axis, differentially affecting individuals throughout life. Research must integrate each component of the brain−gut axis and the influence of biological sex, early-life stressors, and genetic and epigenetic factors in individual patients. Fourth, research priorities to improve diagnostic and management paradigms include enhancement of the provider−patient relationship, longitudinal studies to identify risk and protective factors of FBDs, identification of biomarkers and endophenotypes in symptom severity and treatment response, and incorporation of emerging “-omics” discoveries. These paradigms can be applied by well-trained clinicians who are familiar with multimodal treatments. Fifth, essential components of a successful program will include the generation of a large, validated, broadly accessible database that is rigorously phenotyped; a parallel, linkable biorepository; dedicated resources to support peer-reviewed, hypothesis-driven research; access to dedicated bioinformatics expertise; and oversight by funding agencies to review priorities, progress, and potential synergies with relevant stakeholders. In 2015, the American Gastroenterological Association’s James W. Freston Single Topic Conference focused on advances in the understanding and management of irritable bowel syndrome (IBS). That conference highlighted the need for additional resources and strategies to address gaps in the current understanding of the pathophysiology and management of IBS and, more broadly, of functional bowel disorders (FBDs). A subsequent 2016 meeting, Functional Bowel Disorders Workshop: Future Research Directions in Pathophysiology, Diagnosis and Treatment, was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and aimed to elucidate current gaps in knowledge and recommend strategies to address these gaps. The workshop covered a broad range of topics, including prevalence of FBDs and economic burden; pathophysiology and pathogenesis of FBDs; the role of animal models; neuromuscular dysfunction in FBDs (neurons, smooth muscle, glia, interstitial cells of Cajal) and the microbiome; brain−gut pathways in models of IBS and the role of primary afferent, efferent, and spinal components of the axis; evidence of IBS-related dysfunctional circuits in the human brain; genetic and epigenetic mechanisms and environmental factors; the emerging role of dietary triggers in IBS; current and emerging strategies to manage FBDs; and application of next-generation -omics technologies to diagnose and treat FBDs with precision medicine. The presentations focused primarily on IBS because it is the one of the most common diagnoses in gastroenterology and primary care medicine in the outpatient setting. In addition, clinical symptoms of IBS overlap with those of other disorders often affecting patients seen for chronic pain concerns. Each author was assigned a portion of this manuscript. After the initial draft was written, all authors participated in subsequent revisions. Our consensus viewpoint is that the document accurately represents a synthesis of the presentations at the workshop, including gaps in the current understanding and strategies to address these gaps. The definition of FBDs recently was updated to include disorders that often involve brain−gut interactions and result in any of the following gastrointestinal (GI) symptoms: motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system (CNS) processing.1Drossman D.A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV.Gastroenterology. 2016; 150: 1262-1279Abstract Full Text Full Text PDF Google Scholar The most common conditions in this group (and in gastroenterology in general) include IBS, functional dyspepsia, idiopathic gastroparesis, functional constipation, functional abdominal pain, and disorders of anorectal function; notably, these conditions can arise at any point in life. In pediatric populations, the prevalence of FBDs is increasing, and FBDs are considered a leading cause of school absenteeism.2Varni J.W. Lane M.M. Burwinkle T.M. et al.Health-related quality of life in pediatric patients with irritable bowel syndrome: a comparative analysis.J Dev Behav Pediatr. 2006; 27: 451-458Crossref PubMed Scopus (116) Google Scholar During the past 3 decades, investigators have noted that FBDs increasingly are recognized by concomitant morphologic and physiologic abnormalities. The diagnostic criteria for functional GI disorders are being standardized by the Rome Foundation; by identifying clustering symptoms, clinicians can better differentiate among these disorders, and more reliable data can be collected on the prevalence of FBDs.1Drossman D.A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV.Gastroenterology. 2016; 150: 1262-1279Abstract Full Text Full Text PDF Google Scholar In addition, improved population-based data systems are providing a more accurate representation of the true prevalence of FBDs in the United States. GI disorders are common and costly. Recently, investigators have reported that at least 20% of the US population has chronic symptoms that can be attributable to GI disorders, with common clinical tests showing no evidence of organic causes.3Stanghellini V. Chan F.K. Hasler W.L. et al.Gastroduodenal disorders.Gastroenterology. 2016; 150: 1380-1392Abstract Full Text Full Text PDF PubMed Google Scholar, 4Peery A.F. Crockett S.D. Barritt A.S. et al.Burden of gastrointestinal, liver, and pancreatic diseases in the United States.Gastroenterology. 2015; 149: 1731-1741 e3Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar Everhart and Ruhl5Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases.Gastroenterology. 2009; 136: 376-386Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar determined that GI diseases affect approximately 60 to 70 million US residents annually. In 2004, an estimated 4.6 million hospitalizations, 72 million ambulatory care visits, and 236,000 deaths were attributable to GI diseases.5Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases.Gastroenterology. 2009; 136: 376-386Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar Forty percent of these GI conditions have been attributed to FBDs.5Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases.Gastroenterology. 2009; 136: 376-386Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 6Russo M.W. Wei J.T. Thiny M.T. et al.Digestive and liver diseases statistics, 2004.Gastroenterology. 2004; 126: 1448-1453Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 7Sandler R.S. Everhart J.E. Donowitz M. et al.The burden of selected digestive diseases in the United States.Gastroenterology. 2002; 122: 1500-1511Abstract Full Text Full Text PDF PubMed Google Scholar, 8Shaheen N.J. Hansen R.A. Morgan D.R. et al.The burden of gastrointestinal and liver diseases, 2006.Am J Gastroenterol. 2006; 101: 2128-2138Crossref PubMed Scopus (462) Google Scholar, 9Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part II: lower gastrointestinal diseases.Gastroenterology. 2009; 136: 741-754Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar The direct and indirect costs were estimated to be $142 billion per year.5Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases.Gastroenterology. 2009; 136: 376-386Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar In addition to the economic burden, FBDs affect the individual’s health-related quality of life, work productivity, and activities of daily living. When compared with population norms, individuals with FBDs have worse quality of life and markedly more work and activity impairments.6Russo M.W. Wei J.T. Thiny M.T. et al.Digestive and liver diseases statistics, 2004.Gastroenterology. 2004; 126: 1448-1453Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 8Shaheen N.J. Hansen R.A. Morgan D.R. et al.The burden of gastrointestinal and liver diseases, 2006.Am J Gastroenterol. 2006; 101: 2128-2138Crossref PubMed Scopus (462) Google Scholar, 10Bolge S.C. Doan J.F. Kannan H. et al.Association of insomnia with quality of life, work productivity, and activity impairment.Qual Life Res. 2009; 18: 415-422Crossref PubMed Scopus (155) Google Scholar Research discoveries in the area of brain−gut interactions have improved the understanding of the associated pathophysiologic features relevant to specific FBDs. Furthermore, the findings reported at this workshop indicate that significant advances in the understanding of FBD pathophysiology can be used to identify opportunities for developing much-needed diagnostic and treatment strategies. Excellent reviews have been published recently that describe the current understanding of the pathophysiology and pathogenesis of FBDs, particularly IBS.11McCullough R. McCullough J. Deciphering the pathophysiology of irritable bowel syndrome and functional gastrointestinal disorders-an alternative model for pathogenesis: cytokine controlled transepithelial multi-feedback loop.Transl Gastroenterol Hepatol. 2017; 2: 18Crossref PubMed Scopus (0) Google Scholar, 12Ringel Y. The gut microbiome in irritable bowel syndrome and other functional bowel disorders.Gastroenterol Clin North Am. 2017; 46: 91-101Abstract Full Text Full Text PDF PubMed Google Scholar, 13Gazouli M. Wouters M.M. Kapur-Pojskic L. et al.Lessons learned—resolving the enigma of genetic factors in IBS.Nat Rev Gastroenterol Hepatol. 2016; 13: 77-87Crossref PubMed Scopus (12) Google Scholar The purpose of this article is to focus on identifying gaps in our understanding of the pathophysiology and treatment of FBDs, such as IBS, and to suggest strategies to address these gaps. The development of relevant animal models to study FBDs has been problematic because current diagnostic criteria for FBDs in humans are based on symptoms, which can be difficult to reproduce and interpret in animals. Among the challenges confronting the development of animal models specifically for IBS is the complex clinical phenotype that overlaps with many other conditions (eg, anxiety, depression, fibromyalgia, post-traumatic stress disorder, painful bladder syndrome, chronic pelvic pain, chronic fatigue syndrome). The multifactorial nature of IBS and the complicated interactions among biologic and psychosocial variables are such that no current animal model is ideally suited to investigate the causal mechanisms.14Holschneider D.P. Bradesi S. Mayer E.A. The role of experimental models in developing new treatments for irritable bowel syndrome.Expert Rev Gastroenterol Hepatol. 2011; 5: 43-57Crossref PubMed Scopus (34) Google Scholar However, we note that these limitations are not unique to FBDs; they apply equally to the study of many neurologic and metabolic disorders. Despite the drawbacks of animal models, preclinical research remains an essential tool for elucidating underlying mechanisms and for discovering and validating novel therapeutic interventions. Furthermore, multidimensional outcomes measures are possible in animal models, including abdominal pain, anxiety, and altered bowel habits. It is broadly accepted that the clinical relevance of current animal models comes from the observation that chronic stress-associated visceral hyperalgesia is a common concern of patients with IBS. Animal models are often used to examine how chronic psychological stress (through restraint measures and water avoidance) activates the hypothalamic−pituitary−adrenal axis, which is associated with enhanced abdominal pain (visceral hyperalgesia).15Larauche M. Mulak A. Tache Y. Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study.J Neurogastroenterol Motil. 2011; 17: 213-234Crossref PubMed Scopus (62) Google Scholar Other models examine the role of early-life stress (eg, separation of pups from the mother during the suckling phase and limited nesting) and its long-term effects on visceral pain and behavior.16Walker C.D. Bath K.G. Joels M. et al.Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential.Stress. 2017; : 1-28Google Scholar Therefore, animal models may provide clues to the pathogenesis of IBS because most models have measurably enhanced visceral nociceptive responses (a surrogate for the hallmark symptoms of visceral hyperalgesia and chronic pain reported by humans with IBS).17Greenwood-Van Meerveld B. Prusator D.K. Johnson A.C. Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges.Am J Physiol Gastrointest Liver Physiol. 2015; 308: G885-G903Crossref PubMed Scopus (54) Google Scholar In humans, IBS is a female-predominant disorder, but most animal studies of IBS have used only males to avoid the confounding influence of the estrous cycle on outcomes measures, such as visceral pain. The issue of sex differences within the models has received little attention to date, but recent studies in rodents have shown sexually dimorphic effects of early-life stress on visceral sensitivity.18Chaloner A. Greenwood-Van Meerveld B. Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model.J Pain. 2013; 14: 270-280Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Prusator D.K. Greenwood-Van Meerveld B. Sex-related differences in pain behaviors following three early life stress paradigms.Biol Sex Differ. 2016; 7: 29Crossref PubMed Scopus (0) Google Scholar Thus, future studies should include female animals. Investigators and funding agencies must acknowledge the need to increase sample sizes (and budgets) to compare data from different stages of the estrous cycle and perform studies comparing males and females. IBS treatments targeting peripheral epithelial transporters appear to have transitioned successfully from animal models to humans with IBS, at least with respect to transit abnormalities.20Jin D.C. Cao H.L. Xu M.Q. et al.Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome.World J Gastroenterol. 2016; 22: 8137-8148Crossref PubMed Scopus (3) Google Scholar In addition, the clinical observations of these peripherally acting compounds have been brought back to the bench and defined mechanistically in animal models. Animal models of post-infection (ie, inflammatory) IBS, chronic adult stress induced by water avoidance, and early-life stress are considered highly relevant to human IBS and may facilitate development of novel therapeutics.21Larauche M. Mulak A. Tache Y. Stress and visceral pain: from animal models to clinical therapies.Exp Neurol. 2012; 233: 49-67Crossref PubMed Scopus (148) Google Scholar Animal models have also proven useful for defining CNS mechanisms of sensitization and nociceptive signaling, as well as for the discovery that chronic stress is an important contributing factor to all aspects of IBS. Chronic stress perpetuates and exacerbates visceral hypersensitivity, abnormal motility, and altered barrier function. For example, in rats, repeated water avoidance stress induces colonic hypersensitivity that is dependent on glucocorticoid receptors within the dorsal root ganglion innervating the lower spinal cord22Hong S. Zheng G. Wu X. et al.Corticosterone mediates reciprocal changes in CB 1 and TRPV1 receptors in primary sensory neurons in the chronically stressed rat.Gastroenterology. 2011; 140: 627-637 e4Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 23Hong S. Zheng G. Wiley J.W. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.Gastroenterology. 2015; 148: 148-157 e7Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar or limbic brain areas, such as the central nucleus of the amygdala.24Myers B. Greenwood-Van Meerveld B. Differential involvement of amygdala corticosteroid receptors in visceral hyperalgesia following acute or repeated stress.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G260-G266Crossref PubMed Scopus (46) Google Scholar, 25Tran L. Chaloner A. Sawalha A.H. et al.Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress.Psychoneuroendocrinology. 2013; 38: 898-906Crossref PubMed Scopus (86) Google Scholar Transient receptor potential vanilloid type 1 antagonists26Nash M.S. McIntyre P. Groarke A. et al.7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4 -one, a classic polymodal inhibitor of transient receptor potential vanilloid type 1 with a reduced liability for hyperthermia, is analgesic and ameliorates visceral hypersensitivity.J Pharmacol Exp Ther. 2012; 342: 389-398Crossref PubMed Scopus (0) Google Scholar and central corticotropin-releasing factor receptor antagonists27Tran L. Schulkin J. Greenwood-Van Meerveld B. Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain.Neuropsychopharmacology. 2014; 39: 2633-2645Crossref PubMed Scopus (0) Google Scholar inhibit water avoidance stress−induced colonic hypersensitivity. Experimental models are currently unraveling the epigenetics of IBS23Hong S. Zheng G. Wiley J.W. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.Gastroenterology. 2015; 148: 148-157 e7Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 25Tran L. Chaloner A. Sawalha A.H. et al.Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress.Psychoneuroendocrinology. 2013; 38: 898-906Crossref PubMed Scopus (86) Google Scholar, 28Tran L. Schulkin J. Ligon C.O. et al.Epigenetic modulation of chronic anxiety and pain by histone deacetylation.Mol Psychiatry. 2015; 20: 1219-1231Crossref PubMed Scopus (73) Google Scholar and the plasticity of the CNS after early-life stress.29Prusator D.K. Greenwood-Van Meerveld B. Amygdala-mediated mechanisms regulate visceral hypersensitivity in adult females following early life stress: importance of the glucocorticoid receptor and corticotropin-releasing factor.Pain. 2017; 158: 296-305Crossref PubMed Scopus (2) Google Scholar Animal studies are poised to enhance the understanding of brain−gut microbiome interactions in individuals with IBS.30Moloney R.D. Johnson A.C. O'Mahony S.M. et al.Stress and the microbiota-gut-brain axis in visceral pain: relevance to irritable bowel syndrome.CNS Neurosci Ther. 2016; 22: 102-117Crossref PubMed Google Scholar Finally, neuroimaging of the CNS, which is now possible in rodent models, will allow direct comparison and translation to human brain imaging, as well as reverse translation to relevant animal models.31Hubbard C.S. Karpowicz J.M. Furman A.J. et al.Estrogen-dependent visceral hypersensitivity following stress in rats: an fMRI study.Mol Pain. 2016; 12: 1-10Crossref Scopus (15) Google Scholar Gaps in the current knowledge of the use of animal models to study the pathophysiology of FBDs:•What are the areas of agreement and disagreement between animal and human studies?•What is the basis for the observed differences, for example, genetics, epigenetics, or both?•Can mechanistically focused animal studies (eg, examining the role of biologic sex in FBDs and IBS) be replicated in relevant human tissue samples?•Can animal models be used successfully for reverse translational research? Strategies to address the gaps:•Perform comparative studies on male and female animals to elucidate the mechanisms underlying biologic sex-related differences on clinically relevant outcome measures such as visceral pain (including CNS regions of interest), intestinal barrier function, and the microbiome.•Perform reverse translation from human brain imaging studies of central biomarkers to suitable animal models (eg, knockout or transgenic models) for further mechanistic evaluations.•Use appropriate animal models to perform longitudinal (time course) studies to determine whether IBS is a “top-down” or “bottom-up” syndrome (or both) to essentially determine if the CNS is driving the IBS phenotype or if changes in the GI tract are driving changes in the CNS. Interventional studies will help to determine whether changes in the CNS depend on peripheral pathways or develop independently. Transit through the small and large intestines is slowed in a subset of patients with constipation-predominant IBS and accelerated in a subset of patients with diarrhea-predominant IBS; moreover, dysmotility is reported in a subset of patients with other FBDs.3Stanghellini V. Chan F.K. Hasler W.L. et al.Gastroduodenal disorders.Gastroenterology. 2016; 150: 1380-1392Abstract Full Text Full Text PDF PubMed Google Scholar, 32Boeckxstaens G. Camilleri M. Sifrim D. et al.Fundamentals of neurogastroenterology: physiology/motility—sensation.Gastroenterology. 2016; : 1292-1304Abstract Full Text Full Text PDF Scopus (10) Google Scholar Because one goal of therapeutic interventions is to normalize dysmotility,33Camilleri M. Bueno L. Andresen V. et al.Pharmacological, pharmacokinetic, and pharmacogenomic aspects of functional gastrointestinal disorders.Gastroenterology. 2016; : 1319-1331Abstract Full Text Full Text PDF Scopus (6) Google Scholar improved understanding of the enteric neuromuscular circuitry in the various forms of FBDs is critical for elucidating their origins and essential for developing more effective treatment strategies. We note that knowledge of the enteric neuromuscular pathophysiology in FBDs is partly limited by the relative paucity of human samples available for ex vivo physiologic analysis. Unlike the mucosa, the deeper layers of the gut are inaccessible by traditional endoscopic procedures, although emerging technologies will likely improve future availability of relevant human tissues. Motor patterns in the intestines are generated and controlled by intrinsic reflexes of the enteric nervous system (ENS), the critical elements of which include sensory neurons, interneurons, excitatory and inhibitory motor neurons, smooth muscle, glial cells, and interstitial cells.34Sanders K.M. Ward S.M. Koh S.D. Interstitial cells: regulators of smooth muscle function.Physiol Rev. 2014; 94: 859-907Crossref PubMed Scopus (253) Google Scholar, 35Sharkey K.A. Emerging roles for enteric glia in gastrointestinal disorders.J Clin Invest. 2015; 125: 918-925Crossref PubMed Scopus (103) Google Scholar, 36Furness J.B. The enteric nervous system and neurogastroenterology.Nat Rev Gastroenterol Hepatol. 2012; 9: 286-294Crossref PubMed Scopus (712) Google Scholar Perturbations at any level of this circuitry can disrupt motility. For example, motility that is disrupted by inflammation-induced neuroplasticity persists after recovery from inflammation.37Mawe G.M. Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon.J Clin Invest. 2015; 125: 949-955Crossref PubMed Scopus (55) Google Scholar In animal models with post-inflammatory symptoms consistent with FBDs,37Mawe G.M. Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon.J Clin Invest. 2015; 125: 949-955Crossref PubMed Scopus (55) Google Scholar persistent changes in neuronal and motor functions have been identified. Other motility disorders, such as diabetes-associated gastroparesis, constipation, and idiopathic gastroparesis, are associated with observed changes in the interstitial cells of Cajal,38Farrugia G. Interstitial cells of Cajal in health and disease.Neurogastroenterol Motil. 2008; 20: 54-63Crossref PubMed Scopus (260) Google Scholar and colonic transit can be modulated by disruptions in enteric glial activity.39McClain J. Grubisic V. Fried D. et al.Ca2+ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice.Gastroenterology. 2014; 146: 497-507 e1Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar The ENS can be affected by stress and by enteric bacteria. Stress paradigms that are mediated by corticotropin-releasing factor−expressing enteric ganglia lead to functional changes, such as increased fecal output, increased epithelial secretion and diarrhea, and decreased transepithelial resistance.40Liu S. Chang J. Long N. et al.Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.Neurogastroenterol Motil. 2016; 28: 281-291Crossref PubMed Scopus (3) Google Scholar, 41Li S. Fei G. Fang X. et al.Changes in enteric neurons of small intestine in a rat model of irritable bowel syndrome with diarrhea.J Neurogastroenterol Motil. 2016; 22: 310-320Crossref PubMed Scopus (2) Google Scholar, 42Hyland N.P. O'Mahony S.M. O'Malley D. et al.Early-life stress selectively affects gastrointestinal but not behavioral responses in a genetic model of brain−gut axis dysfunction.Neurogastroenterol Motil. 2015; 27: 105-113Crossref PubMed Scopus (14) Google Scholar, 43O'Malley D. Cryan J.F. Dinan T.G. Crosstalk between interleukin-6 and corticotropin-releasing factor modulate submucosal plexus activity and colonic secretion.Brain Behav Immun. 2013; 30: 115-124Crossref PubMed Scopus (16) Google Scholar Stress also causes changes in enteric neuronal density and neurotransmitter expression.41Li S. Fei G. Fang X. et al.Changes in enteric neurons of small intestine in a rat model of irritable bowel syndrome with diarrhea.J Neurogastroenterol Motil. 2016; 22: 310-320Crossref PubMed Scopus (2) Google Scholar Enteric bacteria (from the altered intestinal microbiomes associated with FBDs) are now believed to regulate aspects of the enteric neural circuitry and affect organ functions beyond the intestine.44Hyland N.P. Cryan J.F. Microbe-host interactions: Influence of the gut microbiota on the enteric nervous system.Dev Biol. 2016; 417: 182-187Crossref PubMed Scopus (84) Google Scholar Numerous studies have demonstrated that soluble mediators found in mucosal biopsies and fecal supernatants from patients with IBS elicit physiologic responses in enteric neurons.45Nasser Y. Boeckxstaens G.E. Wouters M.M. et al.Using human intestinal biopsies to study the pathogenesis of irritable bowel syndrome.Neurogastroenterol Motil. 2014; 26: 455-469Crossref PubMed Scopus (0) Google Sch" @default.
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• W2778077278 title "Functional Bowel Disorders: A Roadmap to Guide the Next Generation of Research" @default.
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