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Working Group #02 Consolidated Post-Conference Call Report.doc Working Group #02 Consolidated Post-Conference Call Report.doc Document Transcript

  • NCDD Functional Gastrointestinal Disorders and Motility Disorders Working Group (WG 2) Consolidated Post-Conference Call ReportChair: Kenton M. Sanders, PhD, University of Nevada School of Medicine, RenoVice Chair: Nancy J. Norton, International Foundation for Functional Gastrointestinal Disorders, MilwaukeeThis document is a collection of the revised reports that were submitted by the above-named NCDDWorking Group (WG) members following their February 21, 2007, conference call.The reports contain the members’ revised goals based on discussions during the call and the list of long-term research goals compiled by Dr. Sanders, distributed by email to the members, and included herebeginning on page 45.The revisions were submitted in preparation for the group’s second conference call to be held on: Monday, March 26, 2007 7:00-9:00 pm Eastern TimeThe numbers in parens [( )s] indicate the pages presenting the goals. These are also given at the beginningof each report. List of Reports PageKenton M. Sanders, PhD (3-5)....................................................................................................................2Michael Camilleri, MD, and Henry P. Parkman, MD (8-9).........................................................................7Carlo DiLorenzo, MD (17-20)...................................................................................................................16Douglas Drossman, MD (26-27)................................................................................................................21Gerald F. Gebhart, PhD (30)......................................................................................................................29Allen Mangel, MD, PhD (32)....................................................................................................................31Emeran Mayer, MD (35-36)......................................................................................................................34Jackie (Jack) D. Wood, PhD, ACAF (39, 41, 43)......................................................................................38Dr. Sanders’ List of Categorized Long-Term Goals..................................................................................45 1
  • NAME: Kenton M. Sanders, PhD, ChairWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 3: Goals1. RESEARCH ADVANCES Research Advance #1 Role of interstitial cells of Cajal (ICC) in gastrointestinal motility and disease. ICC are pacemaker cells, conduits for propagation and coordination of electrical activity, regulators of the basal level of excitability of the musculature, mediators of inputs from motor neurons, and stretch receptors. Other actions, such as a modulatory role of sensory nerve terminals, have been proposed but not yet fully documented. Loss of these cells in a variety of gastrointestinal motility and functional GI disorders provides exciting new hypotheses for the etiology of these diseases.Citations:Sanders KM, Ordog T, Ward SM. Physiology and pathophysiology of the interstitial cells of Cajal: frombench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitialcells of Cajal. Am J Physiol Gastrointest Liver Physiol. 2002; 282:G747-G756.Hirst GD, Edwards FR. Role of interstitial cells of Cajal in the control of gastric motility. J PharmacolSci. 2004; 96:1-10.Sanders KM, Koh SD, Ward SM. Interstitial cells of cajal as pacemakers in the gastrointestinal tract.Annu Rev Physiol. 2006;68:307-343. Research Advance #2 Neural stem cells (neural crest stem cells) persist in the gut after birth. Stem cells from other sources also show some promise of giving rise to functional neurons in the GI tract. The field of directed stem cell therapy is developing and holds some promise for future clinical applications.Citations:Mosher JT, Yeager KJ, Kruger GM, Joseph NM, Hutchin ME, Dlugosz AA, Morrison SJ. Intrinsicdifferences among spatially distinct neural crest stem cells in terms of migratory properties, fatedetermination, and ability to colonize the enteric nervous system. Dev Biol. 2006 Oct 24; [Epub ahead ofprint]Micci MA, Pasricha PJ. Neural stem cells for the treatment of disorders of the enteric nervous system:strategies and challenges. Dev Dyn. 2007; 236:33-43.Micci MA, Kahrig KM, Simmons RS, Sarna SK, Espejo-Navarro MR, Pasricha PJ. Neural stem celltransplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice.Gastroenterology. 2005; 129:1817-1824.Bondurand N, Natarajan D, Thapar N, Atkins C, Pachnis V. Neuron and glia generating progenitors of themammalian enteric nervous system isolated from foetal and postnatal gut cultures. Development. 2003Dec;130(25):6387-400. 2
  • Research Advance #3 We now recognize many of the ionic conductances that are responsible for the excitability of smooth muscle cells, ICC, and enteric neurons. Much has been learned about the control of ion channels by neurotransmitters and hormones. Manipulation of these conductances with small, soluble molecules may provide new opportunities for regulating motility or symptoms of functional GI disorders.Citations:Galligan JJ. Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol Motil. 2002;14:611-623.Neylon CB, Nurgali K, Hunne B, Robbins HL, Moore S, Chen MX, Furness JB. Intermediate-conductance calcium-activated potassium channels in enteric neurones of the mouse: pharmacological,molecular and immunochemical evidence for their role in mediating the slow afterhyperpolarization. JNeurochem. 2004; 90:1414-1422.Sanders KM, Koh SD, Ward SM. (2006) Organization and electrophysiology of interstitial cells of Cajaland smooth muscle cells in the gastrointestinal tract. In: Physiology of the Gastrointestinal Tract. 4thEdition. Ed: L.R. Johnson, Elsevier Press, San Diego, pp. 533-576. Research Advance #4 New sensory transduction mechanisms in visceral afferent neurons: (a) capsaicin receptors (TRP channels), (b) ATP-gated channels, (c) proton-gated channels, and (d) nociceptor-specific Na+ channels.Citations:McCleskey EW, Gold MS. Ion channels of nociception. Annu Rev Physiol. 1999;61:835-56.Dib-Hajj S, Black JA, Cummins TR, Waxman SG. NaN/Nav1.9: a sodium channel with uniqueproperties. Trends Neurosci. 2002; 25:253-259.Pingle SC, Matta JA, Ahern GP. Capsaicin receptor: TRPV1 a promiscuous TRP channel. Handb ExpPharmacol. 2007; 179:155-171.Krishtal O. The ASICs: signaling molecules? Modulators? Trends Neurosci. 2003 26:477-483.Tominaga M. Nociception and TRP channels. Handb Exp Pharmacol. 2007; 179:489-505.Hughes PA, Brierley SM, Young RL, Blackshaw LA. Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons withinthoracolumbar dorsal root ganglia. J Comp Neurol. 2007; 500:863-875.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years):1. Perform gene array studies on interstitial cells of Cajal to determine: (i) what are the baseline phenotypic signatures for different classes of ICC? (ii) what makes these cells unique in relation to smooth muscle cells and neurons?; and (iii) are there new specific proteins that can be used to identify ICC, particularly during pathophysiological changes when Kit expression fades? 3
  • 2. Determine the fate of ICC in animal models of motility and functional GI disorders (i.e., do ICC experience cell death or is their phenotype altered such that they become non-functional).3. Determine the natural turn-over of ICC and whether stem cells exist in the bowel wall that are capable of regenerating ICC.4. Complete the survey of ionic conductances present in smooth muscle cells, ICC and neurons, and determine species differences between major animal models and humans. Expression analysis followed by physiological confirmation is the best approach to this goal.5. Develop dynamic imaging techniques to make it possible to study afferent nerve terminals in the lamina propria and tunica muscularis.6. Develop new cell-specific reagents to select for enterochromaffin cells, different classes of enteric neurons, glia, macrophages, ICC, etc. so these cells can be identified in heterogenous dispersions, sorted by automated cell sorting techniques, and studied with modern cell and molecular biology techniques.7. Test sensitivity to GI pain and sensation and development of hypersensitivity in knock-outs of nociceptive-specific ion channels.8. Start collecting patient reagents for functional GI disorders; reagents should be accompanied by fairly extensive clinical records and should be collected from family members with and without symptoms. Where possible, collect samples of affected organs to blood or other reagents.Intermediate-Term Goals (4-6 years):1. Perform gene array studies to provide genome-wide analysis of the changes in ICC over the period of time in which these cells are lost from tissues in animals with motility and functional GI disorders.2. Determine whether there are common factors causing loss of ICC in animals that develop motility or functional GI disorders.3. Determine changes in receptor profiles, excitability, Ca2+ handling and contractile mechanisms in smooth muscle cells in response to hypertrophy, inflammation, immune mediators, aging and gender- specific conditions.4. Assess factors that regulate gut endocrine cells (enterochromaffin cells, A cells and L cells). Develop isolated cell preparations and strategies to sort and enrich cell preparations of these cells.5. Identify the nociceptors in the wall of the gut that underlie activation of pain pathways.6. Develop a better understanding of the factors responsible for sensory input to the enteric and central nervous systems. Characterize the signaling molecules released from enterochromaffin and other sensory cells in the mucosa, and the post-junctional effectors (i.e., receptors, ion channels, and signaling pathways) in afferent nerve terminals.7. Determine cell-specific receptors, sensory transduction mechanisms, and signaling pathways in GI- specific nociceptors.8. Develop multiple knock-outs of nociceptive-specific ion channels and retest sensitivity to GI pain and development of hypersensitivity in these animals. 4
  • 9. Develop better understanding of the neural circuitry and control mechanisms that generate motility patterns besides the peristaltic reflex. This might provide a means to switch patterns to obtain desirable outputs (constipation or gastroparesis toward propulsive behavior, etc.)10. Begin comparisons of genome-wide phenotypes of patients with different GI motility disorders and family members with and without symptoms. Use new arrays that discern splice variants and polymorphisms.Long-Term Goals (7-10 years):1. Develop new animal models that recapitulate functional bowel diseases.2. Develop strategies to block specific signaling molecules and mechanisms that participate in the stimulation and sensitization of GI-specific afferent nerves.3. Develop strategies to block the factors causing loss of ICC in response to inflammation, infection, diabetes, surgery, etc.4. Develop a strategy for transplantation of ICC or re-establishment of ICC populations from mesenchymal stem cells.5. Study the physiology of enterochromaffin and other sensory cells in the mucosa.6. Study changes in expression and function of cell-specific receptors in animal models of motility and functional GI disorders.7. Develop specific ion channel-blocking drugs for nociceptive-specific ion channels.8. Determine genetic profiles of patients prone to functional GI disorders. Employ computational biology techniques to look for patterns that predispose patients to functional GI disorders.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS We need better techniques to isolate and identify specific types of cells from healthy and diseased gut samples. This is the only way we can determine the specific cellular changes that occur during the development of a disease process. With proper cell isolation techniques, modern technologies such as genomic and proteomic analyses are possible. In many cases, cells of the GI tract do not conserve their phenotype when dispersed and cultured. This is likely due to the role of the microenvironment in establishing and maintaining specific phenotypes. Thus, we need to develop techniques to alter the genetic expression of GI cell types while the cells are still in their native environment. This would greatly speed up studies of the role of specific proteins in cell and tissue function. We need to develop imaging (or other) techniques to study the behavior of afferent nerve terminals in the lamina propria and tunica muscularis. Most research into the mechanisms controlling excitability of these cells is focused at cell bodies, but these regions of the cells might have different receptors, ion channels, and signaling pathways in play than the sensory nerve terminals. We cannot fully understand normal activation, integration, or sensitization until we understand the physiology of nerve terminals. 5
  •  We need to establish more suitable animal models for functional GI disorders. This is the only way to study the cause-and-effect relationship between a suspected pathological factor and the development of symptoms and disease. We need to develop further imaging techniques to determine how ICC communicate and regulate the behaviors of smooth muscle cells, and how ICC respond to neurons in situ. We need to develop better methods for learning how neurons in the enteric nervous system and spinal cord communicate and integrate information. Better large-scale imaging and computational techniques are needed to follow and compute the significance of patterns. 6
  • NAMES: Michael Camilleri, MD, and Henry P. Parkman, MDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 8: Goals1. RESEARCH ADVANCES Research Advance #1 Expanded understanding of mechanisms involved in the brain-gut axis and neurohormonal control of motor (including pacing mechanisms) and sensory functions of the GI tract lending itself to the development of novel pharmacologic treatments of GI motility disorders, functional GI disorders, and obesity: 5-HT3 receptor antagonists, 5-HT4 receptor agonists, corticotropin releasing factor antagonists, ghrelin, nitric oxide and other gas transmitters, mu opioid receptor modulation, cannabinoids, etc.Citations:a. Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology. 2006;131:1925-42.b. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007; 132:397-414.c. Andresen V, Camilleri M. Irritable bowel syndrome: recent and novel therapeutic approaches. Drugs. 2006;66:1073-88.d. Schicho R, Krueger D, Zeller F, Von Weyhern CW, Frieling T, Kimura H, Ishii I, De Giorgio R, Campi B, Schemann M. Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon. Gastroenterology. 2006;131:1542-52.e. Martinez V and Taché Y. CRF1 receptors as a therapeutic target for irritable bowel syndrome. Curr Pharm Des. 2006;12:4071-88. Research Advance #2 Development of improved imaging or diagnostic techniques to better understand normal and abnormal esophago-gastric motility (High resolution manometry, Impedance manometry and Impedance pH, SPECT and MR Imaging), and noninvasive tests to assess gastrointestinal motility (stable isotope breath tests, SmartPill)Citations:a. Simonian HP, Maurer AH, Knight LC, Kantor S, Kontos D, Megalooikonomou V, Fisher RS, Parkman HP. Simultaneous assessment of gastric accommodation and emptying: studies with liquid and solid meals. J Nucl Med. 2004; 45:1155-60.b. Pandolfino JE, Zhang QG, Ghosh SK, Han A, Boniquit C, Kahrilas PJ. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high- resolution manometry. Gastroenterology. 2006;131:1725-33.c. Viramontes BE, Kim DY, Camilleri M, Lee JS, Stephens D, Burton DD, Thomforde GM, Klein PD, Zinsmeister AR. Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying. Neurogastroenterol Motil. 2001;13:567-74.d. Srinivasan R, Vela MF, Katz PO, Tutuian R, Castell JA, Castell DO. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol. 2001; 280: G457-62.e. Marciani L, Coleman NS, Dunlop SP, Singh G, Marsden CA, Holmes GK, Spiller RC, Gowland PA. Gallbladder contraction, gastric emptying and antral motility: single visit assessment of upper GI function in untreated celiac disease using echo-planar MRI. J Magn Reson Imaging. 2005; 22: 634-8. 7
  • Research Advance #3 Improved understanding of the mechanisms of obstructed defecation and fecal incontinence and the use of biofeedback to treat these disordersCitations:a. Lembo A, Camilleri M. Chronic constipation. N Engl J Med. 2003; 349:1360-8b. Bharucha AE, Wald A, Enck P, Rao S. Functional anorectal disorders. Gastroenterology. 2006; 130: 1510-8.c. Chiarioni G, Whitehead WE, Pezza V, Morelli A, Bassotti G. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology. 2006; 130:657-64d. Rao SSC, Miller SK, Brown CK, Nygaard I, Stumbo P, Zimmerman B, Schulze K. Randomized controlled trial of biofeedback, sham biofeedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol (2007) in press Research Advance #4 Role of inflammation as a mechanism for development of GI motility and functional GI disorders and the potential for antibacterial/probiotic approaches in treatment of functional GI disordersCitations:a. Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Tache Y, Wood JD. Fundamentals of neurogastroenterology: basic science. Gastroenterology. 2006; 130:1391-411.b. Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology. 2003;124:1662-71.c. OMahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, OSullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EM. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005; 128:541-51.d. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006; 145: 557-63.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years)• Support basic science investigation of transmitter mechanisms and inflammatory mediators in the transduction and treatment of motor disorders.• Develop better demographic/epidemiology data linked to bioinformatics data to help “finger-print” subtypes of patients with functional GI disorders, including application of novel noninvasive methodology to measure function in order to supplement questionnaire-based data and determine the true prevalence and burden of GI dysmotility.• Develop better methods to identify and correlate abnormalities in sensory and motility components in functional bowel disease patients.• Develop better methods/technologies and experimental designs to address the “disconnect” between a patient’s symptoms and demonstrable changes in validated clinical biomarkers, such as manometry, brain imaging technologies, barostat, telemetry, scintigraphy and other gastrointestinal imaging, etc.• Develop greater understanding of the cause-and-effect relationship of the changes in 5-HT signaling, expression, and reuptake and their implications to gut function and sensation and reversibility in subtypes of functional bowel disorders. 8
  • • Develop registries (phenotypic, symptom information, but also tissue and genetic material) of patients with defined motility disorders that could be used to further research the causes of the disorder and appropriate treatment.• Develop better understanding of the central and peripheral signaling pathways involved in stress- related alterations of motor function, visceral pain ,and inflammation.• Encourage research into methodology development to allow novel approaches to examine the interactions of the enteric nervous system, muscle, and afferent systems.Intermediate-Term Goals (4-6-years)• Develop an RFA mechanism to encourage consortium to apply the information and material from the registries to develop meaningful advances.• Develop a collaborative model between the NIH and industry to foster the development of probe molecules or devices that need to be tested in proof of concept studies.• Determine the pathways that mediate symptoms of patients with defined GI motility disorders.Long-Term Goals (7-10 years)• Determine appropriate therapeutic targets for GI motility and functional GI disorders.• Test the pharmacologic agents or devices in full-scale clinical trials in motility and functional gastrointestinal disorders.• Regenerate the NIH-Industry model to develop drugs and devices for the future that cannot be specified at this stage because they are predicated on the advances of the next 5 years.• Develop registries of a variety of GI motility disorders (achalasia, gastroparesis, chronic intestinal pseudoobstruction, colonic inertia) that will bank phenotypic information, symptoms information, genetic information, and tissue that can be used to define the causes of these disorders and suggest appropriate treatment.• Identify the cause of patients’ symptoms with defined GI motility disorders and determine if treatment directed at a patient’s underlying pathophysiology at the periphery is better treatment than nonspecific symptom modulators that work centrally.• Determine if pharmacogenetic analysis of patients helps to better select the appropriate drugs and dosage of drugs to treat patients with GI motility disorders.• Use simple noninvasive GI motility testing on a large scale to better understand the prevalence of GI motility disorders in the general population. Initially, this would investigate the prevalence of abnormalities in gastric emptying, colonic transit, and visceral sensation.• Understand the neural circuitry of the GI tract with a better understanding of the interactions of the motor efferent nerves, the sensory afferent nerves, and the central nervous system.• To determine if the benefit of novel treatment strategies that are being used in other areas can be successfully used for treatment of patients with defined GI motility disorders. These include GI tract electric stimulation, stem cell transplantation, treatment of inflammation, and GI tract transplantation for severe motility disorders.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS 9
  • • Lack of tissue from affected and comprehensively phenotyped and genotyped individuals with GI motility disorder to help determine the pathophysiology and mechanisms of disease.• Need for better animal models for studying various disease states, including inflammation and irritable bowel syndrome.• Lack of researchers, both clinical and basic, for the investigation of GI motility disorders.• Lack of funding mechanisms for the middle level researchers after career development (e.g., K series) awards.• Lack of translational research that combines both basic sciences in clinical areas; lack of researchers that comprehensively understand the two ends that need to be basis for translational enteric neuroscience.• Lack of long-term stable interaction between industry and NIH for the digestive diseases. The model of NCI and Industry is one that needs to be explored.• Public relations and communication with public and legislators, NIH, foundations, and other Federal agencies.• Attracting more, better trained individuals into the field of GI motility and functional GI disorders.4. PATIENT PROFILE TOPICS • Patient with Persistent Symptoms of Gastroparesis. Gastroparesis is a classic GI motility disorder involving the stomach. This case history illustrates a typical patient who has to try a variety of medications that have limited efficacy and side effects.A 31-year-old female with a 20-year history of insulin-dependent diabetes mellitus presents for theevaluation of nausea, vomiting, post-prandial fullness, and discomfort for 6 months. There has been a lossof approximately 10% of her body weight during the same time period.On examination, she has a body mass index of 20 (normal 21-25 kg/m2). Orthostatic hypotension ispresent upon standing. The abdomen is mildly tender in the epigastric region without distention. Stool isnegative for occult blood.Fasting blood glucose is 160 mg/dl and the HgbA1C value is 8.9 %. Complete blood count (CBC), thyroidfunction tests, aminotransferases, and lipase are normal. Upper endoscopy after an overnight fastdemonstrates some retained solid food, however the mucosa appears normal and a rapid urease test for H.pylori is negative. A gastric-emptying test using a meal consisting of an egg sandwich radiolabeled with99m Tc sulfur-colloid demonstrates 72% retention in the stomach at 2 hours (normal < 60%) and 26%retention at 4 hours (normal < 10%).This patient was diagnosed with diabetic gastroparesis and treated with metoclopramide (Reglan). Shedeveloped depression after starting Reglan, which resolved on stopping it. She was then treated witherythromycin, which helped for several weeks but then her symptoms returned. She was treated withdomperidone using the FDA compassionate use program with partial response. Unfortunately, she couldonly afford low-dose therapy (10 mg po QID). She is currently being considered for either a jejunostomyfeeding tube and/or gastric electric stimulation.COMMENT: The treatment of gastroparesis is predominantly based on expert opinion and consensusguidelines that have been provided through the leadership of AMS and AGA, and are reflected in areview in the New England Journal of Medicine. However, the quality of evidence is relatively poor sincemost recommendations on dietary, nutritional, and drugs or device therapy result from clinical experiencerather than randomized controlled trials.References: 10
  • a. Abell TL, Bernstein VK, Cutts T, Farrugia G, Forster J, Hasler WL, McCallum RW, Olden KW, Parkman HP, Parrish CR, Pasricha PJ, Prather CM, Soffer EE, Twillman R, Vinik AI; American Motility Society. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006; 18:263-83.b. Parkman HP, Hasler WL, Fisher RS; American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004; 127:1592-622.c. Camilleri M. Clinical Practice Series: Diabetic Gastroparesis. N Eng J Med 2007 (February 22, 2007 publication).5. GRAPHICS AND IMAGESA. Brain-Gut axis and mechanisms of sensationB. Gut hormones, satiation, and obesity 11
  • Plasma hormonal measurements showing the fasting and postprandial measurements of insulin, leptin,PYY, and ghrelin. Note the wide separation in insulin, ghrelin, and leptin levels, consistent with theknown effects of obesity compared with controls. In contrast, PYY levels during fasting andpostprandially were not significantly different in the 3 groups. —, normal; – – –, overweight; - - -, obeseTransient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrentfluoroscopy and high-resolution manometry.(A) Isocontour manometric plots of the EGJ during a tLESR. The pressure scale is color-coded with the high-pressure magnitudes represented by the red regions and the low-pressure magnitudes represented by blue. The exact pressure at any point on this spatial-temporal grid can be ascertained using either the isobaric contour tool or the point-and-click smart mouse tool of the ManoView software. The positions of the SCJ and proximal esophageal endoclip are superimposed on the isocontour plots as magenta lines illustrating the temporal relationship between esophageal shortening, EGJ relaxation, and common cavity formation.(B) Spatial pressure variation plots of the same pressure data illustrated in panel A. Each vertical line depicts the axial pressure profile spanning from the pharynx to the stomach with successive lines showing 0.2-s time increments. Note that a common cavity is generated during the relaxation period, indicated by an abrupt intraesophageal pressure increase. Again, the magenta lines indicate endoclip positions. 12
  • C. Novel transmitters in the gastrointestinal tractThe expression of H2S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase(CBS) is shown in enteric neurons of guinea-pig colon, human colon, and myenteric interstitial cells ofCajal guinea-pig ileum. (A) In the guinea-pig submucous plexus, colocalization studies showed that CSE-IR is present in all HU-IR neurons. (B) Rabbit and mouse CSE antibodies label identical neurons. (C)CSE-IR and CBS-IR are found in the same neurons. (D) In human submucous plexus, CSE-IR is presentin all NSE-IR neurons. (E) CSE-positive neurons entirely overlap with CBS-positive neurons in a humansubmucous ganglion. (F) Kit-IR ICC in guinea-pig myenteric plexus also are CSE-IR but not (G) CBS-IR. (H) Double-labeling with NSE shows neuronal expression of CSE in the myenteric plexus of theguinea-pig ileum. Scale bars = 100 μm. 13
  • 14
  • D. Novel agents for the treatment of functional and gastrointestinal motility disorders 15
  • NAME: Carlo DiLorenzo, MDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 17: Goals1. RESEARCH ADVANCES Research Advance #1 Investigation of the Development of the Enteric Nervous System The molecular genetics of multiple endocrine neoplasia type 2B and Hirschsprungs disease, disorders characterized by gross and/or microscopic pathology of the enteric nervous system and associated dysmotility, have been uncovered (1). Intercellular signaling pathways involved in enteric neurodevelopment and mediated by GDNF/GFRa1/RET, EDN3/ENDRB, and NETRINS/DCC have been characterized (2). Nuclear and mitochondrial mutations associated with abnormalities of neuroenteric development have been identified in animal models and human disease. These mutations result in a spectrum of disorders: aganglionosis, absence of specific neuronal cell populations, absent interstitial cells of Cajal, and dysfunctional intestinal smooth muscle (3).Citations:1. Gershon MD, Ratcliffe EM. Developmental biology of the enteric nervous system: pathogenesis of Hirschsprungs disease and other congenital dysmotilities. Semin Pediatr Surg. 2004 Nov;13(4):224-35.2. Stanchina L, Baral V, Robert F, Pingault V, Lemort N, Pachnis V, Goossens M, Bondurand N. Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. Dev Biol. 2006 Jul 1;295(1):232-49.3. Giordano C, Sebastiani M, Plazzi G, Travaglini C, et al. Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine. Gastroenterology. 2006 Mar;130(3):893-901 Research Advance #2 Neuro-immunology and the Gut: Characterization of the Interactions Between the Central Nervous System, Enteric Nervous System, and Immune System A growing understanding of the nature and complexity of the interactions between the central nervous system, the enteric nervous system, and the immune system has led to the recognition that the arbitrary division of gut disorders as inflammatory disorders or functional disorders may be misleading. Indeed, the pathophysiology of many GI disorders involves interactions among the CNS, ENS, and immune system. Perturbations in normal physiology may be triggered by an insult such as an infection, which can result in long-term alterations in the ENS or CNS responses to subsequent stimuli (1, 2). Mast cells and enterochromaffin cells have been found to be markers of mucosal immune activation both in IBS in humans and in animal models (3). Subtle changes in the mucosal immune system may increase the excitability of neurons involved in local reflexes and central pathways in response to food antigens and chemical stimuli. In the other direction, enteric neurons are also involved in the regulation of inflammatory processes and may directly affect local neuroimmune reactions.Citations:1. Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut. 2003; 52: 91-3. 16
  • 2. Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003; 52: 523-6.3. Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C, Di Nardo G, Trevisani M, Campi B, Geppetti P, Tonini M, Bunnett NW, Grundy D, Corinaldesi R. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology. 2007 Jan;132(1):26-37 Research Advance #3 Role of Early Life Events in the Development of Functional Gastrointestinal Disorders Data from animal experiments and observations from clinical experience suggest the importance of early life events in the future development of chronic visceral hypersensitivity and functional gastrointestinal disorders (1, 2). Transient noxious stimulation of the viscera and periods of stressful maternal separation in rats in the first few days of life, and surgery (3) or intubation of the gastrointestinal tract at birth, a period in which the nervous system is most vulnerable, can cause long-standing sensitization of the neural pain circuits despite complete resolution of the initiating event.Citations:1. Al-Chaer ED; Kawasaki M; Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 2000; 119: 1276-85.2. Anand KJ, Runeson B, Jacobson B. Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J Pediatr. 2004 Apr;144(4):449-54.3. Peters JW, Schouw R, Anand KJ, van Dijk M, Duivenvoorden HJ, Tibboel D. Does neonatal surgery lead to increased pain sensitivity in later childhood? Pain. 2005 Apr;114(3):444-54. Research Advance #4 Understanding of the Role of Serotonin and Modulation of Serotenrgic Receptors in Modifying Gut Motor and Sensory Function The understanding that serotonin activates intrinsic and extrinsic primary afferent neurons to promote peristaltic and secretory reflexes and to modulate sensory signaling in the brain-gut axis (1). The identification of different serotonin receptor subtypes has allowed drugs to be designed to modulate gastrointestinal motility, secretion, and sensation and has led to the FDA approval of the first drugs shown to be effective treatment for constipation and diarrhea predominant IBS (2). Polymorphisms in the promoter region of the serotonin reuptake transporter (SERT) gene may be involved in the gut dysfunction in patients with diarrhea predominant IBS (3).Citations:1. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007 Jan;132(1):397-414.2. Nyhlin H, Bang C, Elsborg L, Silvennoinen J, Holme I, Ruegg P, Jones J, Wagner A. A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome. Scand J Gastroenterol. 2004 Feb;39(2):119-263. Yeo A, Boyd P, Lumsden S, Saunders T, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhea-predominant irritable bowel syndrome in women. Gut. 2004 Oct;53(10):1452-8.2. GOALS FOR RESEARCH 17
  • A. Long-Term Goal (7-10 years): “Develop the means to use stem cells as a treatment for gut disorders where smooth muscle cells, ICC or enteric neurons are reduced, absent, or malfunctioning”. Consolidate with “Develop stem cell based strategies to treat fecal incontinence due to structural anal sphincter damage”. Short-Term Goal (1-3 years): Identify histological changes associated with different phenotypic manifestation of functional and motility disorders. That is, one needs first to find out in what conditions “enteric neurons are reduced, absent, or malfunctioning” before considering therapeutic interventions. This should be accomplished through development of a tissue bank much like it has been done in oncology from patients with well-defined conditions (achalasia, Hirschsprung’s etc). This is also part of another long-term goal that can be consolidated here. Intermediate-Term Goal (4-6 years): Identification of early progenitors of the enteric nervous system and the mechanisms controlling their differentiation into functioning nerves controlling motor and sensory function, including sphincter activity.B. Long-Term Goal: “Develop strategies to prevent development or minimize morbidity associated with IBS.” Probably too vague of a goal. Many other long-term goals described in the previous document could be used in the short or intermediate range to achieve this goal. Here is an example of how to group those goals: Short-Term Goals: 1. Determine appropriate therapeutic targets for GI motility and functional GI disorders 2. Understand the therapeutic potential of prophylaxis with antibiotic treatment in the prevention of IBS and FD. 3. Test pharmacologic agents or devices in full scale clinical trials in motility and functional gastrointestinal disorders 4. Use simple noninvasive GI motility testing on a large scale to better understand the prevalence of GI motility disorders in the general population. Intermediate-Term Goals: 1. Assess success of the coordinating committee between NIH-FDA-Pharmaceutical Industry for rationale drug design “from molecule to man.” 2. Evaluate the effectiveness and cost-effectiveness of novel disease management approaches involving novel pharmacological compounds and non-pharmacological strategies (disease education, cognitive behavioral therapy). 3. Demonstrate through multi-center trials standardized physician training programs in GI that show improved patient outcomes and reduced costs. 4. Determine if pharmacogenetic analysis of patients helps to better select the appropriate drugs and dosage of drugs to treat patients with GI motility disorders.C. Long-Term Goal: Develop small bowel pacing”. Here again I tried to consolidate some of the other long-term goals, listing them among either short-term or intermediate goals. 18
  • Short-Term Goals: 1. Understand the role of extrinsic afferent and efferent pathways in coordinating/modulating the intrinsic neural-pacing-muscular processes. 2. Determine how altered activity of extrinsic neurons (autonomic nervous system and central nervous system) influences the GI motility. Intermediate-Term Goals 1. Identify patient subpopulations likely to benefit from small bowel pacing. 2. Develop animal models of intestinal pacing. 3. Understand the physiologic variables (sensation, motility, transit, tone) likely to be affected by intestinal pacing.D. Long-Term Goal: “Improve outcome of small bowel transplantation so that it becomes as routine as kidney transplants are now.” I would probably eliminate this goal. It may apply to a much too small patient population. If we keep it, then what follows would apply. Short-Term Goals: 1. Improve understanding of the motor and sensory functions of the allograft small bowel, stomach and colon. 2. Develop pharmacologic therapies aimed at slowing the accelerated small bowel transit present in most patients with transplanted small bowel. Intermediate-Term Goals 1. Develop more effective and safer immunosuppressive and anti-viral treatments. 2. Develop non invasive techniques to monitor for allograft rejection.E. Long-Term Goal:“Understand developmental processes that lead to functional GI disorders. Are there developmental defects predispose the gut to motor or functional pathologies?.” Here again, I tried to group some long-term goals into achievable short-term and intermediate goals. Short-Term Goals: 1. Develop novel techniques to screen for disorders of gastrointestinal sensory and motor in animal models with targeted genetic alterations. 2. Clarification of the role that adverse environmental factors, such as fetal exposure to drugs, prematurity, physical or sexual abuse, neglect, parental loss, or medical illnesses play in the future development of FBD. 3. Identification of the long-term outcome of childhood FBD and the factors impacting on prognosis Intermediate-Term Goals: 19
  • 1. Identify vulnerability factors for the development of functional disorders (genetic polymorphisms, gene-environment interactions). 2. Based on genetic vulnerability factors, develop early intervention strategies to prevent development of the full clinical syndromes of functional GI diseases. 3. Identification of nuclear and mitochondrial mutations associated with abnormalities of neuroenteric development in animal models and human disease. 4. Understand factors involved in the control of enteric nervous system plasticity.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALSCHALLENGES Lack of reliable animal models for most motility and functional gastrointestinal disorders. Lack of communication between basic and clinical scientists. Absence of biologic markers for most FGIDs. Translation of observations in animal models to human interventions. Few young scientists attracted to work in the area of GI motility and functional disorders.STEPS Develop tissue banks. Encourage and support collaborative efforts within the institution among basic and clinical scientists and among different institutions. Increase financial support for studies of motility and FGID. 20
  • NAME: Douglas Drossman, MDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 26: Goals1. RESEARCH ADVANCES Research Advance # 1 Evidence for Altered Brain-Gut Axis in IBS: Dysregulation of Stress/CNS Function, Mucosal Immunity/Inflammation, and Central Pain Regulation Several lines of evidence in the last few years support the concept of dysregulation of stress circuitry in IBS that is linked to and affects gut function (and vice versa). There is: (a) increased CRH and ACTH reactivity to stress as well as also increased gut response (motility, pain) to CRH (1-4), which can be blocked by CRH antagonists (3); (b) increased mucosal inflammatory activity (5); (c) increasing evidence for stress-associated disruption of intestinal mucosal barrier function (i.e., increased membrane permeability, mast cell activation, and mucosal inflammation leading to visceral sensitization (6-9); and (c) altered limbic system (i.e., anterior cingulate cortex) reactivity to visceral signals leading to increased pain response in IBS that is enhanced by stress (e.g., abuse history) (10-14). These associations can lead to new treatments for IBS and other functional GI disorders based on reduction of stress via psychological or pharmacological treatments (15-19) or by treatment of their mediating pathways including CRH (20;21). In addition, there is now evidence that the mediating mechanisms for reduction in pain can be evaluated via brain imaging (12). Research Advance # 2 Post-infectious IBS Prospective evaluations of post-infectious IBS have shown that up to 20% of individuals getting bacterial gastroenteritis may go on to develop symptoms of IBS (post-infectious IBS; PI-IBS, or post- infectious dyspepsia (22),(23)) and identification of predictive factors show two important features relative to the pathogenesis of this disorder: (a) association of mucosal inflammation and altered mucosal immunity; and (b) association of psychosocial disturbance at time of infection (24-27). Both factors predict the likelihood of continued IBS symptoms. This condition supports the need and can serve as a model to study the relationship as noted above, between stress, mucosal inflammation, and symptoms in IBS and dyspepsia. (See Research Advance #3). Research Advance # 3 Altered Bacterial Flora in IBS and the Role for Probiotics There is emerging evidence that patients with IBS (including post-infectious IBS) may have altered or increased bacterial flora that can affect mucosal inflammation and immune function leading to neural sensitization. The work looking at the effects of “good” and “bad bacteria on mucosal immune function suggests the possible benefits of probiotic bacteria to either prevent or treat this condition (28-33). Further studies are needed to determine the patient subset that might be most responsive to this type of treatment. Research Advance # 4 The Physician-Patient Relationship 21
  •  The physician patient relationship provides a basis for all other clinical interventions and by itself is associated with improved clinical outcome (34). There is a compelling literature, mostly from other medical areas involving diabetes, hypertension, breast cancer, and general primary care that indicates how poor communication and dysfunctional physician-patient relationships in the clinical setting lead to more adverse health outcomes, while conversely more effective relationships produce better outcomes (34;35). Positive outcomes include satisfaction with care, adherence to treatment, improved quality of life and symptoms, improved physiological measures, reduced physician visits and health care costs, and fewer malpractice claims (36-39) (40;41) (42;43). Patients rate highest in expectation the physician’s humaneness and technical competence and their interest in psychosocial factors and the provision of medical education (44); interestingly physicians who question primarily on biomedical issues will receive poorer patient satisfaction (44;45). Both verbal and nonverbal behaviors, including good eye contact, affirmative nods and gestures, fewer negative comments, a partner-like relationship, closer interpersonal distance, and even the tone of the voice are major determinants of satisfaction, treatment adherence, other and improved outcomes (45-48). Conversely, verbal and nonverbal behaviors that are ineffective, or which communicate physician dominance, are associated with more frequent malpractice claims(41;49). More related to “harder” outcomes is the evidence that good physician-patient communication is associated with improved recovery from surgery, reduced symptoms, decreased pain medication use, shortened hospital stays and physiological benefits including reduced blood pressure and blood sugar (37;50). From the standpoint of physician satisfaction, those who exhibit positive interaction skills, tend to like patients more and are more satisfied with their work and their patients liked them more, and when these skills are inadequate, patient compliance is lowered and the therapeutic benefit reduced (44;51). Within gastroenterology, there has been virtually no attention to these skills, and the study of their effects. We do know that physicians tend to underestimate the impact of IBS and functional GI disorders on the patients’ health status and tend to undervalue their effectiveness with these patients, even to the point of stigmatizing them (52;53). In a recent NIH- (NIDDK) funded study assessing the benefit of placebo acupuncture with and without an augmented physician-patient communication against a wait list control, placebo acupuncture without augmented physician-patient communication was only slightly better on a variety of outcomes than a wait list control. However augmented acupuncture placebo showed marked improvement in global symptom scores, adequate relief of treatment, and improved quality of life that was in the clinically meaningful range with benefits similar to medical treatments of proven efficacy (Lembo, Drossman, submitted for publication 2007). Given the potential to significantly improve health outcomes, improve patient satisfaction, and reduce costs and litigation based on these compelling data, a research priority should be given to testing the effectiveness of training programs that teach communication skills and enhance the physician-patient relationship. All of these behaviors can be effectively taught (54;55), and methods exist that are quantifiable and reproducible for research (34;56;57).[Note: The following reference list was added as part of Dr. Drossman’s post-conference call revision.] Reference List (1) Tache Y, Million M, Nelson AG, Lamy C, Wang L. Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents. Gend Med. 2005;2:146-54. 22
  • (2) Dinan TG, Quigley EMM, Ahmed S, Scully P, OBrien S, OMahony L et al. Hypothalamic- pituitary-gut axis dysregulation in irritable bowel syndrome: Plasma cytokines as a potential biomarker? Gastroenterol. 2006;130:304-11. (3) Sagami Y, Shimada Y, Tayama J, Nomura T, Satake M, Endo Y et al. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut. 2004;53:958-64. (4) Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut. 1998;42:845-49. (5) Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterol. 2002;122:1778-83. (6) Yang PC, Jury J, Soderholm JD, Sherman PM, McKay DM, Perdue MH. Chronic psychological stress in rats induces intestinal sensitization to luminal antigens. Am J Pathol. 2006;168:104-14. (7) Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM et al. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterol. 2002;123:1099-108. (8) Barbara G, Stanghellini V, De GR, Corinaldesi R. Functional gastrointestinal disorders and mast cells: implications for therapy. Neurogastroenterol Motil. 2006;18:6-17. (9) Barbara G, Wang B, Stanghellini V, De GR, Cremon C, Di NG et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterol. 2007;132:26-37.(10) Ringel, Y., Drossman, D. A., Leserman, J., Lin, W., Wilbur, K, Suyenobu, B. Y., Berman, S., Whitehead, W. E., and Mayer, E. Association Between Central Activation and Pain Reports in Women with IBS. Gastroenterology 130(.). 2006. Ref Type: Abstract(11) Ringel Y, Drossman DA, Turkington TG, Hawk TC, Bradshaw B, Coleman RE et al. Regional Brain Activation in Response to Rectal Distention in Patients with Irritable Bowel Syndrome and the Effect of a History of Abuse. Dig Dis Sci. 2003;48:1774-81.(12) Drossman DA, Ringel Y, Vogt B, Leserman J, Lin W, Smith JK et al. Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe IBS. Gastroenterol. 2003;124:754-61.(13) Ringel, Y., Drossman, D. A., Leserman, J., Lin, W., Liu, H., Vogt, B., and Whitehead, W. E. Association of anterior cingulate cortex (ACC) activation with psychosocial distress and pain reports. Gastroenterology 124(4), A-97. 2003. Ref Type: Abstract(14) Naliboff BD, Derbyshire SWG, Munakata J, Berman S, Mandelkern M, Chang L et al. Cerebral activation in irritable bowel syndrome patients and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63:365-75. 23
  • (15) Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S et al. Cognitive-Behavioral Therapy vs. education and Desipramine vs. Placebo for Moderate to Severe Functional Bowel Disorders. Gastroenterol. 2003;125:19-31.(16) Creed F, Fernandes L, Guthrie E, Palmer S, Ratcliffe J, Read N et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterol. 2003;124 :303-17.(17) Creed, F. H., Fernandes, L., Guthrie, E., Palmer, S., Ratcliffe, J., Read, N., Rigby, C., Thompson, D. G., and Tomenson, B. The cost-effectiveness of psychotherapy and SSRI antidepressants for severe irritable bowel syndrome. Gastroenterolgy 120(5 (1)), A115. 2001. Ref Type: Abstract(18) Clouse, R. E., Prakash, C., and Anderson, R. J. Antidepressants for functional gastrointestinal symptoms and syndromes: A meta-analysis. Gastroenterology 120(.), A642. 2001. Ref Type: Abstract(19) Jackson JL, OMalley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with anti- depressants: A meta-analysis. Am J Med. 2000;108:65-72.(20) Tache Y. Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology? Gut. 2004;53:919-21.(21) Chang L. Neuroendocrine and neuroimmune markers in IBS: Pathophysiological role or epiphenomenon? Gastroenterol. 2006;130:596-600.(22) Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a meta- analysis. Am J Gastroenterol. 2006;101:1894-99.(23) Mearin F, Perez-Oliveras M, Perelló A, Vinyet J, Ibanez A, Coderch J et al. Dyspepsia after a Salmonella gastroenteritis outbreak: One-year follow-up cohort study. Gastroenterol. 2005;129:98-104.(24) Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52:523-26.(25) Gwee KA. Postinfectious Irritable Bowel Syndrome. Curr Treat Options Gastroenterol. 2001;4:287-91.(26) Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety and depression in post-infectious IBS. Gastroenterol. 2003;125:1651-59.(27) Drossman DA. What does the future hold for IBS and the functional GI disorders? J Clin Gastroenterol. 2005;39:S251-S256.(28) Whorwell PJ, Altinger L, Morel J, Bond Y, Charbonneau D, OMahony L et al. Efficacy of an encapsulated probiotic Bifidobacterium Infantis 35624 In women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581-90. 24
  • (29) OMahony L, McCarthy J, Kelly P, Hurley G, Luo F, OSullivan G et al. Lactobacillus and Bifidobacterium in Irritable Bowel Syndrome: Symptom Responses and Relationship to Cytokine Profiles. Gastroenterol. 2005;128:541-51.(30) Malinen E, Rinttila T, Kajander K, Matto J, Kassinen A, Krogius L et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100:373-82.(31) Drossman DA. Treatment for Bacterial Overgrowth in IBS (Editorial). Ann Intern Med. 2006;145:626-28.(32) Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of Irritable Bowel Syndrome. Am J Gastroenterol. 2000;95:3503-6.(33) Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. Rifaximin improves the symptoms of irritable bowel syndrome: A randomized trial. Ann Intern Med. 2006; [In press].(34) Roter DL, Hall JA. Doctors talking to Patients / Patients talking to doctors: Improving communication in medical visits. 2nd ed. Westport, CT: Praeger Publishing; 2006.(35) Lipkin MJr, Putnam SM, Lazare A. The Medical Interview: Clinical Care, Education, and Research. 1 ed. New York: Springer-Verlag; 1995.(36) Stewart MA. Effective physician-patient communication and health outcomes: a review. CMAJ. 1995;152:1423-33.(37) Kaplan SH, Greenfield S, Ware JE, Jr. Assessing the effects of physician-patient interactions on the outcomes of chronic disease. Med Care. 1989;27:S110-S127.(38) Rosser WW. Approach to diagnosis by primary care clinicians and specialists: is there a difference? J Fam Pract. 1996;42:139-44.(39) Roter DL, Hall JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care. 1998;36:1138-61.(40) Selfe SA, Matthews Z, Stones RW. Factors influencing outcome in consultations for chronic pelvic pain. Journal of Womens Health. 1998;7:1041-48.(41) Levinson W, Roter DL, Mullooly JP, Dull VT, Frankel RM. Physician-patient communication: The relationship with malpractice claims among primary care physicians and surgeons. JAMA. 1997;277:553-59.(42) Jackson JL, Kroenke K. The effect of unmet expectations among adults presenting with physical symptoms. Ann Intern Med. 2001;134 (2):889-97.(43) Stewart M, Brown JB, Boon H, Galajda J, Meredith L, Sangster M. Evidence on patient- doctor communication. Cancer Prev Control. 1999;3:25-30.(44) Hall JA, Dornan MC. What patients like about their medical care and how often they are asked: a meta-analysis of the satisfaction literature. Soc Sci Med. 1988;27:935-39.(45) Bertakis KD, Roter D, Putnam SM. The relationship of physician medical interview style to patient satisfaction. J Fam Pract. 1991;32:175-81. 25
  • (46) Milmoe S, Rosenthal R, Blane HT, Chafetz ME, Wolf I. The doctors voice: postdictor of successful referral of alcoholic patients. J Abnorm Psychol. 1967;72:78-84. (47) Roter DL, Hall JA, Katz NR. Relations between physicians behaviors and analogue patients satisfaction, recall, and impressions. Med Care. 1987;25:437-51. (48) Hall JA, Harrigan JA, Rosenthal R. Nonverbal behavior in clinician-patient interaction. Applied and preventive psychology. 1995;4:21-37. (49) Suchman AL, Markakis K, Beckman HB, Frankel R. A model of empathic communication in the medical interview. JAMA. 1997;277:678-82. (50) Schillinger D, Piette J, Grumbach K, Wang F, Wilson C, Daher C et al. Closing the loop: physician communication with diabetic patients who have low health literacy. Arch Intern Med. 2003;163:83-90. (51) Hall JA, Horgan TG, Stein TS, Roter DL. Liking in the physician--patient relationship. Patient Educ Couns. 2002;48:69-77. (52) Dalton CB, Drossman DA, Hathaway MD, Bangdiwala SI. Perceptions of physicians and patients with organic and functional gastroenterological diagnoses. Journal of Clinical Gastroenterology and Hepatology. 2004;2:121-26. (53) Drossman DA. Challenges in the physician-patient relationship: Feeling "drained". Gastroenterol. 2001;121:1037-38. (54) Dimatteo MR, Taranta A, Friedman HS, Prince LM. Predicting patient satisfaction from physicians nonverbal communication skills. Med Care. 1980;18:376-87. (55) Dimatteo MR, Hays RD, Prince LM. Relationship of physicians nonverbal communication skill to patient satisfaction, appointment noncompliance, and physician workload. Health Psychol. 1986;5:581-94. (56) Chang L, Drossman DA. Optimizing patient care: The psychosocial interview in the irritable bowel syndrome. Clinical perspectives in gastroenterology. 2002;5:336-41. (57) Drossman DA. Psychosocial Sound Bites: Exercises in the patient-doctor relationship. Am J Gastroenterol. 1997;92:1418-23.2. GOALS FOR RESEARCHShort-Term Objectives (1-3 years)Brain-Gut Axis Develop standard methods to assay CRH and ACTH response in patients. Standardize brain imaging methods (underway – Rome Working Team). Set up a consortium of academic centers for brain imaging studies in IBS. Support pilot grants that would evaluate and produce evidence based reviews of research on brain-gut axis.Post Infectious IBS and Altered Fecal Flora 26
  • Develop standardized methods for assaying intestinal fecal flora and mucosal cytokine activity. Set up a registry of patients who acquire bacterial gastrointestinal infection.Physician-Patient Relationship Support grants for evidence-based reviews on outcomes relating to communication skills and augmented physician-patient interactions. Set up an RFA for grant assessing training programs among expert clinicians to teach effective communication skills and to show physician and patient satisfaction and improved outcomes related to adherence to treatment and reduced procedures/costs with improved clinical outcomes, including health-related quality of life. Develop consensus on measurable clinical outcomes in IBS for treatment trials of behavioral outcomes and also of new medications (medication outcomes is underway – Rome Working Team).Intermediate-Term Objectives (4-6 years)Brain-Gut Axis Set up and collect a database registry of patients with IBS (Rome III criteria) of mucosal cytokines, CRH-ACTH assays, and fecal flora arrays. Identify risk factors for altered HPA reactivity (e.g., abuse history, PTSD, psychiatric co-morbidities).Post-Infectious IBS and Altered Fecal Flora Identify targets for treatment of post-infectious IBS. Support a multi-center trial on the use of probiotics for IBS.Physician-Patient Relationship Establish RFAs for multicenter training of communication skills and clinical decisionmaking to show improved direct patient outcomes as well as the generalizability of the training method (see Short-Term Objective 3b above).Long-Term Objectives (7-10 years)1. Brain-Gut Axis a. Develop a model to show the CNS and ENS-mucosal circuitry that explains the role of stress and altered bacterial flora on neuroendocrine dysfunction in IBS.2. Physician-Patient Relationship a. Demonstrate through multi-center trials standardized physician training programs in GI that show improved patient outcomes and reduced costs.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALSMajor Challenges Steps to Achieve Goals1. Lack of standardization for brain imaging Establish a set of consensus guidelines for research (underway with Rome Foundation)2. Lack of standardization for clinical outcomes Establish a consensus set of guidelines among 27
  • in treatment trials NIH, FDA, Pharmaceuticals, and Rome Foundation3. Inadequate standards for mucosal cytokine and Identify standard methods that will be consistentneuropeptides assays across research studies.4. Problems with generalizability of data and Set up a national database registry for patientstreatments across patient populations and with FGIDsresearch sites5. Limited Federal support for clinical studies a. Set up RFAs for this type of research, whichrelating to clinical skill development and patient can legitimize the research area and encourageoutcomes grant submissions b. Partner with organizations outside of GI that focus on this area (e.g., American Academy on Physician and Patient, ABIM)4. PATIENT PROFILE TOPICS1. Provide a case report of a patient with post-infectious IBS. Since this disorder is associated with both previous infection, psychosocial disturbance, and activation of cytokine inflammatory pathways, the case can include premorbid psychological state, clinical details of the infection, cytokine, EC cell assays post-infection, degree of psychological improvement by psychometric scales, and evidence for symptom reduction concurrent with improved mucosal immunity. Possibly Dr. Spiller in Nottingham UK might have such a case.2. Provide a case report of a patient with chronic, severe symptoms who is a high healthcare utilizer with high medical costs who is involved in dysfunctional patient-physician relationships and who is stigmatized by the care. Then show how her improvement was associated with changes in the relationship with the physician concurrent with improved self-efficacy and sense of control of the symptoms leading to marked clinical improvement and reduced clinical costs and healthcare utilization. (Author can provide several such cases with actual patients.)3. Provide a case report of a patient with severe IBS that correlates poor clinical and psychological state with increased pain on rectal distension and abnormal activation of cingulate cortex who then improves both clinically and psychologically concurrent with improvement in the abnormal brain imaging pattern. [This has already been published as a detailed case report (12); see attached PDF file of Case Report from Gastroenterology 2003;124:754-761; file name is “Drossman Case Profile_Alterations of Brain Activity Case”; author can probably arrange to have the patient available if needed.]5. GRAPHICS AND IMAGESSee attached file of relevant PowerPoint images; file name is “Drossman—NCDDimages.” 28
  • NAME: Gerald F. Gebhart, PhDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 30: Goals1. RESEARCH ADVANCES Research Advance #1 Each organ is innervated by two nerves, each of which has some overlapping but also distinct functions. A study characterizing mechanosensory properties of the lumbar splanchnic and pelvic nerve innervation of the mouse colon revealed unexpected and important differences.Citation:Brierley, S.M., Jones III, R.C.W., Gebhart, G.F. and Blackshaw, L.A. Splanchnic and pelvicmechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterol.2004;127:166-178. Research Advance #2 It has long been appreciated that patients with IBS also exhibit somatic hypersensitivity as well as other organ (i.e., non-colon) visceral hypersensitivity. This could arise from either or both peripheral and central mechanisms. Because somatic and visceral afferent inputs converge onto the same spinal cord neurons, it has been assumed that the cross-sensitization arose via a central mechanism. However, two publications suggest a peripheral mechanism, namely that a single visceral sensory neuron can give rise to axons that innervate different organs.Citations:1. Malykhina, A.P., Qin, C., Greenwood- Van Meerveld, B., Foreman, R.D., Lupu, F., and Akbarali, H.I. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol Motil 2006;18:936–948.2. Julie A. Christianson, Ruomei Liang, Elena E. Ustinova, Brian M. Davis, Matthew O. Fraser and Michael A. Pezzone. Convergence of bladder and colon sensory innervation occurs at the primary afferent level. In Press, Corrected Proof, Available online 27 October 2006, Pain – in press. Research Advance #3 New information about molecules that contribute to mechanosensation suggests that transient receptor potential vanilloid 1 and acid-sensing ion channel 3 may contribute to GI mechanosensation.Citations:1. Page, A.J., Brierley, S.M., Martin, C.M., Price, M.P., Symonds, E., Butler, R., Wemmie, J.A., Blackshaw, L.A. Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 2005;54:1408-1415.2. Jones III, R.C.W., Xu, L., Gebhart, G.F. The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid- sensing ion channel 3. J. Neurosci. 2005;25:10981-10989. 29
  • 2. GOALS FOR RESEARCHShort-Term Goals (1-3 years)1. Support for fellows and investigators studying basic mechanisms and models of GI hypersensitivity. By far, the bulk of NIDDK support for basic research has and continues to focus on motility, GI smooth muscle biology, or the intrinsic nervous system/neurons. Those of us studying the sensory side of things are funded by NINDS and have to emphasize the “pain and discomfort” of FGIDs to be relevant.2. Determine physiological and functional differences between the two extrinsic innervations of an organ.3. Initiate studies on genetic bases of GI disorders, including basic science studies that translate whole genome findings back to appropriate animal models to study mechanisms.4. Investigate extrinsic innervation of organs to determine the extent to which a single neuron soma innervates more than one organ.5. Initiate studies to determine the anatomical and functional relationship between the intrinsic and extrinsic innervations of an organ.6. Evaluate current funding topics/awards to ensure breadth of the field is addressed.Intermediate-Term Goals (4-6 years)1. Establish research support mechanisms/meetings to enhance interactions between motility and sensory biologists and between basic GI scientists and clinical GI scientists.2. Establish a process for integrative interactions between basic and clinical scientists, perhaps focused on disorders (e.g., IBS, pancreatitis, NUD, etc.).3. Resolve the physiological and functional differences between the two extrinsic innervations of an organ.4. Resolve the anatomical and functional relationship between the intrinsic and extrinsic innervations of an organ.Long-Term Goals (7-10 years)1. Develop a balanced funding portfolio to insure realistic opportunities for translation of basic findings into meaningful clinical trials and studies.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS Tracing methods/technology to achieve intermediate goal 3. Resources, of course. Commitment – requires assessment of current funding and making commitments to areas underrepresented or ignored.4. PATIENT PROFILE TOPIC [None to contribute] 30
  • 5. GRAPHICS AND IMAGES [None to contribute] 31
  • NAME: Allen Mangel, MD, PhDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 32: Goals1. RESEARCH ADVANCES Research Advance #1 A side effect associated with some of the drugs used to treat irritable bowel syndrome (IBS) is ischemic colitis, which is characterized by abdominal pain and bloody diarrhea. It has been found that ischemic colitis occurs more frequently in patients with IBS than in normal healthy controls. The recognition of this suggests that when IBS treatments are taken a certain number of patients may show signs of ischemic colitis, but this is a consequence of their underlying disease, not an affect associated with the treatment, per se.Citation:Cole JA, Cook SF, Sands BE, Ajene AN, Miller DP, Walker AM (2004) Occurrence of colon ischemia inrelation to irritable bowel syndrome. Am. J. Gastroenterology 99: 486-91. Research Advance #2 There are many different ways to evaluate potential new medicines to determine whether they provide benefit in the treatment of IBS to patients. Over the years many different designs of studies were used to evaluate new treatments. Great strides have been made to set a consistent design for the way new potential medicines are studied for the treatment of IBS, including: how to collect data, how long to study treatments, and what parameters to monitor. By having a strong, consistent way to study new medicines, it is more likely that the results of studies, whether positive or negative, are accurate.Citations:Corazziari E, Bytzer P, Delvaux M et al (2003) Consensus report: clinical trial guidelines forpharmacological treatment of irritable bowel syndrome. Alimentary Pharmacology and Therapeutics 18:569-580Allen W. Mangel (2004) Study design issues in irritable bowel syndrome. Alimentary Pharmacology andTherapeutics 19:141-142. Research Advance #3 Patients develop constipation and other conditions in which contents in their gut moves slower than normal. Why this occurs is unknown. However, we do know that a class of medicines called opiates, which are used to relieve pain, will slow down the movement of contents in the gut. Scientists have now found that an agent that will block where the opiates bind can speed movement of materials through the gastrointestinal tract. This speeding in content movement occurs whether this slowness is due to opiates given to patients to relieve pain or from opiates produced by the patient’s own bodies. This research gives an important clue as to how constipation may develop and how to more effectively treat it.Citations:Gonenne J, Camilleri M, Ferber I etal (2005) Effect of alvimopan and codeine on gastrointestinal transit:a randomized controlled study. Clin Gastroenterol Hepatol 3: 784-91. 32
  • Delaney CP, Senagore AJ, Viscusi et al (2006) Postoperative upper and lower gastrointestinal recoveryand gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo datafrom 3 randomized controlled trials. Am J Surg 191: 315-319.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years):1. Determine in which pharmacodynamic models, healthy volunteers represent a suitable population for study when evaluating therapeutic agents for the treatment of irritable bowel syndrome (IBS) or functional dyspepsia (FD).2. Determine the overlap of IBS with other potential states of smooth muscle hypersensitivity: FD, asthma, migraine, etc. Is there a syndrome of smooth muscle hypersensitivity?3. Identify more predictive animal models for IBS and FD. Reduce the rate of false positives.4. Optimize the study design for treatment trials of IBS and FD: endpoints, duration of treatment, mode of data collection, etc.5. Establish a multi-year, nation-wide registry of IBS and FD patients to ultimately understand the relationship of genotype and phenotype to side effects and efficacy during treatment.Intermediate-Term Goals (4-6 years):1. Understand the role of infection in the etiology of IBS.2. To assist in understanding the pathophysiology of IBS,, identify suitable biomarkers that represent surrogates for IBS treatment trials to serve as a rapid proof-of-concept study for novel therapeutic agents.3. Determine if there is a therapeutic role for agents without systemic bioavailability in the treatment of IBS and FD.4. Continue supporting the IBS/FD registry.Long-Term Goals (7-10 years):1. Determine genotypic patterns for the predisposition for development of IBS and FD.2. Determine genotypic patterns that might predict, during treatment with therapeutic agents, enhanced efficacy as well as the development of specific side effects.3. Understand the therapeutic potential of prophylaxis with antibiotic treatment in the prevention of IBS and FD.4. Understand the pathophysiology of IBS and FD.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS(Please use bulleted format and identify the goal(s) in section 2 to which these challenges/stepsrelate.) 33
  •  Inadequate knowledge exists on directions for advancement in animal models with improved predictability for IBS and FD therapeutics (see short-term goal 3). Lack of database on familial involvement for IBS and FD (see long-term goal 1). Lack of information on genotypic targets for the prediction of efficacy of IBS therapeutic agents or for the prediction of adverse events (see long-term goal 2). Lack of understanding of basic pathophysiology of IBS: how can patients have diarrhea, constipation, or alternating patterns (see long-term goal 4). Absence of coordination of activities between NIH-FDA-Pharmaceutical Industry (see short-term goal 6; long-term goal 5.) Perception that drugs are being “developed with public funds” and therefore price of pharmaceuticals should be dramatically reduced (see short-term goal 6; long-term goal 5). 34
  • NAME: Emeran Mayer, MDWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 35: Goals1. RESEARCH ADVANCES Research Advance #1 Characterization of the neurobiology of brain gut interactions, in particular: o The role of the central and peripheral CRF/CRF receptor signaling system during the stress response o The role of the peripheral serotonin/5HT receptor signaling system o The role of the neurokinin signaling systemTranslational significance:These advances have already resulted in two new approved medications for IBS. The CRF signalingsystem is probably the best characterized modulatory system within the brain gut axis and antagonistsdirected at normalizing a sensitized CRF system hold great promise for a variety of stress-sensitive GIdisorders, including IBS and cyclical vomiting syndrome. Research Advance #2 Characterization of the role of the human brain in the perception and modulation of visceral afferent signals from the upper and lower GI tract. o Identification of brain regions and networks involved in the processing and in the modulation of visceral afferent signals o Identification of cortico-limbic interactions in symptom modulation, which may be relevant to link the large body of psychosocial information gathered in epidemiological studies with neurobiological substrates o Development of novel imaging techniques to guide and monitor drug development in animal models and in humans o In combination with genetic analyses (“imaging genetics”), the identification of brain circuits that are involved in genetically determined differential responses to anxiety and emotional responsesTranslational significance:Neuroimaging techniques have enabled us to objectively study the neurobiological mechanisms withinthe human brain that underlie such complex functions as cognitions and coping styles related to gutsymptoms that relate to the sensory and affective dimensions of visceral pain, that are involved inendogenous pain modulation by opioids and dopamine. These new findings form the basis for identifyingrational drug targets and monitoring therapeutic effects of candidate drugs. Research Advance #3 Characterization of the interactions between different cell types within the gut wall in the regulation of gut function and in the generation of visceral pain: o Interactions between interstitial cells of Cajal (ICCs), enteric neurons, and smooth muscle cells. Characterization of ICCs as primary pacemakers of gut rhythmicity 35
  • o Interactions between intrinsic and extrinsic neurons, enterochromaffine cells (ECCs), and immune cells within the gut wall o Characterization of receptors on visceral afferent neurons, which play a role in the encoding of nociceptive afferent signals o Interactions between enteric glia and gut epithelium involved in the regulation of intestinal permeabilityTranslational significance:A better understanding of alterations in these interactions holds great promise for the treatment of motilitydisorders characterized by delayed gut transit (slow transit constipation). A better understanding ofsignaling from ECCs to neurons, including vagal afferent neurons may result in new treatments of gutdisorders and other systemic disorders. The characterization of receptors on visceral afferents involved inthe encoding of nociceptive signals has already provided several novel targets for drug development. Research Advance #4 The beginning recognition of the importance of cross-talk between the intestinal microflora and the gut epithelium in a variety of gut disorders. Even though this field is still in its infancy, and existing data probably flawed, there is a rapidly growing body of evidence to suggest that important signaling pathways exist between the microflora and the gut (including signaling to enterchromaffine, immune, and nerve cells), which may contribute to normal homeostasis and which may be altered in various disease states, such as IBD, obesity, and possibly IBS.Translational significance:An understanding of microbial host interactions during development and during adulthood has potentiallygreat importance for the understanding of various disease states. Manipulation of these interactions in thefuture by pharmacological and/or dietary interventions may provide an exciting new avenue for therapiesof a large number of chronic illnesses, including IBD, obesity, and functional GI disorders.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years):1. Identify biological markers (in the periphery or in the brain) that show strong correlations with symptoms in common functional and motility disorders.2. Determine the validity of animal models for common functional and motility disorders (face, construct and predictive validity).3. Characterize alterations in the gut-based serotonin signaling system (SERT, modulators of SERT expression; number of ECCs, 5-HT content, etc.).Intermediate-Term Goals (4-6 years):1. Identify distinct brain circuits involved in autonomic regulation, appetite control, HPA axis regulation, pain modulation, and emotional and cognitive modulation. Characterize these networks in healthy control populations (identify sex-based differences) as well as in various patient populations (including obesity, IBD, functional dyspepsia, IBS, reflux negative GERD).2. Characterize signaling systems and receptors within these distinct circuits using PET ligand imaging in rodents and in humans. 36
  • 3. Correlate the individual circuits identified in goal 1 and identify possible correlations of these circuits (“intermediate phenotypes”) with distinct genotypes (genome-wide search for polymorphisms and haplotypes).Long-Term Goals (7-10 years): [Revised post-conference call]1. Identify vulnerability factors for the development of functional disorders (genetic polymorphisms,gene-environment interactions) and based on these vulnerability factors, develop early interventionstrategies to prevent the development of the full clinical syndrome.2. Characterize the vagal homeostatic system (vagal antinociception, vagal anti-inflammatory reflex;ECC-vagal afferent interactions) in health and disease.3. Characterize the role of the microflora in bidirectional brain gut interactions in health and disease.4. Characterize the role of cognitive and emotional processes (with a particular focus the underlyingneurobiological substrates and receptor systems – using brain imaging techniques) in the generationand/or modulation of symptoms in common chronic GI disorders, including FGID, IBD, GERD, CVS.5. Evaluate the effectiveness and cost-effectiveness of novel disease management approaches involvingnovel pharmacological compounds and non-pharmacological strategies (disease education, cognitivebehavioral therapy).6. Develop stem cell based strategies to treat fecal incontinence due to structural anal sphincter damage.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALSA. Novel technologies and national core facilities:1. Put major emphasis on the development and support of novel neuroimaging techniques aimed at the brain, spinal cord, and the gut (enteric nervous system, ICCs).2. Foster the development of multi institutional consortium agreements, which take advantage of national core resource labs for such expensive techniques as neuroimaging, in particular imaging genetics approaches, genotyping of the microflora, and advanced cell and in vivo imaging techniques.3. Generation of large national and international databases that can be accessed by multiple users, for example databases for genetic polymorphisms, intermediate disease phenotypes, genetic characterization of the entire microflora, etc.B. Emphasize translational research approaches1. Support only research proposals with strong translational relevance for common clinically relevant disorders, in which the studied mechanisms have a clear relevance for the clinical program. (I personally believe we have enough information about the mechanisms involved in lower esophageal sphincter function or in the regulation of gastric emptying, both targets with poor correlation with symptoms in common GI disorders.)2. Restrict funding to proposals that demonstrate that studied mechanisms are disease and symptom relevant (e.g., strong correlations between studied mechanisms and symptoms [this is DEFINITELY not happening at the moment]). 37
  • C. Foster interdisciplinary research approaches with horizontal and vertical integration1. Develop better strategies to identify, and manage interdisciplinary national research consortia.2. Support interdisciplinary research efforts that look at discipline cross cutting questions, such as the mechanisms underlying functional pain syndromes in different specialties, the mechanisms underlying the overlap between these syndromes, and the mechanisms underlying the known overlap of these functional syndromes with psychiatric disorders, such as anxiety and depression. The current approach of funding silos of purely specialty based research is a waste of money.3. Support interdisciplinary research efforts between different subspecialites within and outside of GI, such as microbiology, genetics, inflammation, neuroscience, etc. to provide cutting-edge research expertise for studies on functional, motility, and inflammatory disorders.4. Support interdisciplinary research teams consisting of clinical investigators and basic scientists where clear clinically relevant questions are addressed with cutting-edge basic science approaches.5. Foster long-term interactions between synergistic, multidisciplinary research teams across the country in such areas as host microbial interactions, mind brain body interactions, etc.D. Improve relationships with industry and with academic institutions1. Develop synergistic research relationships with industry.2. Exert stronger influence on academic institutions to share overhead and to use overhead to provide adequate infrastructure for funded investigators. 38
  • NAME: Jackie D. Wood, PhD, AGAFWORKING GROUP: Functional GI Disorders and Motility Disorders (WG 2)Page 39, 41, 43: Goals1. RESEARCH ADVANCES: Enteric Mast Cells and FGIDS• Multiple lines of evidence suggest that understanding the cellular biology of the enteric mast cell will be a central key to understanding, diagnosing, and treating functional gastrointestinal disorders (FGIDs).• Mast cell hyperplasia is a common finding in mucosal biopsies from the large intestine of IBS patients.• Elevated numbers of mast cells, which occur in IBS and inflammatory states, evoke symptoms by releasing a plethora of chemical substances that act at receptors on enteric neurons, sensory afferent terminals, smooth muscle, and the intramural vasculature.• Receptors for mast cell mediators are expressed in the enteric nervous system (ENS) where they act to excite individual neurons and suppress neurotransmission.• Excitation of intestinal secretomotor neurons by mast cell mediators and simultaneous suppression of norepinephrine release from sympathetic nerve terminals underlie neurogenic secretory diarrhea and explain symptoms of diarrhea-predominant IBS, infectious enteritis, and food allergies.• Receptors for mast cell mediators are expressed on intramural terminals of spinal and vagal sensory afferents.• Actions of mast cell mediators on sensory terminals in the gut increase sensitivity to distension and forceful muscle contractions, which might be a factor in the visceral hypersensitivity associated with some of the FGIDs.• Advancing knowledge of mast cell biology and pathophysiology. Enteric mast cells are logical targets for therapeutic intervention in some of the FGIDs.Citations:1. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli- Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126:693-702.2. Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martinez C, Casellas F, Saperas E, Malagelada JR. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2006 (In Press).3. OSullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, OMorain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000;12:449-57.4. Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR. Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology 1998;114:6408. 39
  • 5. Santos J, Alonso C, Guilarte M, Vicario M, Malagelada JR. Targeting mast cells in the treatment of functional gastrointestinal disorders. Curr Opin Pharmacol 2006;6(6):541-546.6. Williams RM, Berthoud HR, Stead RH. Vagal afferent nerve fibres contact mast cells in rat small intestinal mucosa. Neuroimmunomodulation 1997;4:266-70.7. Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 2004;127:635-57.8. Wood JD. Neuro-pathophysiology of IBS. J Clin Gastroenterol 2002; 35(Suppl.)11-22.9. Wood JD. Effects of bacteria on the enteric nervous system: implications for the irritable bowel syndrome J Clin Gastroenterol 2007; (In Press)2. GOALS FOR RESEARCHShort-Term Goals (1-3 years):1. To test the hypothesis that functional reciprocal reflex connections between spinal afferent endings in the gut wall and enteric mast cells are determinants of visceral sensitivity and inflammatory cell migration.2. Fully characterize the release of mast cell mediators (e.g., histamine and mast cell proteases) by ELISA assay in response to electrical stimulation of spinal afferent nerves and neuronal cell types in the enteric nervous system in human and guinea-pig in vitro intestinal preparations.3. Identify through pharmacological methods the receptors and their subtypes expressed by enteric mast cells, which when activated, stimulate release of mast cell mediators in human and guinea-pig intestine.4. Follow-up pharmacological suggestions of involvement of specific receptors and receptor subtypes with application of immunohistochemical methodologies aimed at confirming the localization of receptors for putative neurotransmitters / paracrine modulators (e.g., neurokinin, calcitonin gene- related peptide and corticotropin releasing factor) in human and guinea-pig intestine.5. Determine with pharmacological methods whether receptor-mediated stimulation of the release of specific mast cell mediators (e.g., histamine vs. mast cell proteases) is tied to activation of specific receptors (e.g., neurokinin-1 receptors vs. receptors for calcitonin gene-related peptide vs. receptors for corticotropin releasing factor).6. Establish which of the currently available mast cell stabilizing drugs (e.g., cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast potassium, quercetin, ketotifen, olopatadine, desloratadine and pyrilamine maleate) are most efficacious in suppression of the release of mast cell mediators in response to stimulation of spinal afferents and neurons of the enteric nervous system7. Determine efficacy of anti-IgE humanized monoclonal antibodies, such as omalizumab or TNX901, as mast cell-stabilizing agents in the human and animal models for mast cell mediator release.Intermediate-Term Goals (4-6 years)1. Identify genes associated with human enteric mast cells and identify polymorphisms in genes of significance. Apply cellular / magnetic sorting methodologies to address the question of whether 40
  • enteric mast cells all express the same genetic and functional phenotype or are there heterogenous subpopulations expressing differing phenotypes. For example, do all human enteric mast cells express NK-1 receptors or is expression of NK-1 receptors restricted to a subpopulation with unique properties. Likewise, the goal should be to establish whether or not there are differing phenotypes with respect to stored preformed mediators and lipid derived mediators and the kinds of signals required for release of each specific mediator.2. Define the mechanisms by which mast cells release their contents abruptly and massively following antigen-induced activation via high-affinity receptors for IgE in relation to what appears to be slower and more selective emptying of granule contents as a predominant mechanism in the regulation of autoimmune and chronic inflammatory disorders.3. Obtain a step-by-step description of the post-receptor intracellular signaling cascades, specific to mast cells in human and guinea-pig intestine (e.g., Ca2+ receptors and channels, mitogen-activated kinases, Syk tyrosine kinases) as selective therapeutic targets.Long-Term Goals (7-10 years):1. Identify among the currently available mast cell stabilizing drugs (e.g., cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast potassium, quercetin, ketotifen, olopatadine, desloratadine and pyrilamine maleate) in clinical trials, the most effective in treatment of diarrhea- predominant IBS, functional abdominal pain, and perhaps one or the other forms of functional dyspepsia.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE THE GOALS• Successful achievement of the goals is contingent on availability of targeted funding. Technology and methodological protocols required for success in meeting the goals are currently available and feasibility is established.1. RESEARCH ADVANCES: Stress and FGIDS• A major impact of stress on the intestinal tract is reflected by symptoms reminiscent of the diarrhea- predominant form of IBS.• Cramping abdominal pain, fecal urgency, and explosive watery diarrhea are hallmarks not only of diarrhea-predominant IBS, but also infectious enteritis, radiation-induced enteritis, and food allergy.• The stress scenario starts with stress-induced compromise of the intestinal mucosal barrier and continues with microorganisms or other sensitizing agents crossing the barrier and being intercepted by enteric mast cells.• Mast cells signal the presence of microorganisms or other sensitizing agents to the ENS (i.e., the brain-in-the-gut), which uses one of the specialized programs (i.e., programmed defense) from its library of programs to remove the “threat.”• Stimulation of mucosal secretion flushes the threatening agent into the lumen and maintains it in suspension.• Powerful propulsive motility, which propels the secretions together with the offending agent rapidly in the anal direction, is linked to secretion. 41
  • • Cramping abdominal pain accompanies the strong propulsive contractions.• Fecal urgency is experienced when arrival of the large bolus of liquid distends the recto-sigmoid region and reflexly opens the internal anal sphincter, with continence protection provided only by central reflexes that contract the puborectalis and external anal sphincter muscles.• Sensory information arriving in the brain from receptors in the rapidly distending recto-sigmoid accounts for the conscious sensation of urgency, threat of incontinence, and explosive watery diarrhea and might exacerbate the individual’s emotional stress as the enteric defense program “runs.”• Stress activates a brain-mast cell connection.• Neural inputs to mast cells from the brain release chemical signals to the ENS with effects that mimic the symptoms of antigenic stimulation (i.e., cramping abdominal pain, fecal urgency, and explosive watery diarrhea).• Corticotropin-releasing factor (CRF) and related peptides are key molecules mediating stress responses.Citations:1. Castagliuolo I, Wershil BK, Karalis K, Pasha A, Nikulasson ST, Pothoulakis C. Colonic mucin release in response to immobilization stress is mast cell dependent. Am J Physiol Gastrointest Liver Physiol 1998;274:G1094-1100.2. Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Taché E, Wood JD. Fundamentals of neurogastroenterology: basic science. Gastroenterology 2006; 130:1391-1411.3. Peck OC, Wood JD. Brain-gut interactions in ulcerative colitis. Gastroenterology 2000;118:807-808.4. Santos J, Saunders PR, Hanssen NP, Yang PC, Yates D, Groot JA, Perdue MH. Corticotropin- releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat. Am J Physiol Gastrointest Liver Physiol 1999;277:G391-9.5. Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM, Perdue MH. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 2002;123:1099-108.6. Wood JD, Grundy D, Al-Chaer ED, Aziz Q , Collins SM, Ke M, Tache Y. Fundamentals of Neurogastroenterology: Basic Science. In: Corazziari E, Delvaux M, Drossman DA, Spiller RC, Talley NJ, Thompson WG, and Whitehead WE, eds. Rome III: The Functional Gastrointestinal Disorders. 3rd ed. McLean, Virginia: Degnon Associates, 2006:31-87.7. Wood JD. Pathophysiology Underlying the Irritable Bowel Syndrome. In: Johnson LR, Barrett KE, Ghishan FK, Merchant JL, Said HM, Wood JD, eds. Physiology of the Gastrointestinal Tract 4th ed. San Diego, Elsevier, 2006, pp 1009-1031.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years): 42
  • 1. Test the hypothesis that brain-gut interactions, which occur during stress, involve the release of corticotropin releasing factor (CRF) from specific subsets of enteric neurons in the small and large intestine.2. Determine the distribution and cellular localization of CRF and its receptors in the enteric nervous system (ENS) and the mast cell population in a guinea-pig model and the human small intestine.3. Characterize the actions of CRF on electrophysiologically, morphologically, and neurochemically identified neurons in the myenteric and submucosal plexuses of guinea-pig intestine.4. Test the hypothesis that cold-restraint stress elevates expression of CRF in the guinea-pig ENS.5. Test the hypothesis that upregulation of CRF and its actions on ENS neurons are factors in stress- induced alterations of intestinal secretion and propulsive motor behavior.Intermediate-Term Goals (4-6 years)1. Test the hypothesis that stimulation of spinal afferents evokes release of CRF from mast cells in the human and guinea-pig small intestine.2. Test the hypothesis that experimental stimulation of secretomotor neurons (i.e., neurons now known to synthesize CRF) evokes secretion (e.g., histamine and proteases) from mast cells in human and guinea-pig small intestine.3. Test the hypothesis CRF is released during mast cell degranulation (e.g., in response to compound 48/80 or IGe) to activate CRF1 receptors now known to be expressed by neuronal neighbors of secretomotor neurons in the intestinal submucosal plexus.Long-Term Goals (7-10 years):1. Evaluate available CRF receptor antagonists (e.g., α-helical CRF) in clinical trials for efficacy in treatment of diarrhea-predominant IBS, each of the multiple categories of functional dyspepsia, and functional abdominal pain and bloating.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE THE GOALS• Successful achievement of the goals is contingent on availability of targeted funding.• Technology and methodological protocols required for success in meeting the goals are currently available and feasibility is established.1. RESEARCH ADVANCES: Neuropathy in the Brain-in-the-Gut• Autoimmune attack targeted to neuronal elements of the enteric nervous can underlie irritable bowel- like symptoms that progress to chronic pseudo-obstruction.• Enteric inflammatory neuropathy disrupts the integrative functions of the brain-in-the-gut (i.e., the ENS) including reduction in the population of inhibitory motor neurons to the musculature. Without the ENS, the gut does not work!• Advanced depletion of inhibitory motor neurons is manifest as disinhibitory motor disease characterized by achalasia in smooth muscle sphincters and hyperactive, disorganized contractile behavior of intestinal circular muscle that results in pseudo-obstruction. 43
  • • Detection of antienteric neuronal antibodies in the serum of patients with early symptoms of a functional gastrointestinal motility disorder may prove to be a useful diagnostic test for inflammatory enteric neuropathy.Citations:1. Wood JD. Neuropathy in the brain-in-the-gut. Eur J Gastroenterol Hepatol 2000;12:597-600.2. Wood JD. Neurobiology of the Enteric Nervous System. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia: WB Saunders, 2005, pp 249-277.3. Krishnamurthy S, Shuffler MD. Pathology of neuromuscular disorders of the small intestine and colon. Gastroenterology 1997; 93:610-639.4. Smith V, Gregson N, Foggensteiner L. Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement. Gastroenterology 1997; 112:1366-1371.5. Verne GN, Sallustio JE, Eaker EY. Anti-myenteric neuronal antibodies in patients with achalasia: A prospective study. Dig Dis Sciences 1997; 42:307-313.6. Eaker EY. Antimyenteric neuronal antibodies and motility. Gastroenterology 1998; 114:421-422.7. De Giorgio R, Guerrini S, Barbara G, Stanghellini V, De Ponti F, Corinaldesi R, Moses PL, Sharkey KA, Mawe GM. Inflammatory neuropathies of the enteric nervous system. Gastroenterology 2004;126:1872-83.8. Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002;123:1972-1979.2. GOALS FOR RESEARCHShort-Term Goals (1-3 years): 2. Promote early testing for early detection of autoimmune enteric neuronal neuropathy with a view to treatment and prevention of the devastation of ensuing sphincteric achalasia (e.g., lower esophageal) chronic intestinal pseudoobstruction and dependence on parenteral nutrition. 3. Develop reliable, efficient, and inexpensive serological tests for enteric neuropathic autoimmunity (e.g., circulating antienteric neuronal antibodies) that can be applied in diagnostic evaluation during early indications of a FGID (e.g., IBS) in humans. 4. Test the hypothesis that the presence of circulating antienteric neuronal antibodies is associated with manometrically-determined small bowel motility abnormality (i.e., hyperactive- uncoordinated circular muscle contractions and absence of a migrating motor complex in the interdigestive state) in patients with Rome III based diagnosis of IBS or other FGID. 5. Establish a convincing argument that a Rome III diagnosis of IBS, in combination with the presence of circulating antienteric neuronal antibodies and the characteristic manometric small intestinal motility pattern described by Stanghellini, Camilleri, and Malagelada JR (Gut 44
  • 1987;23:824-828) for small intestinal pseudoobstruction, is justification for obtaining laparoscopic full thickness biopsies to confirm a diagnosis of autoimmune enteric neuropathy.Intermediate-Term Goals (4-6 years):1. Develop an animal model for immune-related enteric neuropathy.Long-Term Goals (7-10 years):1. Establish the prevalence of autoimmune enteric neuropathy in world-wide cohort of patients who have a Rome III symptom-based diagnosis for a FGID.2. Pursue effective treatment strategies (e.g., high dose steroids and immune suppressant drugs) for early reversal of autoimmune neuropathies once a definitive diagnosis is made.3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS• Successful achievement of the goals is contingent on availability of targeted funding. Technology and methodological protocols required for success in meeting the goals are currently available and feasibility is established. 45
  • Categories for Long -Term Goals(Please note: items in black are from original pre-conference call reports. Items in green were contributed from “atlarge” investigators and were felt to make valuable additional points for the report. Ignore redundancies, they will beedited out at a later time.)Molecular targets for functional GI diseases and motility disordersDetermine specific changes in expression and function of cell-specific receptors in animal models ofmotility and functional GI disorders.Determine the cause and effect relationship of changes in 5-HT signaling in IBS and IBD. Understand theimplications and the mechanisms of these changes.Cellular components involved in functional GI diseases and motility disordersClearly understand the excitability/contractile mechanisms in human GI muscles –translate knowledge ofthese mechanisms to human muscles.Develop strategies to block the factors causing loss of ICC in response to inflammation, infection,diabetes, surgery, etc.Develop a strategy for transplantation of ICC or re-establishment of ICC populations from mesenchymalstem cells.Develop the means to use stem cells as a treatment for gut disorders where smooth muscle cells, ICC orenteric neurones are reduced, absent, or malfunctioning.Develop stem cell based strategies to treat fecal incontinence due to structural anal sphincter damage.Determine whether the altered activity of intrinsic neurons and/or smooth muscles are involved in thepathogenesis of FD and IBS.Identify the specific roles of each class of neuroendocrine cells in afferent neural activityDevelopment of the apparatus neuromuscular apparatusUnderstand developmental processes that yield the functional gut. Are there developmental defectspredispose the gut to motor or functional pathologies?Understand changes in ENS, glia, ICC, smooth muscle that occur with aging. Alterations in gut functionare one of the hallmarks of aging and one of the major determinants of the quality of life of the aged.NeurobiologyUnderstand the role of glial cells in gut neurobiology and motility.Understand how the intrinsic nervous system communicates with the extrinsic nervous system.Understand the role of extrinsic afferent and efferent pathways in coordinating/modulating the intrinsicneural-pacing-muscular processes.Determine how altered activity of extrinsic neurons (autonomic nervous system and central nervoussystem) influences the GI motility. 46
  • Identify the role of spinal and brainstem "reflexes" involving sympathetic and parasympathetic efferentpathways in the normal and diseased GI tract.Understand the neural circuitry of the GI tract and develop a better understanding of the interactions withmotor nerves, the sensory nerves, and the central nervous systemUnderstand whether altered activity of extrinsic neurons is involved in the pathogenesis of FD and IBS.Understand the linkages between the submucosal and myenteric plexi in regulation of host defense and insignaling from the luminal microenvironment.Characterize the vagal homeostatic system (vagal antinociception, vagal anti-inflammatory reflex; ECC-vagal afferent interactions) in health and disease.Characterize the role of cognitive and emotional processes (with a particular focus the underlyingneurobiological substrates and receptor systems – using brain imaging techniques) in the generationand/or modulation of symptoms in common chronic GI disorders, including FGID, IBD, GERD, CVS.Inflammatory cells and mediatorsIdentify genes associated with human enteric mast cells and identify polymorphisms in genes ofsignificance.Determine the effectiveness of mast cell stabilizers on symptoms of functional GI diseases and motilitydisorders.Pain and sensory pathwaysUnderstand the physiology of enterochromaffin and other sensory cells in the mucosa.Determine what initiates nociceptive neural activity in the gut.Develop specific ion channel-blocking drugs for nociceptive-specific ion channels.Characterize signals that activate intrinsic and extrinsic afferent nerve fibers and determine how generatorpotentials occur in these nerves.Understand the sensory innervation of the gut and how it interconnects with the sensory and efferentinformation from other viscera and how it connects to higher brain activity. Develop strategies to blockspecific signaling molecules and mechanisms that participate in the stimulation and sensitization of GI-specific afferent nerves.Role of microflora in functional GI diseases and motility disordersCharacterize the role of the microflora in bidirectional brain gut interactions in health and disease.Determine how luminal factors (gut flora, inflammation, diet, infection, etc.) influence the relativenumbers, balance, and specific functions of gut endocrine cells.Integrative physiology and animal modelsDevelop new animal models that recapitulate functional bowel diseases and motility disordersUnderstand how cellular components function together to yield whole organ behaviors. 47
  • Determine the mechanisms of neural regulation of the mucosal barrier.Understand the complex local interactions of bacteria, nutrients, epithelial cells, neuroendocrine cells,immunocompetent cells, neurons in the mucosal and submucosal apparatus.Put what has been learned about the circuitry and physiology of the enteric nervous system into apathophysiological context. A goal should be to produce mechanistic models of how the enteric nervoussystem contributes to motility disorders.Wiring for the peristaltic reflex in rodents is understood, but the circuitry for other motor patterns shouldbe determined. This could lead to better modeling and make it possible to switch between motilitypatterns for therapeutic purposes.Determine how enteric circuitry can switch from the unidirectional movements of peristalsis to mixingmovements and how this is altered in pathophysiology.Develop a model to show the CNS and ENS-mucosal circuitry that explains the role of stress and alteredbacterial flora on neuroendocrine dysfunction in IBS.Understand the pathophysiology of IBS and FD.Genetics of functional GI diseases and motility disordersDevelop registries of GI motility disorders (e.g. achalasia, gastroparesis, chronic intestinalpseudoobstruction, colonic inertia) and bank clinical phenotypic information, symptoms, geneticbackground, and patient reagents that can be used in coordinated studies to determine causes of thesedisorders and develop appropriate treatments.Determine genetic profiles of patients prone to functional GI disorders. Employ computational biologytechniques to look for patterns that predispose patients to functional GI disorders.Determine genotypic patterns for the predisposition for development of IBS and FD.Identify vulnerability factors for the development of functional disorders (genetic polymorphisms, gene-environment interactions).Based on genetic vulnerability factors, develop early intervention strategies to prevent development of thefull clinical syndromes of functional GI diseases.Determine pharmocogenomics patterns that might predict efficacy of available therapeutic agents andwhether side effects will develop for drug treatments.Technology and therapeuticsDevelop small bowel pacing.Increase our understanding and ability to use non-invasive or semi-invasive electrical recording fordiagnostic purposes and to utilize electrical stimulation to alter motility patterns and/or gut sensation.Improve outcome of small bowel transplantation so it can become as routine as kidney transplants.Develop strategies to prevent development or minimize morbidity associated with IBS.Determine appropriate therapeutic targets for GI motility and functional GI disorders 48
  • Understand the therapeutic potential of prophylaxis with antibiotic treatment in the prevention of IBS andFD.Test pharmacologic agents or devices in full scale clinical trials in motility and functional gastrointestinaldisordersAssess success of the coordinating committee between NIH-FDA-Pharmaceutical Industry for rationaledrug design “from molecule to man.”Use simple noninvasive GI motility testing on a large scale to better understand the prevalence ofGI motility disorders in the general population. Initially, this would investigate the prevalence ofabnormalities in gastric emptying, colonic transit, and visceral sensation.Outcomes and doctor/patient impactEvaluate the effectiveness and cost-effectiveness of novel disease management approaches involvingnovel pharmacological compounds and non-pharmacological strategies (disease education, cognitivebehavioral therapy).Demonstrate through multi-center trials standardized physician training programs in GI that showimproved patient outcomes and reduced costs.Identify the cause of patients’ symptoms with defined GI motility disorders and determine if treatment ofa patient’s underlying pathophysiology at the periphery is better treatment than nonspecific symptommodulators that work centrally.Determine if pharmacogenetic analysis of patients helps to better select the appropriate drugs and dosageof drugs to treat patients with GI motility disorders.To determine the benefit of novel treatment strategies that are being used in other areas can besuccessfully used for treatment of patients with defined GI motility disorders. These include GI tractelectric stimulation, Stem cell transplantation, treatment of inflammation, and GI tract transplantation forsevere motility disorders. 49