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Working Group #02 Ideas for Commission Report.doc


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Working Group #02 Ideas for Commission Report.doc

  1. 1. National Commission on Digestive Diseases Ideas for Working Group II Discussions (i.e. views of your colleagues*)1. What do you view as the major research advances during the past 5 years?- Psychological stress is one of the most important factors in the pathogenesis infunctional GI diseases (FD and IBS). From the view point of brain gut axis, the possiblerole of central CRF in mediating stress-induced motor abnormalities in the stomach andcolon is an important finding.- Understanding the role of infection in the development of IBS- Long term effects of adverse early life experiences on colonic hypersensitivity- Long term effects of a prior inflammatory insult on colonic sensitivity.- Key discoveries are that specific events/challenges can sensitize the system viaperipheral and/or spinal and supraspinal mechanisms to produce colonic hypersensitivityand abnormal GI motility. Examples that I believe are significant relate to 1) the affect ofnot only stress but also anxiety on the GI tract.- Delayed gastric emptying has been reported to occur in between 30% and 50% ofpatients with FD. Impaired vagal efferent activity has been shown in subsets of FDpatients. However, the possible role of vagal nerve in mediating postprandial gastricmotility has not fully been studied. There is an important role of vagal nerves inmediating postprandial gastric motility and gastric emptying.- Molecular genetics of multiple forms of human dysmotility (e.g., Hirschsprungs, IBD,neurogenin-3 & congenital malabsorbtion, etc.).- As colonic transit in the proximal colon was significantly accelerated in diarrhea-predominant IBS patients, it has been suggested that accelerated transit through theproximal colon is a factor in the pathophysiology of diarrhea-predominant IBS. 5HT3receptor antagonists are known to be effective for the patients with diarrhea-predominantIBS. It was recently demonstrated that luminal application of 5HT3 receptor antagonistsprevent stress-induced hyper-motility of the proximal colon in rats. This suggests thatstress can stimulate EC cell of the proximal colon to release 5HT and that mucosal 5HT3receptors mediate the hyper-motility of the proximal colon- Significance of 5-HT in the bidirectional communication between the brain and gut- Demonstration that 5-HT signaling is altered in various disease states is an importantfinding. 1
  2. 2. - Discovery of the mechanosensitive nerve endings in the upper and lower GIT.Mechanisms of mechanotransduction by specialized low-threshold mechanoreceptors inthe guinea pig rectum.- Serotonin, serotonin receptor pharmacology, SERT. While it has been known for along time that 5HT played a role in mediating or transducing the signal from luminalstimulus, the recent focus on identifying the receptor type, receptor location, and the roleof SERT has driven a great deal of motility research in the past 4 or 5 years. Theimportance of SERT became particularly clear during this time period. The significanceof “serotonology” was enhanced by the development of promotility drugs acting on thissystem. This potential role in mediating some of the motility changes in IBS and IBD islikely to make serotonin a hot area in the future.- Discovery of role of serotonin from enterochromaffin cells in vagal afferent activity- Neural stem cells (neural crest stem cells) persist in the gut postnatally and stem cellsfrom a variety of sources show some limited promise of being able to give rise tofunctional neurons in some model systems. This is a long way from clinical utility, butholds some promise.- Discovery of spatio-temporal relation between slow waves and motility- Biology of interstitial cells of Cajal (anatomy, electrophysiology, immuno-histochemistry, and development). Although some of the "breakthroughs" in this areapreceded 2002, progress made in the last 5 years has been impressive.- Work on ICC has enhanced our understanding of the neuromuscular regulation ofmotility.- Development of methods to visualize pacemaker cells in vivo.- ICC, classification of ICC types and role of ICC as mediator between neuron andsmooth muscle cell. Work on ICC has dramatically altered the way we look atregulation of smooth muscle. It has challenged the model accepted for over a century asthe only way nerves may influence muscle activity. I believe that understanding themany and varied roles and types of ICC was a breakthrough. As above, the role of ICCin pathology is likely to be a major area of investigation in the future- Another important group of findings concern the ICC and their roles in generating therhythmic activity of the muscle and in mediating transmission to the muscle. This clearlymeans that targeting ICC is a viable option for the therapeutic modulation of motility.- I think that in the last five years, extremely important advances are being made inunderstanding the role of interstitial cells of Cajal in motility, and this perhaps representsthe single major advance in understanding of motility in this time frame. 2
  3. 3. - Discovery of how pacemaker cells generate gastric peristalsis. Electrical eventsunderlying organized myogenic contractions of the stomach. Discovery thatneuromuscular transmission is mediated by Interstitial Cells. Involvement ofintramuscular interstitial cells of Cajal in neuroeffector transmission in thegastrointestinal tract.- In functional diseases, the most important finding is not a finding at all. It is therealisation, or accumulation of evidence, that IBS is a real entity, not a psychosomaticdisorder, and that it can be treated by therapeutic strategies aimed at the gut, not at thebrain. This has been strengthened by the (limited) success of Tegaserod. It is nowrecognised that IBS is an enteric neuropathy, that it is commonly a post-infectiousdisorder, and that 5-HT signaling systems are somehow involved. This means we knowwhere to focus effort.- Improved understanding of enteric receptorology and ion channelology is leading tonew drugs and a better understanding of the mechanisms of action of the drugs we have.- We now have a very good understanding of the enteric neural circuitry that controlsmall intestine and colon function, and we also have a good understanding of theneurotransmitters involved.- Providing a mechanism for understanding neuronal plasticity following inflammationrepresents an important advance in our understanding of the regulation of motility,especially that specific mechanistic targets have been identified in this context.- Another advance would be the plasticity of enteroendocrine cells in signaling to theENS to regulate myenteric reflexes, again focusing on the pathophysiologicalimplications of this finding. Of course, we add a few transmitters to the list – maybe themost interesting is hydrogen sulfide, others may have their favourite.- An integrative view of biological factors involved in FBD: Im thinking of microflorainteracting with epithelium and native immune system + neuro-muscular function (entericnerves, glial cells, ICCs, smooth muscle cells). Each of these "components" has beenmore (or less extensively assessed), although an integrative view is lacking- Understanding of gastrointestinal (neuro-hormonal) regulation of food intake will opennew perspectives in gastroenterology and specifically in neurogastroenterology- Understanding whether (and how) gut signaling to the CNS is altered in obesity- Discovery of microflora role in obesity- Understanding the role of intestinal microflora on GI functions- Functional Brain imaging. The understanding of how information is transferred fromthe gut to the CNS was largely limited to fiber recordings and ablation studies. The 3
  4. 4. advent and application of imaging to brain regions has opened up a whole new level ofunderstanding. While its application to normal motility remains to really provide us ajump forward, it has provided a new tool to look at pathologies that involve dysmotilitysuch as IBD and IBS. I think of the advances in imaging as more of a generaltechnological advance than I do an informational advance at this stage. I would includeunder this point advances in all forms of imaging including endosonography, andmicroscopic imaging as well.- Developing an understanding of the role of brain in gut function and the benefits ofbrain imaging in determining abnormalities.- The findings that visceral organs can talk to one another.- Progress with electrical stimulation of the gut- We have made great advances in understanding signaling pathways and mechanismsthat has opened new horizons and brought new hypotheses about the mechanismsunderlying abnormalities in gut functions, including, but not limited to, motility infunctional and inflammatory bowel disorders but also in drug induced motilityalterations. The serotonergic system could serve as example since it has gained a lot ofattention and there is now increasing evidence pointing to serotonergic signalingabnormalities in the pathogenesis of functional GI disorders.- Plasticity of the enteric nervous system occurs in inflammation and neuropathies thatare likely to contribute to many symptoms in GI motility disorders.- There are close interaction between the nervous and endocrine systems in activatingpathways regulating many aspects of GI functions from nutrition, digestion, absorption,aversion to disease like inflammation.2. What should be our goals for research over the next decade?- To develop the animal model of FD.- Developing new and better animal models for the major GI diseases such as IBD, IBS,and the functional bowel disorders. The models we have are poor and mimic onlycomponents of the disorders. This is after all the goal of all our research efforts, not tomention that the ‘buzz word’ for any funding effort is now ‘translational’ research. I dothink, though, that we in GI motiltiy lag behind other areas because we cannot mimicdisease processes well and therefore cannot begin to design good translational studies,understand mechanisms well, and therefore begin to design good approach to solve theproblems. It is amazing that solving diarrhea/constipation is still one of our major goalsafter centuries of being afflicted with this specific problem! We need good models toshow us where thing go wrong. 4
  5. 5. - To develop the animal model of IBS. Acute stress model has been used for the IBSmodel in rats. Chronic stress model should be developed as well in rats, because longterm stressful life may be the cause of IBS in humans.- The outstanding work from international investigators over the last ten years has givenus a model that we can test in physiology, and importantly, in pathophysiology. In orderto test this model we need to have valid animal models for research. Currently, in manycases we do not have acceptable valid animal models, and their development will be animportant goal over the next few years.- We understand the ionic basis for the regulation of motility at the level of smoothmuscle, interstitial cells and enteric neurons. At this point identification of transporter orchannelopathies have not been clearly made, and I think an important goal is tounderstand, again, the pathophysiology and genetic alterations of the molecularcomponents that underlie motility.- Identifying relation between cellular properties to organ functions: determining the roleof pacemaker cells, neurons and muscle in determining macroscopic behaviour of theGIT.- Role of extrinsic afferent and efferent pathways in coordinating/modulating theintrinsic neural-pacing-muscular activities processes- To study how the altered activity of extrinsic neurons (autonomic nervous system andcentral nervous system) influences the physiological GI motility.- To study whether the altered activity of extrinsic neurons are involved in thepathogenesis of FD and IBS. If so, how?- To study whether the altered activity of intrinsic neurons and/or smooth muscles areinvolved in the pathogenesis of FD and IBS.- A major goal in motility related research over the next decade will be to put into apathophysiological context, what we have learned regarding the circuitry and physiologyof enteric neural control. Modeling IBD is happening, but for other disorders there hasbeen less progress and a goal it to describe all motility disorders fully in a mechanisticsetting.- We have made good progress identifying the components of the perstatic reflex, at leastin guinea pig. We need to use this information to understand how other motor patternsare generated and what components of the circuitry are affected by various diseasestates. Ultimately, this could to a more successful approach to computer modeling of thegut than has been accomplished to date.- We have a valid model to test for the regulation of motility, but it could be argued thatthis model is far from perfect, since it only really represents unidirectional flow that may 5
  6. 6. be considered to be essentially a peristaltic like movement. With regard to thesegmentation and mixing movements that are self evident in video recordings of gutmotility, I am not at all convinced that we understand the circuitry underlying this, sincethe descending systems of inhibition are predominant and it is not clear to me howswitching of this unidirectional machinery occurs to give rise to mixing movements.Furthermore, once we understand such movements, again the issue will be to understandthem in a pathophysiologically relevant situation. I believe that we still have aconsiderable goal to attain in this regard.- We need to know more about the signals that activate intrinsic and extrinsic afferentnerve fibers and how generator potentials occur in these nerves.- Identifying the site of initiation of afferent nociceptive neural activity in the GIT.- 5-HT signaling changes in IBS and IBD. It is now important to determine the causeand effect relationship, the implications and the mechanisms of these changes.- We need to know more about the neural regulation of the mucosal barrier.- Establish the role of the dozens of biologically active substances present and releasedby enteric neurons- Identifying specific roles of each class of neuroendocrine cells in mediating afferentneural activity- Identifying the complex local interactions of bacteria, nutrients, epithelial cells,neuroendocrine cells, immunocompetent cells, neurons and mucosal and submucosalapparatus- Identifying the role of the numerous spinal and brainstem"reflexes" involvingsympathetic and parasympathetic efferent pathways in the normal and disease GITmotility- Understanding the role of glial cells in gut neurobiology and motility. This cell type isclearly more that we thought all these years. I think we knew it was important but it wasso difficult to isolate, to find an end point to measure, and there was just so much else todo! I think that the CNS work that has shown that it has clear roles in mediatingsynaptic transmission and plasticity must mean that the same important roles are likely tobe present in the ENS. There is important work indicating that the Glia play a role ininflammation and there is that great paper showing that glia play a major role in colitis. Iam willing to bet that if the glial cell finds a champion in the same manner that youchampioned the ICC; and the same level of high quality, intense effort is applied, it willbe come an equal player in motility. 6
  7. 7. - By the end of 10 years, reduce absenteeism associated with functional bowel disease by50% and physician visits by a third. By the end of 10 years, find an effective treatmentfor gastroesophageal reflux disease.- Our field needs focus on disease oriented research. Our field has made phenomenonaladvances during the last forty years, but we still do not have a clear understanding ofmost major motility disorders. As a result, there are few effective therapeutic approachesthat can help patients with motility dysfunction. By comparison, many other fields, suchas cancer and Alzheimer’s disease, are way ahead of us. Correspondingly they havegreater visibility and more funding. We have all the technology we need to accomplishthis goal.- Understanding the sensory innervation of the gut and how it interconnects functionallywith the sensory and efferent information from other viscera and how it connects tohigher brain activity. This area would include visceral hypersensitivity, viscero-viseraland viscero-somtaic interaction, and the more advanced PET scanning areas of study.We know a good deal, but there is much more to learn and it is difficult to reallyunderstand how the sensory pathways interact physiologically as opposed toanatomically; the latter seems easier to work out.- Understanding the developmental aspects of the gut and, conversely, the aging of thegut. While there have been major advances in understanding the development of the gut,there is still much to understand. We still need to learn how the various signals interactto yield a ‘normal’ gut and where the defects occur that may ultimately predispose todevelopment of pathologies. We know very little about the changes in ENS, glia, ICC,smooth muscle that occur with aging. Alterations in gut function are one of thehallmarks of aging and one of the major determinants of the quality of life of the aged.As the US population ages and we baby-boomers head towards this stage of our lives,this will present a major area of concern and attention. Identifying and understandingthese changes, and development of therapies is likely to become a major area of targetedresearch and funding.- Most motility research is focused on the myenteric plexus as the key centre forregulation of motility, and indeed, that is not inappropriate. However, recognition of therole of the submucosal plexus in contributing importantly to physiologic actions ofmotility by providing appropriate secretion and other anachonictivity through the entericsignaling systems is somewhat lacking. I believe an important goal will be to recognizethe important role motility has in host defense, and a full understanding of linkagesbetween the submucosal and myenteric plexus in regulation of host defense, in particular,and in signaling from the luminal microenvironment.- In pediatrics there is a particularly important disconnect between one of the majorsurgeries that children undergo, and knowledge of the pathophysiologic mechanismsassociated with GI disease. Thus, gastrointestinal reflux disease is one of the largestproblems facing children, and yet with fundoplication being the third most commonoperation that children face after appendectomy and hernia repair. The diagnosis, 7
  8. 8. management and indeed, animal models of this disorder are severely lacking, particularlyin the context of a developing GI tract, and these represent an important goal in terms ofoverall GI morbidity.- The gut EEG needs to be better understood. Knowledge of pacing of electrical activityin the gut as a diagnostic tool and its uses as a diagnostic therapeutic tool is quite limited,and I would say that one goal might be to develop a better understanding of theelectromechanical activity of the gut in terms of what it may bring to diagnosis ortreatment of motility disorders.3. What are the major challenges to achieving goals?- Establishing suitable animal models for functional GI disorders (Ed: this commentrepeated 8 times!)- There is a major challenge to better define IBS. Currently I see a major limitation in allclinical trials of IBS because of ridiculously high and variable placebo response rates. Iregard this as a failure of the tools used to assess IBS that can’t distinguish a normalphysiology from pathophysiology, and therefore, probably one of the most importantchallenges is a biological description of IBS, and I would perhaps rank this very highly inour challenges, and indeed, would represent a major advance in many ways.- There is a need to integrate cellular events with whole system physiology, bydeveloping a frame that unifies morphology (anatomy, histology, histochemistry,molecular biology) with physiology (changes in states of cells, tissue, organs and GITsystem). This requires conceptual frames that facilitates the understanding of themultiple level of complexity of relevant phenomena in time and space (spatio-temporalanalysis).- One important approach is to study GI motility from the view point of the brain gutaxis in pathophysiological conditions.- establish the recording system of the central nervous system in a conscious state inexperimental animals (fMRI or PET).- establish the recording system of the autonomic nervous system in a conscious state inrats and dogs.- establish the simultaneous recording system of neuronal activity and GI motility in ratsand dogs.- Topographical mapping of the ENS. We have advanced out understanding of thechemical coding, electrophysiology, and morphology of single enteric neurons yet theganglia themselves are a mystery. If the CNS is a model, then there must be sometopographical or function organization with in the enteric ganglion for input, integrationand output. Perhaps the organization is across an aggregate of several ganglia. In any 8
  9. 9. case, I doubt that it is a random conglomerate. I have no idea how to tackle this questionbut I do believe it is a technical challenge.- Interneurons. The vast majority of neurons in the ENS that mediate motility reflexesare interneurons. They are the real site of integration, of coordinating motor and sensoryreflexes, etc. At present we know much about motor and sensory components of reflexarcs but very little about the large numbers of interneurons inbetween. I think achallenge has been and will remain in determining how to study these neurons in thecontext of specific motility patterns.- Determine how to switch between patterns of motility. It is clear that there is only oneset of neural circuits, one set of ICC, one muscle system. Considering only the smallintestine, the pattern of activity can be mixing, short propulsive movements, more intenseor sustained propulsive movements, the MMC or retropulsion. How is the switchingbetween these motor programs controlled, and, in any one mode, how is the intensity ofthe activity regulated?- Technically the challenge is to visualise state of activity of relevant cells (muscle cells,pacemaker cells, neurons, neuroendocrine cells) in a live context of tissue (in vitro or invivo), organ (in vitro or in vivo) and system (in vivo) and develop quantitative analysis ofspatio-temporal patterns. These methods need then to be applied to a broad variety ofpeople with normal and diseased GIT functions to establish incidence of normal andabnormal patterns and associated symptoms.- What is the link between inflammation and changed properties of enteric neurons,muscle and possibly ICC. Is it possible to intervene? That is, if a person had a severeattack of gastroenteritis, could we treat the person to prevent later development of afunctional disorder?- Determine how to replace regions of defective bowel. As there are increasing numbersof older people, there will be greater incidence of bowel resection and more people livingwith ileostomies and colostomies. Can we work out better transplantation therapies,maybe including tissue engineering solutions.- Determine the link between disorders of GI function (e.g., constipation and diarrhea)and pain and discomfort from the gut.- Determine what can and cannot be extrapolated from animal experiments to human, andin the process to refine animal models.- Other important challenges are to better utilize imaging technologies to image theliving gut, refine genetic approaches to make ENS or ICC specific targeting vectors forconditional knockout of function in adult animals, application of bioinformatics tomotility disorders and further refinements of proteomic and metabolomic technologies tothe gut and motility specifically. 9
  10. 10. Technical, procedural and general issues regarding personnel and the mechanismsof research (i.e. viewed by the editor as challenges, but not specific scientificquestions)- (Note from Ed: there were many comments calling for more collaborative and multi-center programs and far more translational investigation. These points were consolidatedin comments below. The need for “bigger science” seemed to be a common view amongmany investigators)- Fewer people seem to be coming into, and staying in the field. This is partly due tofunding. Along those lines, our field has struggled at study section with an inability ofour representatives on study section to reach consensus, and therefore our grants oursuffering. As you know, with cutoffs as low as they are, you cant have anything wishy-washy let alone negative said about a grant.- I think that the best chance would be to fund a consortium of research teams, whowould work closely together to solve the problems. This might mean funding 10laboratories and clinical research groups, who would agree to work together, would shareexpertise and would have a system in place that at least some researchers wouldeffectively be employees of the consortium, and could move easily between researchsites. There would need to be a governance structure, agreed targets and adequatefunding, guaranteed for a sustained period of time (e.g., 7 years, plus opportunity at 5years for renewal to extend to a total of 10 years). I would see putting together such aconsortium being done by a national body that is commissioned to do so. It would not beby a competitive grants process, although expressions of interest might be invited. Thisprocess might grow out of the current National Commission on Digestive Diseases. Thegoverning council of the consortium would have a very important coordinating role, anda degree of authority that would sustain (even force) the collaboration.The value of achieving the aims that I have set above may be as much as $10 billion peryear. A commensurate investment might be $30 million a year. I am sure that you knowthese numbers better than I do.- Intellectually: is mandatory that Neurogastroenterologists identify human targetsrelevant to improving health. There is still a big discrepancy between the complexity ofthe research goals and the relatively paucity of rational interventions in GIT diseasesassociated with neurogastroenterology- Returning to a pathophysiologic point of view on GI functional disorders rather thansticking to the symptomatic approach of the Rome initiative - while it has enlarged ourunderstanding of functional disorders, it has neither broadened the acceptance of FBD inthe public nor has it been very successful in generating new treatment options (drugs).- I think a major challenge for all of research is how to find the road back to functionalphysiology. We have to find a way to attract the brightest and most innovative youngminds to this area. We have to make functional gut physiology as attractive asneuroscience, or molecular/cellular biology. The future needs innovative minds thinking 10
  11. 11. of how the advances of molecular biology and genetics are translated into normalfunction and to pathology of the gut. As a subnote, this also would include retainingfunding for functional motility research.- I think another important goal will be the translation of a lot of animal work to humansamples and human models. Considerably more can be done now than it ever couldutilizing human tissues, and an important goal will be relevant translation ofunderstanding of the enteric system of animals to humans.- Another important challenge is to develop appropriate ethical procedures for bankingof human tissue in the GI area and for dealing with the ethical dilemmas that are faced inthe current regulatory systems that we have. I think this is very important if we want tofurther advance work on human tissues.*Notes about collection of and dissemination of information: A random group ofprincipal investigators currently funded by the NIDDK for motility and functional GIdisorders was polled for opinions on the questions represented by the 3 sub-headingsabove. This poll was meant to collect a broad range of views to enhance the discussionsof Working Group II (Functional GI Disorders and Motility Disorders) of the NationalCommission on Digestive Diseases. In addition to the group of principal investigatorsfunded by the NIH, a group of prominent investigators from the international communitywas also polled. The list above is a summary of comments received by Feb 7, 2007, andfurther comments will be appended if received at a later time. Ideas, in essence, alreadyincorporated into pre-conference reports by Working Group II members were notnecessarily repeated on the list above. Names and references and identity ofcontributors were edited for objectivity. This list was circulated to the Working Group IImembers before the 1st group discussion so they would be able to consider the views of abroad base of active investigators. Dr. Robert Hammond (Executive Director, NCDD)also requested that this list be posted on the NCDD Bulletin Board, and I will takeadvantage of this offer to make the document as open and available as possible. Thanksto all who contributed.Kenton SandersFeb 7, 2007 11