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  • 1. NCDD Inflammatory Bowel Diseases Working Group (WG 5) Consolidated Post-Conference Call Report As of April 10, 2007 Chair: Daniel K. Podolsky, MD, Massachusetts General Hospital, Boston Vice Chair: Eugene B. Chang, MD, University of Chicago This document is a collection of the revised reports that were submitted by the above-named NCDD Working Group (WG) members following their March 8, 2007, conference call. The reports contain the members’ revised goals based on discussions during the call. Revisions in preparation will be incorporated as received. List of Current Reports Page Genetics, Jerome I. Rotter, MD...................................................................................................................2 Microbiology, R. Balfour Sartor, MD..........................................................................................................4 Immunology and Inflammation, William F. Stenson, MD, & Stephan Targan, MD....................................8 Epithelial Biology, Daniel K Podolsky, MD, & Eugene B. Chang, MD [revision in preparation].............11 Systems Biology, Jeffrey Gordon, MD [revision in preparation]...............................................................13 Clinical Research, William Sandborn, MD, & Brian Feagan, MD............................................................15 Pediatrics, Richard Grand, MD..................................................................................................................18 1
  • 2. NAME: Jerome I. Rotter, MD, Cedars-Sinai Medical Center, Los Angeles WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Genetics 1. RESEARCH ADVANCES Research Advance #1  The identification of NOD2/CARD15 as a susceptibility gene for Inflammatory Bowel Disease (IBD) has highlighted the importance of innate immunity in the etiological pathways of Crohn’s disease. Citation: Hugot et al. Nature 411:599-603, 2001. Research Advance #2  Identification of TNFSF15 (TL1A) and IL23R as IBD susceptibility genes has led to investigation of the interface between the innate and adaptive immune functions in disease pathogenesis. Citations: Yamazaki et al. Hum Mol Genet 14:3499-3506, 2005; Duerr et al. Science 314:1461-1643, 2006. Research Advance #3  Genetic analyses have improved our understanding of the categorization of disease; in particular, research has identified genetic subgroups such as patients with highly reactive disease. Citations: Abreu et al. Gastroenterology 123:679-688, 2002; Devlin et al. Gastroenterology in press, 2007. Research Advance #4  The genetic heterogeneity of disease has been linked to heterogeneity of the natural history of disease. Citations: Mow et al. Gastroenterology 126:414-424, 2004; Dubinsky et al. Am J Gastroenterol 101:360-367, 2006. 2. GOALS FOR RESEARCH 1. Current and future trials of treatments for IBD should include the known genetic markers to help identify pharmacogenetic and subgroup effects. In addition, genome-wide association methods should be used to study the genetics of response to IBD therapy in both clinical trials and clinical studies. These studies would eventually lead to clinical trials targeting specific therapies to patients based on genotype. 2. Increase the efforts to study IBD in specific population subgroups including pediatric cases and minority populations (African-Americans, Hispanic-Americans of Latin American descent, Hispanics of Caribbean descent, Asian-Americans). These increased efforts should encompass (i) intense study of relatives of pediatric IBD cases with extensive, semi-annual phenotyping and antibody measurements to better understand pre-clinical natural history; (ii) utilization of genetic tools to better understand the effect of gene variants from different ancestral genomes; (iii) further study of environmental effects in these subgroups; and (iv) 2
  • 3. improved study of gene-environment interaction effects using direct measurement of environmental exposure. 3. Study function of genetic variants by in vivo studies of patients with specific genetic haplotypes combined with in vitro studies. This might be best accomplished by an IBD Functional Genomics Consortium, as has been mentioned by other members of this Committee. Such efforts could utilize and expand upon the current understanding of the interactions of genetic susceptibility as defined by a growing number of specific genes and variants in those genes, together with pathophysiological phenotypes (for example, gut antibodies) to more clearly delineate the basic biological mechanisms involved in IBD subtypes. 3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS  Obtaining DNA samples from clinical studies of therapies (for short-term goal 1 and intermediate- term goal 1). [Editor’s Note: These references are to goals listed in the original Pre-Conference Call Consolidated Report; this challenge/step does relate to the first goal listed above.]  Large-scale epidemiological studies of patients with genotyping of a large number of genetic markers and phenotyping of a large number of serum antibodies to gut microbial flora and to infectious agents. 4. PATIENT PROFILE TOPIC Please give brief description of an idea for a patient profile relevant to this research topic. 5. GRAPHICS AND IMAGES If you have access to the graphic/image, please send as email attachment; if not, please provide information on the source of the graphic/image. 3
  • 4. NAME: R. Balfour Sartor, MD, University of North Carolina, Chapel Hill WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Microbiology Authors Note: The microbiology subcommittee was composed of Gerald Tannock, Ph.D. (Univ. of Otago, New Zealand), Arlette Darfeuille-Michaud, Ph.D. (Univ. d’Auvergne, France), Vince Young, M.D., Ph.D. (Michigan State University), Jim Versalovic, M.D. (Baylor College of Medicine), James Fox, Ph.D. (MIT), and Ingo Autenrieth, M.D., Ph.D. (Univ. Tubingen, Germany 1. RESEARCH ADVANCES Research Advance #1  Techniques for the molecular detection of components of the complex intestinal microbiota and their localization in human subjects. This lays the foundation for technology to identify alterations of components of the exceedingly complex bacterial and fungal microbiota of the ileum and colon in Crohn’s disease, ulcerative colitis, and pouchitis compared with normals. Citations: Eckberg PB et al. Science 308: 1635-8, 2005. Gill SR et al. Science 312: 1355-9, 2006. Swidsinski A. et al. World J. Gastroenterology 11: 1131-40, 2005. Swidsinski A. et al. J. Clin. Microbiology 43: 3380-9, 2005. Research Advance #2  Functional changes in the commensal (normal) intestinal bacteria can profoundly influence inflammation and metabolic function in mammalian hosts. These observations suggest that functional alterations of intestinal bacteria (expression of genes that mediate epithelial adhesion, invasion, and persistence within epithelial cells and phagocytic cells) influence their ability to injure the mucosa and incite pathogenic immune responses. In addition, metabolic activities of bacteria can activate host epithelial responses and influence nutrient absorption. Citations: Turnbaugh PJ et al. Nature 444: 1027-31, 2006. Sonnenburg ED et al. PNAS 103:8834-9, 2006. Darfeuille-Michaud A. et al. Gastroenterology 127: 412-21, 2004. Research Advance #3  Select members of the complex intestinal microbiota can induce pathogenic immune responses that lead to chronic, T cell-mediated inflammation in genetically susceptible hosts. Dominant bacterial antigens exist that stimulate pathogenic immune responses. These stimuli are host and bacterial species specific. These observations suggest that a manageable number of bacterial species and dominant antigens induce pathogenic responses, laying the foundation for identifying clinically important subsets of patients that will selectively respond to therapy through selective immune responses to a panel of microbial antigens. Citations: Kim S et al. Gastroenterology 128:891-906, 2005. Lodes M et al. JCI 113:1296-1306, 2004. 4
  • 5. Papadakis KA et al. Inflammatory Bowel Diseases Jan., 2007 epub. Mow WS et a. Gastroenterology 126: 414-24, 2004. Research Advance #4  Bacterial components stimulate innate immune responses in the mucosa of normal hosts that are protective. Dysregulated host innate immune responses can lead to chronic intestinal inflammation driven by commensal bacteria. Bacterial products can modulate innate immune responses, such as NFκB activation. Citations: Rakoff-Nahoum S et al. Cell 118:229-241, 2004. Neish AS et al. Science 289:1560-3, 2000. Collier-Hyams et al. J. Immunology 175:4194-8, 2005. Kelly D et al. Nature Immunology 5:104-12, 2004. Ruiz et al. J. Immunology 174:2990-2999, 2005. Beckwith J et al. Gastroenterology 129:1473-84, 2005. 2. GOALS FOR RESEARCH A. Highest-Priority Short-Term Goals (1-3 years) 1. Reliably distinguish mucosal-associated vs. luminal bacterial and fungal populations in the normal human ileum, cecum, and distal colon by molecular and culture-based methods. Contrast these with fecal microbial populations. 2. Identify dominant bacterial antigens that stimulate pathogenic T cell responses in animal models and determine their responses in IBD patients. Investigate clinical subsets of Crohn’s disease, ulcerative colitis, and pouchitis patients. 3. Determine the influence of dietary components on the composition and function of intestinal bacteria. Intermediate-Term Goals (4-6 years) 1. Determine the influence of host genetic susceptibility factors (NOD2/CARD 15, ATG 16L1, etc.) on the composition and spatial arrangement of intestinal microbiota. 2. Identify changes in mucosally associated and luminal microbiota (bacteria and fungi) in the ileum, right and left colons of patients with Crohn’s disease and ulcerative colitis in comparison with normal subjects. Emphasize differences in clinical subsets of patients. 3. Identify/characterize components of microbial species that can induce or downregulate inflammation. Long-Term Goals (7-10 years) 1. Characterize and understand bacterial biofilm formation/regulation and how microbial biofilms influence intestinal inflammation and homeostasis. 5
  • 6. 2. Identify familial associations of microbial populations and separate the influence of genetics from common environmental factors (study monozygotic vs. dizygotic twins) compared with spouses and nonaffected siblings or offspring as controls. B. Lower Priority but Still Important Short-Term Goals (1-3 years) 1. Identify sequential changes in the microbial species inhabiting the neoterminal ileum after ileocecal resection for Crohn’s disease and creation of ileal pouches in ulcerative colitis from the time of surgery to onset of clinical disease. 2. Determine the prevalence of bacterial virulence factors that regulate mucosal adherence, invasion, and resistance to bacterial killing in IBD patients vs. normals. Analyze the actively inflamed vs. normal ileum and cecum of patients with Crohn’s disease, ulcerative colitis, and pouchitis. 3. Identify mechanisms of protection by probiotic bacteria and prebiotics. Intermediate-Term Goals (4-6 years) 1. Identify the microbial genes that are selectively regulated by the inflammatory process and how expression of these genes influence mucosal function (microbial-host inflammatory crosstalk). 2. Perform antibiotic and/or probiotic clinical trials in subsets of patients selected by unique microbial composition, immune responses to bacterial/fungal antigens, or host genetic characteristics (NOD2/CARD 15, ATG 16L1, etc.). Long-Term Goals (7-10 years) 1. Genetically manipulate bacteria to treat and prevent intestinal inflammation. 2. Identify mammalian molecules that mediate the attachment of mucosally adherent bacterial strains and the regulation of their expression. Are these different in IBD vs. normal patients? 3. Develop reliable gnotobiotic animal models with defined groups of bacterial/fungal species to investigate bacterial/host interactions that determine mucosal homeostasis vs. chronic inflammation (move from monoassociated rodents to colonization with groups of defined species). 3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS A. Challenges  Develop standardized techniques to process mucosal biopsies for molecular analysis of bacteria.  Develop rapid quantitative high throughput techniques to define individual members of complex microbial communities.  Develop reliable databases of bacterial 16s rRNA genes. It is estimated that 20% of such sequences in public databases are incorrect.  Develop bioinformatic platforms to analyze the voluminous data generated by the molecular analyses. B. Steps To Achieve Goals 6
  • 7.  Perform multicenter, multidisciplinary studies to identify changes in the microbiota in very well- characterized, clinically relevant, and genetically defined patient subsets.  Perform multicenter studies with large numbers of well-defined IBD patient subsets to determine immunologic (serologic and T cell) responses to defined microbial antigens that are identified in animal models.  Promote clinically relevant studies in animal models and translational research of rapidly applying observations from in vitro and animal model studies to patients. 4. PATIENT PROFILE TOPIC Please give brief description of an idea for a patient profile relevant to this research topic. 5. GRAPHICS AND IMAGES If you have access to the graphic/image, please send as email attachment; if not, please provide information on the source of the graphic/image. 7
  • 8. NAME: William F. Stenson, MD, Washington University School of Medicine, St. Louis Stephan Targan, MD, Cedars-Sinai Medical Center, Los Angeles, and WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Immunology and Inflammation 1. RESEARCH ADVANCES Research Advance #1  The association of mutations in several genes with human IBD. Citations: Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314:146103. (links data from mice implicating IL-23 and Th-17 cells to IBD pathogenesis in humans.) Gaya DR, Russell RK, Nimmo ER, Satsani J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 2006;367:1271-1284. Research Advance #2  The identification of the normal commensal flora as the likely target of the abnormal intestinal immune response in inflammatory bowel disease. Citation: Sartor RB. Intestinal microflora in human and experimental inflammatory bowel disease. Curr Opin Gastroenterol 2001;4:324-330. Research Advance #3  The identification of the distinct immune response patterns that differentiate the pathogenic mechanisms responsible for tissue injury in Crohn’s disease and ulcerative colitis. Citations: Mottet C, Uhlig HH, Powrie F. Cutting Edge: Cure of Colitis by CD4(+)CD25(+) Regulatory T-cells. J Immunol 2003;170:3939-43. (One of many papers on Treg effects on chronic intestinal inflammation). Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigi S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. Nonclassical CD1d-restricted NK T-cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004;113:1490-1497. Research Advance #4  The identification of innate immunity as the first line of defense against enteric commensal and pathogenic flora and its role in IBD pathogenesis. 8
  • 9. Citation: Abreu MT, Fukata M, Arditi M. TLR signaling in the gut in health and disease. J Immunol 2005;174:4453-4460. Research Advance #5  Demonstration that serologic reactivity to multiple bacterial antigens correlates with complications of surgery in small bowel Crohn’s disease. Citation: Mow WS, Vasiliauska EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, Landers CJ, Abreu-Martin MT, Rotter JI, Yang H, Targan SR. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology 2004;126:414-24. (Retrospective study showing that serologic reactivity to multiple bacterial antigens correlates with complications and surgery in small bowel Crohn’s disease). 2. RESEARCH GOALS Short-Term Objectives 1. Define the normal innate and adaptive immune responses to the commensal bacteria and enteric pathogens. Studies of the adaptive immune response would include definition of the roles of antigen- presenting cells and both effector and regulatory T-cells. 2. To identify the differential potential of various gut bacterial strains in inducing intestinal inflammation in animal models of IBD. 3. To better define the immunologic effects of drugs currently used to treat IBD and drugs in the pipeline. 4. To better understand the role of probiotics in modulating the immune response to animal models of colitis and human IBD. Intermediate-Term Objectives 1. To determine if the mucosal innate immune system is defective in IBD and how this results in an abnormal adaptive response. What are the key T-cell effector mechanisms in Crohn’s disease (i.e., Th-1 vs Th-17), and what are the key T-cell effectors in ulcerative colitis (i.e., what is the role of IL-13-producing Th-2 cells in this disease)? Are there defects in the generation or function of regulatory cells? 2. Correlate genetic and serologic markers (and combinations of markers) with functional immune defects in clinically defined subsets of IBD patients. Generate mouse models of these genetic/immune defects. 3. To determine if the innate/adaptive immune response to commensal bacteria is abnormal in IBD. Is the abnormal immune response to commensal bacteria in IBD determined by genetic abnormalities in the host? Do different genetic abnormalities predict specific immunologic abnormalities? Do combinations of mutations predict immunologic abnormalities? Do different genetic abnormalities predict an altered immune response to specific bacterial strains? 9
  • 10. 4. If there is an alteration in the immune response to commensal flora in patients with IBD, to determine if that altered immune response is directed against all commensal bacteria, a subset of commensal bacteria, or specific strains? 5. In Crohn’s disease there appears to be an abnormal immune response against the commensal flora. Is the spectrum of bacteria against which this abnormal immune response is directed the same in all IBD patients or are there subgroups of IBD patients in which the abnormal immune response is directed against specific subgroups of intestinal flora? Long-Term Objectives 1. To determine if genetic or serologic markers predict prognosis or the response to specific therapies in IBD. 2. To develop medical therapy based on an improved understanding of the defects in the innate and adaptive immune system in IBD. 3. To develop medical therapy for subsets of IBD patients based on genetic and serologic markers that are predictive of specific functional immunologic defects. 3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS 1. Continue to support broad cooperative initiatives like the IBD Genetics Consortium and more broadly publicize the services offered through this consortium and how investigators would access it. 2. The NIH should sponsor an IBD Translational Consortium consisting of both basic and clinical investigators. This consortium would be coordinated with the Genetics Consortium. The translational consortium might be along the lines of the Immune Tolerance Network (ITN) that is currently an initiative of the NIAID. The key part of the ITN are core laboratories for various important assays. For the IBD translational consortium, a core for measurement of specific genetic loci would be crucial. A second core would be needed for immunologic assays and biomarkers and a third for bioinformatics to assemble and analyze the clinical and laboratory data. An alternative would be supplementing existing cores that are present in NIDDK Digestive Disease Centers to support this effort. The translational consortium would need a mechanism to bring together patients and core labs that might be geographically dispersed. The initial project for this consortium would be to define the natural history of IBD in well defined patients using the new genetic and immunologic markers that have been developed in the recent past. This project would address the question of whether there are subgroups of IBD patients that can be defined using genetic or immunologic markers that have a defined clinical course. The second question would be whether serologic biomarkers could be used to establish prognosis for patients prospectively. Prognostic biomarkers could change therapy. One possibility would be accelerated therapy with immune modulators and biologics in patients who are going to have a more severe and complicated course. 10
  • 11. NAME: Daniel K. Podolsky, MD, Massachusetts General Hospital, Boston, and Eugene B. Chang, MD, University of Chicago WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Epithelial Biology [Revision in preparation] 1. RESEARCH ADVANCES Research Advance #1  A constellation of studies have led to a more comprehensive – but still incomplete – understanding of the molecular basis of barrier function and demonstration of its importance in maintaining normal mucosal homeostasis and its disruption as important in the pathogenesis of chronic inflammatory bowel disease. These include the composition of the tight junction and its functional regulation, Ultimately, understanding this dynamic regulation should enable strategies for enhancing the barrier to prevent IBD or restore it once damage has occurred. Research Advance #2  In addition to its role in forming the mucosal surface barrier, the epithelial cell compartment has key capabilities of innate immune response, including expression of both TLRs and Nods and production of key effectors such as defensins. These may be central to the functional outcome of contact and interaction with luminal flora – both commensal populations and enteric pathogens. Alterations in these factors and processes are found in IBD. In concert with better understanding of the composition of the luminal flora, it may form the basis for rational modulation of that flora to maintain or restore mucosal health. Research Advance #3  Despite possessing a robust variety of receptor and signaling pathways that should eventuate in inflammation in the context of ubiquitous and constant contact with microbial flora, the epithelium remains in a state of “tolerance” or hyporesponsiveness. While the value of this hyporesponsive posture in allowing peaceful co-existence with a omnipresent luminal flora, they point implicitly to a key question for further study: How is this state abrogated in circumstances where that may be needed (exposure to true enteric pathogen) and altered in the context of IBD in the absence of a specific pathogen? Research Advance #4  A variety of both direct and circumstantial observations implicate a role for alterations of the epithelial cell compartment in the central pathogenesis of IBD. These include development of colitis in murine models resulting from genetic alterations of epithelial cell-expressed product, expression of proteins encoded by human IBD susceptibility genes in the epithelium. Collectively these underscore the importance of comprehensive efforts to study this compartment to achieve an understanding of the pathogenesis of IBD. Research Advance #5  Partial delineation and functional location of the intestinal stem cell compartment and implication of key signaling pathways (wnt; notch-delta) and transcriptional factors (math, hes) that may regulate the stem cell compartment and lineage specification. 11
  • 12. Research Advance #6  Definition of key components of the coordinated repair response to injury and ability to enhance repair through novel strategies for delivering recombinant proteins that play an important role as highlighted by studies of trefoil peptides. These may enable new therapeutics, complementing those targeted to inflammatory processes per se which may also have particular importance as prophylactic interventions. 2. GOALS FOR RESEARCH Short-Term Goals 1. Establish self sustaining primary intestinal/epithelial cell cultures. 2. Establish practically useful mucosal organ culture models. 3. Identify and isolate the intestinal stem cell compartment. 4. Develop comprehensive epithelial signaling network delineation. 5. Full inventory of cell populations interacting with epithelial compartment. 6. Complete determination of molecular basis of epithelial tolerance. Intermediate-Term Goals 1. Development of a humanized model of intestinal mucosa in vivo. 2. Development of techniques for functional and direct cellular imaging of intestinal/colonic epithelium in vivo in both man and experimental models. 3. Characterization of inflammatory imprinting of epithelial cell compartment (e.g., by proteomic, expression profiling. etc.). 4. Characterization of epithelial imprinting by bacterial populations. 5. Temporal resolution of interactions between epithelial cells and other cell populations. 6. Full definition of the signature of stem cells and hierarchy of cell lineages. 7. Use of chemical biology and other approaches to identify entities that can effectively modulate epithelial barrier, repair pathways, innate response pathways, etc. Long-Term Goals 1. Model bacterial-epithelial interactions in in vitro and in vivo to develop effective interventions using probiotic or derivative approaches (from microbial product modeling) for both prophylactic and therapeutic utility. 2. Therapeutic use of pro-repair factors. 3. Development of functional replacement therapy using intestinal stem cells. 12
  • 13. 4. Effective regulation of innate immune responses within the epithelial compartment. 13
  • 14. NAME: Jefrrey Gordon, MD, Washington University School of Medicine, St. Louis WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Systems Biology [Revision in preparation] Symbiotic relationships between microbes and animals are a pervasive theme of life on our microbe- dominated planet. We are no exception: the total number of microbes that colonize our body surfaces is thought to exceed our total number of somatic and germ cells by an estimated 10-fold. Our bacterial and archaeal symbionts provide us with traits we have not had to evolve on our own. In this sense, we should consider ourselves to be a composite of species, both microbial and human, our genetic landscape to be a summation of the genes embedded in our own human genome and in the genomes (microbiome) of our microbial partners, and our metabolic features as a co-evolved amalgamation of human and microbial traits. This view of ourselves as a supraorganism, whose health and predisposition to various diseases are influenced by our microbial ecology, also raises an important question about whether there is a microbial dimension to human evolution, a micro-evolution, which is driven by our own rapidly advancing technology with its attendant changes in our lifestyles and biosphere, and whether changes in our gut microbial ecology are contributing factors to the rise in the incidence in inflammatory bowel diseases in developing countries that are becoming “Westernized”. The field of metagenomics focuses on cultivation-independent, genome-anchored characterization of microbial communities. Meta in Greek, means “transcendent” or “a higher level”. Metagenomics, therefore, transcends the individual genome and looks at higher levels of organization - the community genome, proteome and metabolome. Newly introduced, highly parallel DNA sequencers promise to propel us into a new era in which microbiology expands its focus from the properties of single organisms to the operations of entire communities, and where investigators address longstanding and fundamental, questions about humans. How do we acquire and maintain our microbial communities? Do all humans share an identifiable ‘core’ microbiota and microbiome (defined here as a set of shared organismal and gene lineages)? Should differences in our microbiome be viewed as features that are profoundly affected by our genotypes, by our individual environmental exposures, and by our physiological status? How is the human microbiome evolving (within and between individuals) over varying time scales as a function of our changing diets, societal structures, and biosphere? What affects the diversity of the microbiome, and how does diversity impact its resiliency and microbial- host responses to various physiological or pathophysiological states? How should we define members of the microbiome when microbes possess pan-genomes (the sum of all genes present in all members of a ‘species’) that have varying degrees of ‘openness’? Finally, how can we use the answers to these questions to devise ways to intentionally manipulate our microbiota and microbiome to promote health, and to prevent or treat IBD? Recommendations 1. A human (gut) microbiome project should be supported. This should be a global project that involves periodic sampling of individuals with varying degrees of genetic relatedness. 2. Sampling should be from defined regions of the gut (e.g., initially fecal communities). The first target should be populations residing within the USA (in urban and rural areas with a view to assess the effects of lifestyle), followed by sampling outside of the USA in developing countries. Issues about depth of sampling of the microbiomes of individuals need to be addressed, as do issues about how much sampling over time should be performed on a given individual. 3. A concomitant effort should be made to sequence the genomes of cultured representatives of a range of phylotypes identified in 16S rRNA datasets of the gut microbiota. This will entail improvements in the technology for culturing previously unculturable organisms, as well as new genome assembly and annotation schemes. 14
  • 15. The goal of recommendations 1-3 should be to generate a set of reference gut microbiomes that provide a framework for identifying changes associated with disease states, such as IBD, and developing new analytic tools for economically defining the composition and functional capacities of gut microbial communities. 4. A logical extension of these studies will be to go beyond DNA-level analysis and characterize gut meta-transcriptomes, meta-proteomes and meta-metabolomes. 5. Marrying metagenomic methods with gnotobiotics should help promote definition of the operating principles, and functions of gut communities. 6. The computational challenges for this project are great and require the development of new algorithms, including better methods for phylogenetic binning, new statistical tools for defining distances between communities, and new methods for in silico modeling microbial-microbial and microbial-host interactions (including syntrophic relationships). 7. A critical determinant of the success of this project will be to deposit metagenomic datasets in databases that include information about sample collection, sample preparation, and relevant metadata about sample donors. These databases should be constructed in a way that allows comparisons among microbial communities from the guts of different individuals/populations, from other human and animal habitats, as well as from the environment. As such, these databases will spur development of new data-mining tools, spawn new methods for continuous annotation updates, and serve to break down the artificial barriers between environmental and medical microbiology. 8. There should be seamless tie-ins between the gut microbiome project and the NIH‘s structural genomics initiative. 9. Sustainable resources for ongoing research need to be created and include, but are not limited to, a robust network for global sampling of human populations and creation of large insert libraries from sequenced communities for functional screens. 10. Obtaining sustainable resources for this type of ongoing research will also require that a number of important educational issues be addressed: Public education: place an emphasis on ending the war metaphor about human-microbial interactions Educating governments: address issues related to sampling on a global scale, including obtaining informed consent to harvest microbial communities from the gut (including fecal samples), overcoming barriers to exchange of bio-specimens between countries, and intellectual property issues. Educating scientists: create interdisciplinary programs to support/sustain/attract those who are, will and/or need to work in this area (e.g., in addition to gastroenterologists, immunologists and microbiologists, need microbial ecologists, population geneticists, evolutionary biologists, environmental/chemical engineers, computer scientists, chemists). 15
  • 16. NAME: William Sandborn, MD, Mayo Clinic, Rochester, Minnesota, and Brian Feagan, MD, Robarts Research Institute, London, Ontario, Canada WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Clinical Research Additional input was received from Bruce E. Sands, Stephen B. Hanauer, and Edward V. Loftus. 1. RESEARCH ADVANCES Clinical trials have shown that inhibition of tumor necrosis factor (TNF) is an effective therapy for IBD. 1-4 Introduction of TNF antagonists into the clinic has dramatically improved the quality of life of patients. This discovery has provided new insight into the pathogenesis of UC (previously believed to be a TH2- like disease), stimulated research into mechanisms of action, and has shown the feasibility of long-term biologic therapy. Similarly, studies that showed benefit for inhibition of the α4 integrin with natalizumab5,6 and the α4β7 integrin with MLN-027 indicated that lymphocyte homing is an important mechanism for initiating and/or perpetuating human IBD. Although safety concerns exist8, selective inhibition of cell trafficking is a promising new mechanism for targeted therapy. Alternatively, immune stimulation with granulocyte macrophage colony-stimulating factor (sargramostim) is a unique concept that provides strong support for the role of defective innate immunity in pathogenesis.9;10 From a disease management perspective, an important conceptual advance is that early intervention with highly effective agents, administered either singly or in combination, may be superior to traditional "step care".11-15 Utilization of combination therapy at the first manifestation of clinical disease has the potential to modify the natural history of IBD. However, the early use of more aggressive therapy requires careful patient selection. In this regard, the evolving reclassification of IBD based on clinical phenotype, serology, and genetics may lead to a molecular classification that can be used to predict prognosis and guide treatment16-18. Citations: 1 Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T et al. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor for Crohn's Disease. N Engl J Med 1997;337:1029-35. 2 Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF et al. Maintenance Infliximab for Crohn's Disease: The ACCENT 1 Randomised Trial. Lancet 2002;359:1541-49. 3 Hanauer S, Sandborn WJ, Rutgeerts P.J., et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I Trial. Gastroenterology 2006;130:323-33. 4 Rutgeerts P, Sandborn J, Feagan B.G., Reinisch W, Olson A, Johanns J et al. Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2005;353:2462-76. 5 Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Zadorova J, Rutgeerts P et al. Natalizumab for Active Crohn's Disease. N Engl J Med 2003;348:24-32. 6 Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrence IC et al. Natalizumab Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med 2005;353:1912-25. 7 Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JWD. Treatment of Ulcerative Colitis with a Humanized Antibody to the Alpha 4 Beta 7 Integrin. N Engl J Med 2005;352:2499-507. 8 Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J et al. Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy. N Engl J Med 2006;354:924-33. 9 Dieckgraefe BK, Korzenik JR. Treatment of Active Crohn's Disease with Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor. Lancet 2002;360:1478-80. 16
  • 17. 10 Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ, Sargramostim in Crohn's Disease Study G. Sargramostim for Active Crohn's Disease. N Engl J Med 2005;352:2193-201. 11 Markowitz J, Grancher K, Kohn N, Lesser M, Daum F, The Pediatric 6MP Collaborative Group. A Multicenter Trial of 6-Mercaptopurine and Prednisone in Children with Newly Diagnosed Crohn's Disease. Gastroenterology 2000;119:895-902. 12 Lemann M, Colombel JF, Duclos B, Veyrac M, Dupas JL, Delchier JC et al. Infliximab in Steroid Dependent Crohn's Disease Patients Treated with Azathioprine or 6-Mercaptopurine:A Randomized Double-Blind Placebo Controlled Trial. Gastroenterology 2003;125:3. 13 Hommes D, Baert F, vanAssche G, Caenepeel F, Vergauwe PHT, Devos M et al. The Ideal Management of Crohn's Disease: Top Down Versus Step Up Strategies, a Randomized Controlled Trial. Gastroenterology 2006;130:108-09. 14 Sandborn WJ, Colombel JF, Panes J, Scholmerich J, McColm JA, Schreiber S. Higher Remission and Maintenance of Response Rates with Subcutaneous Monthly Certolizumab Pegol in Patients with Recent-Onset Crohn's Disease:Data From Precise 2. Am J Gastroenterol 2006;101:S454-S455. 15 Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes D, Li J et al. Early Crohn's Disease Shows High Levels of Remission to Therapy With Adalimumab:Sub-Analysis of CHARM. Gastroenterology 2007;In Press. 16 Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein C, Brant SR et al. Toward an Integrated Clinical, Molecular and Serological Classification of Inflammatory Bowel Disease: Report of a Working Party of the 2005 Montreal World Congress of a Gastroenterology. Canadian Journal of Gastroenterology 2005;19:5-36. 17 Targan SR, Landers CJ, Yang H, Lodes MJ, Cong Y, Papadakis KA et al. Antibodies to CBirl Flagellin Define a Unique Response That is Associated Independently with Complicated Crohn's Disease. Gastroenterology 2005;128:2020-28. 18 Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR et al. The Monecular Classification of the Clinical Manifestations of Crohn's Disease [see comment][erratum appears in Gastroenterology.2003 Jul;125(1):281]. Gastroenterology 2002;122:854-66. 19 Gale EA, Bingley PJ, Emmett CL, Collier T, European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. European Nicotinamide Diabetes Intervention Trial (ENDIT):A Randomized Controlled Trial of Intervention Before the Onset of Type 1 Diabetes. Lancet 2004;363:925-31. 2. GOALS FOR RESEARCH Short-Term Objectives (1-3 years) In the short-term, investigators should determine if the surrogate outcome of mucosal healing correlates with clinically relevant outcomes (disease-related complications, surgery, disability). These studies might be integrated into RCTs that assess the efficacy of early intervention with highly effective agents such as anti-metabolites and biologics. A related priority is to determine whether durable drug-free remission can be induced following treatment with these regimens. Prospective validation of clinical, serologic, (pANCA, ASCA, OmpC, I2, CBir1), and genetic markers (CARD 15, OCTN, IL-12/IL-23, etc.) of disease progression is a priority since risk -stratification of patients is likely essential to the widespread use of early aggressive therapy. RCTs should determine if the therapeutic index of combination therapy is superior to monotherapy. Patient preference studies are essential to evaluate the balance between the risks (serious adverse events) and benefits (efficacy) of new and existing regimens Strategies to prevent sensitization to foreign proteins should be encouraged given the emerging importance of biologics in treatment algorithms. Evaluation of new surgical techniques such as fecundity-sparing operations for ulcerative colitis should be considered. Prevention of post-surgical recurrence of CD is an unmet medical need. Agents that require evaluation for this indication include antibiotics, anti-metabolites, and biologics. Intermediate-Term Objectives (4-6 years) In the intermediate term cohort studies should be conducted to assess the safety of drugs, to evaluate environmental risk factors, and to examine gene-environmental interactions. Small molecules should be 17
  • 18. developed as alternatives to monoclonal antibodies targeting TNF and integrins. New approaches should be identified to stimulate the innate immune system as a treatment for Crohn's disease. Malignancy remains an important clinical problem. Accordingly, development of chemoprevention therapies, improved screening algorithms, and evidence-based management for dysplasia are priorities. Given the ambitious nature of the research agenda, surrogate end points and biomarkers should be developed to improve the efficiency of clinical research. Long-Term Objectives (7-10 years) In the long-term, primary prevention of disease in people who are genetically at risk should be investigated. Elimination or avoidance of environmental risk factors and RCTs of preventative interventions should follow the model developed in Type I diabetes.19 [See citation above.] 3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS The following challenges were identified and the steps to address the challenges that were proposed. a. Challenge: No definitive diagnostic features, no molecular classification scheme currently exists. Furthermore, no studies of molecular epidemiology, and no large prospective population-based cohorts studies have been performed. Step: Prospective, long-term incident cohort studies should be performed to characterize the natural history of the disease, to assess the safety of therapies, and to develop and validate phenotypic, serologic, and genetic markers. b. Challenge: It has become difficult to recruit patients into investigator initiated RCTs. As a consequence, the clinical research agenda is being driven by the pharmaceutical industry. This is largely a resource issue. Step: Enhanced mechanisms to support both clinical trial infrastructure and specific studies should be developed by the NIH and 3rd party payers. c. Challenge: Safety assessments are limited to post-approval requirements to develop registries for specific biologic agents and do not address the full range of agents that are used in clinical practice. Step: To develop a registry to assess the safety of various classes of drugs currently in use in clinical practice with input and co-sponsorship from the NIH, the FDA, and the CDC. d. Challenge: No uniform definitions exist for disease specific disability, disease modification, assessment of prognosis, or rate of disease progression. Parenthetically, there is little recognition by the FDA of the ability of academic investigators to contribute to study design and instrument development. Step: To develop a structured interaction between the FDA, NIH, CDC, VA, Medicare and CMS, and the academic community to standardize the endpoints and trial design. 4. PATIENT PROFILE TOPICS A patient with severely active Crohn’s disease, refractory to other treatment options, that was effectively treated with a TNF antagonist would emphasize this important advance in clinical research. 18
  • 19. NAME: Richard Grand, MD, Children’s Hospital, Boston WORKING GROUP: Inflammatory Bowel Diseases (WG 5) SUBGROUP: Pediatrics 1. RESEARCH ADVANCES Research Advance #1  First epidemiological study of incidence and prevalence of IBD in pediatric patients in the United States. Citation: Kugathasan S, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population based study. J Pediatr 2003;143: 525-531. Research Advance #2  First characterizations of differences in IBD expression in children of varying ages, and of unique pediatric pathological findings in biopsies of affected children with IBD compared to adults. Citations: Heyman MB, et al. Children with early onset inflammatory bowel disease: analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35-40. Glickman JN, et al. Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings. Am J Surg Pathol 2004;28,190-197. Robert ME, et al Patterns of inflammation in mucosal biopsies of ulcerative: perceived differences in pediatric populations are limited to children younger than 10 years. Am J Surg Pathol 2004; 28: 183-189 Research Advance #3  Recognition of hypovitaminosis D and altered vitamin D status in children with IBD, and inflammation-induced alterations in bone remodeling. Impact of Crohn’s disease on final adult height. Citations: Pappa HM, et al. Vitamin D status in children and young adults with inflammatory bowel disease Pediatrics 2006;118:1950-1961. Sylvester FA, et al. Are activated T cells regulators of bone metabolism in children with Crohn disease? J Pediatr 2006:148:461-466. Sawczenko A, et al. Clinical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics 2006;118:124-129. Research Advance #4  First approach to mechanisms of iron malabsorption in children with IBD, demonstrating inflammation-induced block in iron absorption due to elevated IL-6 and hepcidin levels. 19
  • 20. Citation: Semrin G, et al. Impaired intestinal iron absorption in Crohn’s disease correlates with disease activity and markers of inflammation. Inflamm Bowel Dis 2006;12:1101-1106. 2. GOALS FOR RESEARCH Short-Term Goals (1-3 years) 1. Genetic basis of phenotypic heterogeneity. 2. Genetics of growth failure in IBD. 3. Regulation of inflammation-induced iron malabsorption. 4. Developmental regulation of innate immunity. 5. Impact of IBD on psycho-social development. Intermediate-Term Goals (4-6 years) 1. Regulation of regional specificity in the intestine. 2. Identification, isolation, and characterization of intestinal stem cells. 3. Defining the role of vitamin D in intestinal inflammation. 4. Role of probiotics in altering inflammation in the intestine. 5. Developmental immunology and risks for developing IBD. Long-Term Goals (7-10 years) 1. Defining the genetic basis of syndromes mimicking IBD in children. 2. Define the interaction of epithelial development and the development of the enteric nervous system. 3. MAJOR CHALLENGES AND STEPS TO ACHIEVE GOALS  We need to understand the barriers to participation in clinical research in pediatric IBD. Step: Expand access to clinical research sites. Examples include, but are not limited to, NIH CTSA centers.  Creating robust databases for accession of IBD genetic and phenotypic data from multiple pediatric sites. Step: Develop mechanisms for funding consortia designed to produce reliable data for use in genotype/phenotype studies, clinical trials, and long-term followup outcome studies.  Identifying well-characterized patients and families who are willing to participate in clinical trials in pediatric IBD. 20
  • 21. Step: Support the creation of pediatric IBD centers through the NIDDK center program.  Working with FDA to advance the support of clinical trials in children with IBD . Step: Develop cross-agency working groups and extramural collaborations to address this issue.  Establishing programs within NIH to support studies of early-onset IBD. Step: A new RFA is indicated for this purpose. 4. PATIENT PROFILE TOPIC A pediatric patient with Crohn’s disease who has had growth failure and is being treated with both infliximab and nasogastric nutritional therapy. 5. GRAPHICS AND IMAGES If you have access to the graphic/image, please send as email attachment; if not, please provide information on the source of the graphic/image. 21