Working Group: #3 Infections of the GI Tract

June 18-19, 2007 NCDD Meeting

Working Group Members

Chair: Mitchell Cohen, MDVice-Chair: Richard Blumberg, MD

Members: Mary Estes, PhD

Alessio Fasano, MDRichard Fedorak, MD

James Kaper, PhDCynthia Sears, MD

Phillip Tarr, MD

Research Goals – Short TermEstablish criteria for accessible, potentially renewable, archives of enteric specimens in a panel of disease states. Establish a repository for patient samples (serum, stools, cDNA) that can be used as a resource for implementing preventive and acute intervention strategies.

Augment microbial “censusing” capacities of the intestinal microbiota with special emphasis on bacteria. Begin to develop a comprehensive understanding of the intestinal microbiome and the effect of the host genome on microbial colonization. Begin to understand the consequences of interactions between GI pathogens and normal gut flora on GI function.

Research Goals – Short TermDevelop animal models to manipulate the microbial community in the gut.

Understand the mechanisms of action of probiotics.

Perform well designed case-control pathogen discovery projects and case-control host microbiota investigations.

Develop new point-of-care diagnostics to easily and rapidly diagnose known infectious agents of diarrheagenic diseases.

Conduct epidemiologic investigations using state-of-the-art molecular diagnostic tools to define current infectious etiologies, establish the true incidence of etiologic agents of diarrheal disease and the health impact of acute and persistent enteric infection in distinct subgroups of hosts including normal, and immune compromised populations, e.g., solid organ transplant, bone marrow transplant, oncology patients.

Research Goals – Short Term

Perform studies to understand how common conditions such as age, malnutrition, or diabetes mellitus modify mucosal innate and adaptive immunology and physiology, altering susceptibility to enteric illnesses, and vice versa.

Understand the role of host genetics in the response to GI infections.

Research Goals – Short Term

Perform clinical trials to define effective therapies (antibiotic and non-antibiotic) for initial and recurrent Clostridium difficile disease.

Understand the mechanisms of rotaviral replication/pathogenesis to provide new approaches to treatment and a paradigm for other enteric viral infections.

Research Goals – Short Term

Perform studies to better understand the short-term (and long-term) burden and impact of enteric infections on cognition and health. Comprehensive outcome measurements should be developed to guide and standardize assessments in different populations.

Identify and characterize enteric parasite strains with increased virulence in humans as one strategy for determining key antigens for inclusion in vaccine trials.

Research Goals – Short Term

Establish local centralized networks for health care professionals, including primary care physicians, to promptly report any case of a suspected act of bioterrorism related to foodborne diseases.

Research Goals – Short Term

Assay the population of bacteria in the gut in a variety of disease states using approaches that maximize economy and computational power.

Move forward with vaccination strategies against high-frequency bacterial enteric disorders. Relatively few are easily amenable to targeting, but cholera and possibly infections caused by enterotoxigenic E. coli would lend themselves to immunoprophylaxis.

Research Goals – Intermediate

Determine the role of GI viruses, including the less well-studied ones (such as enteric adenovirus, coronaviruses, Aichi virus, and picorbirnaviruses) as well as better known viruses (including rotaviruses, caliciviruses, and astroviruses) in causing gastroenteritis.

Research Goals – Intermediate

Study human genetic polymorphisms influencing susceptibility to enteric infections. Such studies may identify important immune pathways required for protective immunity and support long-term research goals of rational vaccine development. Characterize host factors that influence immune response to vaccines for GI pathogens.

Research Goals – Intermediate

Complete genome projects for human enteric helminths.

Initiate clinical testing of new generation enteric parasite vaccines.

Develop animal models for studies of enteric infectious disease pathogenesis, new therapeutic agents, and testing of prototype vaccines.

Research Goals – Intermediate

Identify correlates of immunity for a variety of enteric pathogens.

Establish the efficacy of appropriate candidate enteric vaccines using the human challenge model.

Know if gastrointestinal biota, both pathogenic and non-pathogenic, cause other non-GI human diseases.

Identify novel biomarkers to predict the development of systemic diseases secondary to the exposure to enteric pathogens.

Research Goals – Intermediate

Pursue evidence for alterations in microbiota under conditions relevant to pathophysiologic disorders i.e., infectious diarrhea, IBS, IBD, obesity, with animal models and people.

Develop a central database repository where all known actions of particular strains of probiotics could be sent and compiled.

Research Goals – Intermediate

Disseminate vaccines for enteric infections to susceptible populations.

Initiate trials of interventions to modulate the gastrointestinal bacterial microbiota to prevent systemic and intestinal disease.

Attenuate host response to specific human infections.

Determine if currently unknown gastrointestinal infectious agents exist and identify them.

Research Goals – Long Term

Expand studies to define the long-term impact of symptomatic and asymptomatic enteric infection on physical and cognitive development in young children, adolescents, and young adults.

Integrate measures to control enteric parasitic infections including vaccine distribution, potential mass treatment protocols (e.g., wide-scale deworming, preventive chemotherapy agents) as well as development of efficient, cost-effective approaches to addressing environmental factors contributing to enteric parasite disease burden.

Research Goals – Long Term

Develop vaccines and immunotherapeutics for common enteric infections of immunocompromised hosts. Translate the understanding acquired from animal model and Phase I human studies to permit human Phase II-III vaccine and other novel therapeutic agent trials.

Research Goals – Long Term

Study the feasibility of developing vaccines or other agents against “non-pathogenic” bacteria that might trigger pathologic intestinal inflammation.

Conduct appropriately designed and powered large-scale, placebo-controlled, randomized double blind clinical trials to demonstrate safety and efficacy and substantiate the potential for novel interventions to treat or prevent enteric infections.

Explore the boundaries of genetically modified organisms designed for delivery of biologically relevant therapeutic molecules.

Research Goals – Long Term

Major Challenges/Steps To Achieve Goals

Lack of repositories for human samples, research reagents, and animal model development. Lack of databases, communication networks, and scientific resources to develop and sustain longitudinal, large population field studies and productive international collaborations.

Continued use of archaic bacterial enteric detection technology that needs to be dramatically improved and integrated with the ability to detect agents across taxa, i.e., including viral and protozoal pathogens. Need for rapid, sensitive point-of-care diagnostics to detect all known enteric pathogens.

Needed clarification of pathways triggered by specific pathogens and by bacterial communities in the gut.

Need for improved genetics and replication systems for viral pathogens. Need for development of technology and resources to study viral pathogens in human challenge models.

Major Challenges/Steps To Achieve Goals

Major Challenges/Steps To Achieve Goals

Most soluble antigens are poorly immunogenic when delivered directly to the host via mucosal surfaces.

Vaccines for some enteric pathogens such as enterotoxigenic E. coli (ETEC) and Shigella species will require multiple antigens

Immunity to some enteric pathogens such as Campylobacter and norovirus seems to be strain-specific due to high antigenic diversity

Critical antigens required for immunity to some pathogens (e.g., enteroaggregative E. coli and Cryptosporidium), have not been identified.

Major Challenges/Steps To Achieve GoalsCorrelates of protective immunity are not established for many GI pathogens, thus requiring human challenge studies or field trials to study vaccine efficacy.

Many oral vaccines are less immunogenic when given to persons in developing countries (e.g., Sabin oral polio, rotavirus, cholera and Shigella vaccines. The reason(s) for this reduced immunogenicity must be elucidated in order to overcome them.

Vaccines with target populations primarily in developing countries, such as cholera, typhoid, and intestinal parasite vaccines, will not be manufactured by pharmaceutical companies in industrialized countries due to minimal profit profiles.

Major Challenges/Steps To Achieve Goals

Our limited understanding of the intestinal microbiota and microbiome diminishes our potential to identify novel approaches to treatment and to identify those microbes that result in long-term gastrointestinal sequelae.

Major Challenges/Steps To Achieve Goals

The relative paucity of small mammal models and an artificial intestine or in vitro models for studies of intestinal physiology, mucosal immunity, and microbial-host interactions limit our potential to make fundamental insights prior to clinical trials. New models will facilitate the basic scientific studies of intestinal biology and will improve rational selection of therapeutics for clinical applications.

Need for new in vivo imaging systems that can be applied in animal models and humans to study pathogenesis.

Major Challenges/Steps To Achieve GoalsNeed to identify “silent” epidemics and outbreaks of enteric pathogens to better understand the epidemiology of foodborne diseases. Need for an infrastructure and improved technology to more promptly identify food and waterborne outbreaks.

The listing of probiotics as food supplements and/or natural health products that do not require rigorous clinical evidence for efficacy is in direct conflict with the existing and proposed use of these agents as drugs to treat disease.

There is a great need for multidisciplinary teams of researchers in human studies to obtain a complete picture incorporating immune function, transcriptome, microbiology, and clinical responses.