Discovering the complex role of intestinal microbial communities in IBD
Early CCFA-supported research helped to prove that the millions of bacteria, viruses and fungi that inhabit the human gut (i.e., our “microbiome”) are a key link between genetic susceptibility and the onset and progression of IBD. However, due to the microbiome’s enormous complexity (i.e., it varies from person-to-person and also changes day-to-day), the different functions and interactions of these organisms continue to be largely unknown. In 2008, CCFA established the Microbiome Initiative, a consortium of the country’s top IBD researchers, to study the precise mechanisms by which intestinal microbiota contribute to Crohn’s disease and ulcerative colitis. Our goal is the translation of new insights and discoveries into specific strategies for microbiome-targeted interventions that more effectively treat, and may even prevent, IBD.
As most intestinal bacteria cannot be grown in a laboratory setting, little is known about their composition or function in healthy individuals, and even less about their alterations in IBD patients. Identifying “bad bacteria” and “good bacteria” in this complex and rapidly changing environment is a tremendously complicated challenge. CCFA’s Microbiome Initiative has been a major contributor to the international effort to define the components of the intestinal ecosystem, utilizing systems and chemical biology methods and powerful computational procedures just now being applied to the IBD problem.
Since its formation, the Microbiome Initiative has progressed through a number of phases. Early work resulted in cutting-edge tools and techniques for identifying bacteria and viruses that play a role in IBD, an essential step toward addressing the translational need and therapeutic opportunity for the first microbiome-based therapies in IBD.
Recent progress in CCFA-sponsored microbiome research includes:
- Identification of 171 metabolites whose levels are altered in IBD patients and therefore could have a role in driving the origin and progression of IBD. Biological testing (i.e., assays) is assessing the impact of these metabolites on inflammatory response and the ability of the intestinal wall (known as mucosa or epithelium) to self-repair.
- A model of mucosal healing has been generated using organoids technology that is being used to evaluate the effects of the identified metabolites on epithelial proliferation (a measurement of mucosal healing).
- A screening platform to evaluate hematopoietic response to bacterial metabolites has been implemented and validated, specifically enabling study of the formation of blood cells with pro-inflammatory (Th17) and anti-inflammatory (Treg) functions, which are highly relevant to IBD. Several biologically active metabolites have been uncovered that are shown to modulate the formation of these very relevant cell types.
- The disease-causing role of different microbial metabolic pathways has been elucidated using genetically modified bacteria, which are defective in a given metabolic pathway. The effects of these mutant bacteria on the development of experimental colitis was evaluated in a mouse model of IBD, resulting in the identification of three microbial metabolic pathways that play a robust role as drivers of IBD.
- Participants have been recruited to the FARMM study, a controlled feeding experiment designed to shed light on the difference in gut metabolites in patients consuming a normal Western diet, a vegan diet, or receiving exclusive enteral nutrition as used in the treatment of Crohn’s disease.
- An international competition resulted in three new, complementary projects: The Virome of Inflammatory Bowel Disease (Scott Handley, Washington University St. Louis); Personalized IBD: the role of microbiome diversity in intestinal inflammation (Jose Clemente, Mount Sinai School of Medicine, New York); and IBD and Bacterial Composition during Pregnancy and in Newborn Meconium (Inga Peter, Mount Sinai School of Medicine, New York)
To date, 41 publications have been reported by investigators supported, in part or in full, by the Microbiome Initiative, including six publications in 2015 alone.
The Microbiome Initiative includes a broad group of IBD investigators who are studying large populations of defined IBD subsets (i.e., ulcerative colitis, Crohn’s disease subsets, postoperative recurrence, etc.). Investigators share their knowledge, resources and samples to have a better understanding of how the microbiome in different subsets of IBD is similar (or different), and to identify the best microbial biomarkers for IBD.
Lead Principal Investigator: Jonathan Braun, UCLA
- Balfour Sartor, UNC School of Medicine
- Ramnik Xavier, Massachusetts General Hospital (MGH)
- Curtis Huttenhower, Broad Institute
- Thad Stappenbeck, Washington University School of Medicine
- Kenneth Simpson, Cornell University
- James Lewis, University of Pennsylvania
- Gary Wu, University of Pennsylvania
Current Activities & Objectives
The Microbiome Initiative has created a pipeline to advance what we’ve learned so far so that it can be clinically targeted. Current research is being conducted in three parallel Tracks that will result in a productive pipeline of validated microbial targets and initial lead molecules suitable for entry into pre-clinical therapeutic development. Current Tracks include:
- Track 1: Mechanistic validation of candidate microbial biochemical pathways and products that drive disease states.
- Track 2: Development of lead molecules for microbiome-based therapy.
- Track 3: Identification of an additional class of candidates based on their association with disease flares and environmental disease factors, including testing a human dietary intervention (i.e., FARMM) to target microbial pathways and products.
Early Microbiome Initiative work established that the microbial communities associated with IBD are distinguished by distinctive functions and their products. This insight uncovers the possibility that these products represent the molecular basis for the disease impact of the microbiome in IBD. Identifying which of these products are key to the disease mechanisms in IBD, and establishing which can be effectively targeted, represents a powerful approach to uncover microbiome-based therapies for Crohn’s disease and ulcerative colitis. The Microbiome Initiative is designed to address this translational need and therapeutic opportunity.
Going forward, the Microbiome Initiative will continue to build on past discoveries, prioritizing research with the greatest potential of leading to new, more effective treatment options to improve the health and quality of life of patients with IBD. Specific activities include:
- Completion of the evaluation of the biological effects of 84 high-priority metabolite candidates using the different inflammation and epithelial repair assays that have been developed and described above.
- Beyond this high-priority list, an expanded list of candidate metabolites will be developed for analysis, using the bioinformatics pipeline generated by the Microbiome Initiative and a major new IBD dataset.
- Definition of the metabolite hits “mechanism of action” (MOA), which is the identification of the biochemical processes by which the main identified metabolites produce an effect on the different inflammatory and epithelial repair screening assays as described above.
- Completion of the identification of microbial metabolites within the human gut in patients consuming a normal Western diet, a vegan diet, or receiving exclusive enteral nutrition, derived from the FARMM study. Other multi-omic analysis (e.g. proteomics) of patient biosamples will be also completed.
Please contact Andres Hurtado-Lorenzo with any questions or comments regarding CCFA’s Microbiome Initiative.