Inside our Microbiome Initiative—Creating Molecular and Bioinformatic Tools for the Development of IBD Cures
We know that intestinal microbial agents have a key role in causing IBD, but only a limited number of the enormously complex bacteria, viruses, and fungi have been identified, and their functions are largely unknown. This project will transform the field by (1) Identifying the components, genes and metabolic products of intestinal bacteria and viruses in normal healthy people, (2) Comparing the bacterial and viral species, genes, and metabolic products in IBD patients with those of people without IBD to identify unique differences in IBD patients, (3) Developing bioinformatic techniques to analyze these huge data sets so that all IBD investigators can effectively utilize the results, which will be in public databases accessible to all investigators, and (4) Developing a gene chip that can easily be used by IBD investigators to determine if a functional gene is present in a clinical or experimental sample.
CCFA Microbiome Consortium (Phase 5: 2014-2017)
Lead PI: Dr. Jonathan Braun, UCLA
PIs: Dr. Balfour Sartor, Dr. Ramnik Xavier, Dr. Curtis Huttenhower, Dr. Thad Stappenbeck, Dr. Kenneth Simpson , Dr. James Lewis, Dr. Gary Wu
The latest iteration of the CCFA microbiome consortium will focus on three activities:
(i) Mechanistic validation testing of established candidate microbial pathways and products, by an integrated team of systems biology experts and their technology platforms;
(ii) Initiation of lead molecule development by a chemical biology team for select pathways uncovered by validation testing;
(iii) Novel short-term patient studies to test dietary interventions that may target these candidate microbial pathways and products, and to uncover new and refined targets. Both the systems biology team and patient cohorts leverage existing network of technology experts and established cohorts.
It is now widely accepted that IBD results from altered interactions between gut microbes and the intestinal immune system, but the precise mechanisms by which intestinal microbiota contribute to IBD remain to be elucidated. In particular, the challenge for the microbiome in IBD has become translational: How can we elevate this understanding to a level that uncovers specific strategies for microbiome-targeted interventions to treat or prevent IBD? Work by the prior phase of the CCFA Microbiome Consortium (CCFMC) 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, represent a powerful approach to uncover microbiome-based therapies in IBD. This project is designed to address this translational need and therapeutic opportunity. For its next phase of activity, the CCFAMC has created a pipeline to advance this information so that it can be clinically targeted. This includes mechanistic validation of candidate microbial biochemical pathways and products that drive disease states (Track 1), development of lead molecules for microbiome-based therapy (Track 2), identification of an additional class of candidates based on their association with disease flares and environmental disease factors (Track 3). It also tests a human dietary intervention to target microbial pathways and products (Track 3). These tracks can be conducted in parallel, so in the upcoming three years, we expect a productive pipeline of validated microbial targets, and initial lead molecules suitable for entry into pre-clinical therapeutic development.
This project will leverage the infrastructure and scientific leaders of the Helmsley Trust network of investigators at the levels of systems biology (Broad/MGH, the CCFA Genetics Consortium) and existing IBD patient cohorts. It will also leverage the resources of a major NIH U54 grant secured by members of the CCFAMC, which was spawned by the Phase 4 of CCFAMC.
Microbiome Consortium (Phase 4: 2012-2015)
PIs: Dr. Jonathan Braun, UCLA (Lead PI), Dr. Balfour Sartor, Dr. Skip Virgin, Dr. Ramnik Xavier, Dr. Nita Salzman, Dr. Kenneth Simpson, Dr. Luciano Marraffini
Based on the successes of phases 1-3, the final phase of the microbiome consortium was initiated in January 2011 to identify gut microbioata and their link to IBD flares and remission. The Consortium involves seven multidisciplinary, multi-institutional groups that include a broad group of IBD investigators who are studying large populations of defined IBD subsets (UC, Crohn’s disease subsets, postoperative recurrence, etc). The 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.
CCFA Gut Microbiome Phases 1, 2 and 3 (2008-2015)
PIs: Dr. Jeffrey Gordon, Dr. Rob Knight, Dr. Balfour Sartor
Phase 1 of the Gut Microbiome Initiative was initiated on March 2008 and was completed in October 2008. The goal of Phase I was to develop novel techniques designed to study the microbiomes of both identical and non-identical twins and their mothers, all whom have healthy guts (154 patients total).The study allowed investigators to develop techniques to perform metagenomic (comprehensive analysis of bacterial genes) studies in a small fraction of the time and costs originally projected.
Phase 2 was instituted in October 2008 and is now completed. This phase delved deeper into analyzing the intestinal communities of twin pairs with the communities of their fathers, mothers, and siblings. The gut microbiomes of identical twins were then sequenced in-depth to create “population genomes,” and pilot projects were conducted to explore the patters of gene expression in the gut microbiome. Finally, additional computational tools were developed to analyze massive datasets generated by deep sequencing of the rare biosphere, gene expression profiles, and community structure variation over time.
Phase 3a builds on the results and collected data of the earlier phases with deep sequencing and new tools for computational analysis. This work has been remarkably successful and was completed in 2012. The new tools generated as part of this research form the basis of phases 3b and 4.