A new phase for the microbiome

For the last five years, scientists at the Broad Institute have been helping generate a catalog of the trillions of microorganisms living on – and in – the human body. We now know that these passengers, collectively known as the microbiome, are not merely cargo; they have physiologic effects, both positive and detrimental, on their human hosts.

The Human Microbiome Project (HMP) began as an effort to systematically uncover all of these microbes that call the human body home. While the HMP’s first phase set a baseline of the identity and genetic makeup of the microbiome of a healthy person, a new three-year “multi-omic” study led by Broad senior associate member Ramnik Xavier and Broad associate member Curtis Huttenhower takes the project into its second phase with a high-resolution look at the roles played by microbes and their interactions with the host, both in health and disease.

The Broad team joins forces with partners at several other institutions in this ambitious new effort. These partners include clinical researchers at Massachusetts General Hospital (MGH), Emory University Hospital, Cincinnati Children’s Hospital, and Cedars-Sinai Medical Center; viral genomics scientists at Baylor College of Medicine; epithelial stem cell experts at Washington University; proteomics researchers at UCLA and Lawrence Berkeley National Laboratory; and computational analysis experts at the University of Colorado. The team will also rely upon expertise and resources from the Broad’s Genomics and Metabolite Profiling Platforms, in addition to the institute’s Technology Labs and researchers specializing in single-cell techniques.

“This effort is only possible with everyone chipping in for clinical coordination, data generation, experiments, and analysis,” said Huttenhower, an associate professor of computational biology and bioinformatics in the Harvard School of Public Health.

The new project builds upon insights gleaned during the HMP’s initial phase. “It became clear during the first phase of the project that although healthy microbiomes can vary between people and over time, the microbiome of someone with a disease is often very different from that of a healthy person,” said Dirk Gevers, a Genome Sequencing and Analysis Program group leader at the Broad Institute and a lead scientist on the new effort.

In the first phase of the HMP, scientists collected microbes from five body areas of healthy people and sequenced the microbial genomes. The genes represented in those genomes provided clues to what roles those microbes might play. To explore the role of the microbiome in disease, the Broad scientists are now embarking on an effort, in conjunction with Harvard School of Public Health, to generate a more detailed, functional map of the gut microbiome in healthy people and those with inflammatory bowel disease (IBD), a set of conditions, including Crohn’s disease and ulcerative colitis, that affects 1.5 million Americans and has been studied at the Broad since the institute’s inception.

The microbiomes of healthy people and those with Crohn’s disease or ulcerative colitis will be subjected to a variety of “omics” techniques, such as proteomic, metabolomic, or transcriptomic analyses. These techniques go beyond the scope of the first phase, which identified which genes were present in the genomes, by revealing the activity of those genes in health and disease. “This ‘multi-omic’ approach will provide us an opportunity to see how those organisms are using their genetic capacity in a disease context,” said Gevers.

The Broad-led project, one of three grants awarded in the HMP’s second phase, also takes a major step forward by incorporating the “multi-omic” analysis of the human host, too. This work will build on previous research by Xavier and other scientists that suggests that in inflammatory diseases like IBD, the host response to microbes is disrupted. “In IBD, the interplay between microbes and the host is abnormal,” said Xavier, who is also the Chief of Gastroenterology at MGH, and the director of MGH’s Center for the Study of Inflammatory Bowel Disease. “By incorporating both the host and microbe in this study, we hope to get a much more detailed picture of this broken interaction.”

In the new study, stool, biopsy, and blood samples will be taken from subjects – six healthy people, twelve patients with Crohn’s disease, and twelve patients with ulcerative colitis – at each of the collection sites at MGH, Emory, Cincinnati, and Cedars-Sinai. The patients will be followed from the first diagnosis of IBD, with samples taken every two weeks for the next year. In the first phase of HMP, participants were only measured at two or three timepoints, so this dense, longitudinal data will give an unprecedented look at how the microbiome and host response changes over the course of disease.

The researchers face new challenges in generating and organizing such a massive amount of complex data. Techniques for collecting samples that were developed during the first phase might be insufficient for the variety of data types in the new study, so the team will need to adjust the sample collection methods.

Another challenge will be building on the expertise developed during the first phase of the HMP to incorporate not just sequencing, but many new data types. "There are good methods now for observing the human microbiome using DNA sequencing, but that approach alone might not tell you what the bugs are doing," said Huttenhower, who will guide the development of new analysis tools and methods to integrate multiple sources of high-throughput data. “In this phase, we specifically want to understand the biomolecular activity that's occurring over time, which will require connecting many different data types into network models that capture microbial regulation and metabolism, and their effects on host cells and disease outcome."

That biological insight could one day lead to new approaches for managing IBD. Fecal transplants have shown promise for treating recurrent infections from C. difficile, a dangerous bacterium that causes severe inflammation in the colon, but they have not shown the same cure rate for IBD, possibly because the human host response is still awry. A better understanding of the host-microbe relationship may put researchers in a position to design more tailored solutions for IBD that both deliver beneficial microorganisms and repair the dysfunctional host response.

One of the major successes of the HMP’s first phase was to put a wealth of data in the public domain and bring together a community of researchers with many different areas of expertise. Rapid data release was a priority for the first phase of HMP, and the team is planning the same sort of data sharing here, not only of sequences, but also of clinical and experimental protocols, software, and tutorials.

The data in this new effort are even more diverse than in the first phase. “There’s been a huge expansion in the field of microbiome research since 2008,” said Gevers. “One of its most intriguing features is that it very quickly became a field with interdisciplinary interests, incorporating skills in bioinformatics, molecular evolution, community ecology, microbiology, and computer science, in addition to clinical research. Such a wide variety is essential to produce the most valuable microbiome data and get the most out of these new data types.”