Microbiome projects
The microbiome is the ecological community of commensal, symbiotic, and pathogenic microorganisms that share our body space. This microbial community is complex and abundant, with estimates of the total species that inhabit an individual ranging well into the thousands. Although it is evident that we understand only a small component of the human microbiome, there is growing recognition that resident microbial communities influence human health and disease.
Much of our understanding of the human microbiome comes from culture-based approaches. Unfortunately, as much as 20% to 60% of the human-associated microbiome is presently uncultivable. Profiling bacterial communities by culture-free approaches has been enormously important in helping scientists identify the species present, quantify their abundances, and determine their functions. Methods to examine the complexity of microbiome samples include generating sequencing libraries from DNA (metagenomics) and RNA (metatranscriptomics) as well as small molecule and metabolite libraries (metabolomics). Additionally, IgA-sequencing is used to target members of the microbial community that are coated in IgA and therefore recognized by the human immune system.
Investigators at the Broad continuously strive to develop and apply better methods in microbiome research that make data generation more accessible to all members of the scientific community. Our researchers are also leading efforts to build extensive biobanks of culturable bacterial isolates, such as the Broad Institute-OpenBiome Microbiome Library and the Global Microbiome Conservancy isolate collection, that will facilitate mechanistic studies of the human microbiome. Moreover, the Broad has a state-of-the-art gnotobiotic mouse facility to provide findings with in vivo relevance in mucosal defense and immunity.
Graduate students and post-doctoral fellows interested in human microbiome projects at the Broad, please email Dr. Ramnik Xavier at rxavier@broadinstitute.org.
Highlights from microbiome research at the Broad:
Microbiome and disease
Lee JWJ, Plichta D, Hogstrom L, et al. Multi-omics reveal microbial determinants impacting responses to biologic therapies in inflammatory bowel disease. Cell Host Microbe. 2021;29(8):1294-1304.e4. doi:10.1016/j.chom.2021.06.019
The gut microbiome is known to influence responses to medication, such as biologic therapy for inflammatory bowel disease (IBD). Investigators at the Broad and Massachusetts General Hospital used multiple ‘omic techniques to reveal microbial factors that impact the responses of patients newly diagnosed with IBD to either anti-cytokine or anti-integrin biologic therapy. Metagenomic analyses of patient samples found that the number of different species in the microbiome before treatment indicated preferential responses to anti-cytokine therapy, while metabolomic analyses showed that these responses correlated with the abundance of microbes capable of 7α/β-dehydroxylation of primary to secondary bile acids. Proteins found in the circulation, measured by proteomics, that reflect microbial diversity identified patients more likely to achieve remission with anti-cytokine therapy. Together, these multi-omic profiles may help determine optimal therapeutic strategies for patients and serve as targets for the development of newer therapies.
Kong L, Lloyd-Price J, Vatanen T, et al. Linking Strain Engraftment in Fecal Microbiota Transplantation With Maintenance of Remission in Crohn's Disease. Gastroenterology. 2020;159(6):2193-2202.e5. doi:10.1053/j.gastro.2020.08.045
As a type of inflammatory bowel disease, Crohn’s disease (CD) arises from dysfunctional interactions between genetics, the immune system, and the gut microbiome. Replacing the microbiome through fecal microbiota transplantation (FMT) is a promising approach for the treatment of CD. Researchers at the Broad, in collaboration with investigators in France, assessed microbiome composition before and after FMT using metagenomic data from CD patients in remission and linked the gain, loss, and replacement of specific microbes to the maintenance of remission. Their results pointed to microbes that may be beneficial to transmit or eliminate through FMT and provided criteria that may help identify personalized FMT donors to more effectively maintain remission in patients with CD.
Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019;569(7758):655-662. doi:10.1038/s41586-019-1237-9
Broad investigators were part of an NIH-funded, multi-institute collaboration known as the Integrative Human Microbiome Project that incorporated metagenomic, metatranscriptomic, and metabolomic profiles of the gut microbiome to provide a comprehensive view of the dysfunction occurring during inflammatory bowel disease (IBD) activity. Mapping taxonomic, functional, and biochemical shifts in 132 individuals over the course of one year, the researchers identified metabolites found exclusively in IBD patients and uncovered distinct microbial enrichments in the two major forms of IBD, Crohn’s disease and ulcerative colitis. In addition to generating valuable resources for the scientific community, this study established a foundation for the next phase in clinical translation of the microbiome.
Discovery of bioactive microbial gene products in inflammatory bowel disease
Zhang Y, Bhosle A, Bae S, et al. Discovery of bioactive microbial gene products in inflammatory bowel disease. Nature. 2022;606(7915):754-760. doi: 10.1038/s41586-022-04648-7. PMID: 35614211.
The CD4+ T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn's disease
Pedersen TK, Brown EM, Plichta DR, et al. The CD4+ T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn's disease. Immunity. 2022;S1074-7613(22)00410-1. doi: 10.1016/j.immuni.2022.08.016. PMID: 36115338.
