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 firstname.lastname@example.org.
One way bacteria adapt to rapidly changing environments is through phase variation, the alternation between genetic states (often in an off/on manner) within a population. Investigators at the Broad and MIT developed a computational algorithm called PhaseFinder to examine phase variation resulting from DNA inversions in bacteria found in aquatic and terrestrial habitats as well as host organisms. Analyzing over 50,000 bacterial genomes, the researchers determined that invertible DNA regions, called invertons, were more prevalent in host-associated bacteria and mediated adaptation to the human gut environment and antibiotic resistance after treatment.
Improving our understanding of how the microbiome interacts with its human host has been hindered in part by the limited number of bacterial isolates available to test mechanistic hypotheses. Furthermore, microbiome research has centered largely on industrialized European and North American communities, providing little information about the microbiomes of non-industrialized populations that are often more diverse. To address these obstacles, Broad and MIT researchers are leading two important initiatives: the Broad Institute-OpenBiome Microbiome Library (BIO-ML) and the Global Microbiome Conservancy (GMbC). The BIO-ML is a biobank of nearly 8,000 distinct gut bacteria isolated from healthy humans—including thousands of microbial strains implicated in disease, such as IBD—and corresponding multi-omic data. The GMbC aims to build extensive archives of human gut isolates from communities around the world; its isolate collection comprises approximately 10,000 gut bacteria and their genomes from under-represented populations. This collection was used to demonstrate that gut bacteria continuously acquire new capabilities based on the lifestyle of the human host.
In a study selected by Cell Host & Microbe editors as one of their favorite reports of 2021, Broad investigators identified a class of ADP-ribosyltransferases (ADPRTs) in gut microbiome commensals that function as fitness factors and aid in colonization. An in-depth analysis of an abundant Bacteroides ADPRT, named Bxa, revealed that it is triggered by bile acids and oxidative stress, targets non-muscle myosin II in host epithelial cells, and remodels the actin cytoskeleton. Bxa also induces secretion of inosine, which the bacteria are capable of utilizing to form biofilms. The widespread nature of these ADPRTs suggests that such host modification mechanisms may be common properties of commensals.