Human Microbiome Project Program Highlights
A research team at the NIH, funded in part through the Common Fund Human Microbiome Project, have sequenced and analyzed the DNA of fungi that inhabit skin sites of healthy adults in order to define populations across the skin. This work yields insights that will pave the way for studies to examine the role fungi on the skin play in maintaining health and also how associated factors may contribute to the formation of skin conditions. Of the sites examined, the feet were found to be the home of the most diverse and complex sites. This study has been published in the May 22, 2013 early online issue of Nature.
For more information read the NIH press release here
A team of scientists at the Oak Ridge National Laboratory (ORNL) funded by the NIH Common Fund Human Microbiome Project (HMP) have made new discoveries about a microbe that is important in human oral health. Using cutting-edge technology, the team was able to complete full sequencing of the genome from a single cell. The ability to isolate just a single bacterial cell and sequence the genome is an important component of examining the human microbiome because it allows for the study of species that cannot be cultured in the lab. The organism the examined is most closely related to sulfate reducers, which are normally found in salt marshes, sewer pipes, hot springs, and surprisingly the human mouth. Studies have shown that this type of bacteria is elevated in patients suffering from periodontitis, a disease marked by swelling and infection of areas that support our teeth. New findings presented in the current study show that this species uses a unique coding scheme that likely allows it to successfully compete in the complex oral microbial environment. The technology advancement and scientific findings reported in this study will increase our understanding of the role that our microbes play in oral health.
Campbell JH, O'Donoghue P, Campbell AG, Schwientek P, Sczyrba A, Woyke T, Söll D, Podar M. UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota. Proc Natl Acad Sci USA 2013, Mar 18. PMID: 23509275.
The NIH Common Fund’s Human Microbiome Project (HMP) has just published two seminal papers in the June 14, 2012 issue of Nature and a series of additional papers in several PLoS journals (click here for more), the NIH announces on June 13, 2012. These milestone studies are centered on the project’s ambitious and unparalleled examination and analysis of the microbiomes of a healthy cohort consisting of over 240 individuals. The resources and resulting analysis shed light onto the intricate details of the complete healthy human microbiome and pave the way for future studies in the field. The diversity both within and among body sites highlights an important and complex association between humans and associated microbes.
A comprehensive community resource
One of the two Nature papers from the June 14 issue examined a population of 242 healthy adults, each of whom were sampled at 15 (male) to 18 (female) body sites, with each person sampled on one to three distinct occasions. This unparalleled effort led to DNA sequencing of microbial eukaryotes, archaea, bacteria, and viruses (both mammalian and bacterial). Using standardized protocols and methods across the four sequencing centers, the consortium was able to generate 5,177 unique microbial taxonomic profiles (from 16S rRNA gene sequences) and over 3.5 Tbp of metagenomic sequence. Furthermore, their studies led to the assembly of hundreds of reference genomes from the human microbiome. These efforts have led to an expansive generation of genomic data and also extensive data related to functional proteins and site-specific metabolism. The targeted approach of assembling data in a site-specific manner allowed the researchers to assemble less abundant organisms that were common across the cohort. In addition to the microbial analyses, healthy cohort subjects also submitted blood samples so that human genome analysis and cell-line development can be implemented in future studies. This foresight in the project’s planning unlocks an area of great potential for benefits to human health. Much of the data, other than protected health information, is publicly available via NCBI HMP project page and the HMP Data Analysis and Coordinating Center (DACC).
Extensive analysis of the healthy human microbiome
After establishing standards for data generation, the HMP consortium continued on to conduct a comprehensive analysis of the largest human cohort and set of distinct, clinically relevant body habitats to date (five major habitats). This is the first study to include metagenomic data (data that does not rely on culturing microbes) across body habitats from a cohort of this magnitude, in an attempt to describe the basics of overall host associated microbial life as well as the basics of microbial life for each host site examined. The research team found that there was strong site specialization both within and among subjects but that the diversity and abundance of each habitat’s signature microbes varied widely among the healthy subjects. Somewhat surprisingly based on the genetic sequence with large phylogenetic variations and general variation among the individual samples, there was remarkable functional stability. In essence, the authors illustrate that while the compositions vary widely the functionality is similar, meaning that there are many ways to construct microbial communities to perform similar functions.
Through this analysis, the consortium was also able to make general characterizations about the human microbiome. One finding was a limited, but commonly detectable, number of pathogens, leading to speculation that a low abundance of potentially harmful microbes might in some cases be beneficial to the host. Another interesting finding was patterns of alpha and beta diversity, where alpha diversity is defined as the diversity within a site and beta diversity is defined as that observed among subjects. For example, saliva was shown to have high alpha diversity (many different taxonomical units) but low beta diversity (very similar among the cohort). Human sites varied widely in alpha and beta diversity and future characterizations of the microbiome and its relation to human diseases will likely shed further light onto the importance of these variations in healthy and disease states.
A major finding from the analysis of the healthy cohort was a number of well-validated correlations of taxa (groups of organisms) and function with host phenotypes. Some of the greatest correlations observed were between ethnicity and microbiome composition across all body habitats and a positive correlation of vaginal pH to microbial diversity (higher pH having higher diversity). Furthermore, there was an intriguing association of age with skin microbiome-associated metabolic pathways and oral microbiome composition, and a modest correlation between microbial composition and body mass index. Overall, many correlations were observed but as of now most of the data is not fully understood and requires future studies and examinations of additional factors including diet and host genetics.
A true team effort
The results presented in these papers highlight a remarkable level of collaboration among a large number of researchers. Interactions and collaborations among the two clinical centers and four sequencing centers were paramount for success. During the early stages of the program, data were being generated at an exponentially faster rate than analyses could be performed. To address these issues, the consortium formed the Data Analysis Working Group (DAWG), which consists of members from the genome centers and computational tools groups in addition to several experts not directly supported by the HMP. This was critical for the success of this large-scale and collaborative process. The partnerships and synergism from this teamwork will continue to fuel microbiome research.
The two landmark papers and the series of companion papers establish a foundation to catalyze and aid a myriad of studies ranging from basic to translational to clinical. For more information about the NIH Common Fund Human Microbiome Project please visit the Common Fund HMP and HMP Data Analysis and Coordinating Center (DACC) websites.
A highly adapted genome: Sequence of immune-regulating bacteria reveals why culturing attempts have been unsuccessful
A team of researchers, funded in part by the NIH Common Fund’s Human Microbiome Project, have sequenced and analyzed a class of unique bacteria that has eluded growth in the lab setting for over forty years. These segmented filamentous bacteria (SFB) are found in mice and other mammals and are known as the first commensal (non-pathogenic) bacteria identified that affect the host immune system. In the current study, researchers collected droppings from mice that were only colonized with SFB and used next generation sequencing platforms to obtain the sequence and construct the complete genome. They found that the genome was much smaller than closely related species and similar to other “minimal” bacteria that have been studied. This was due to a lack of many genes related to metabolism. It appears that much of the genetic material was lost because the bacteria rely on the host for a great deal of what they need to grow and survive. In fact, one of the few classes of genes in abundance are those related to transport of metabolites from the environment (host gut). These findings explain why is has been so difficult to grow these organisms outside of the host and highlights the close association of these bacteria with their host. This incredibly close association between host and microbe could be one reason as to why these bacteria help recruit immune cells that protect their host from pathogenic enteric bacteria. Although SFB have yet to be discovered in humans, the findings from this study will be an important resource for further examination of the role microbes play in host immune systems and overall metabolism.
Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, Huttenhower C, Littman DR, Ivanov II. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe. 2011 Sep 15;10(3):260-72. PMID 21925113.
Dr. Lita Proctor, coordinator for the Human Microbiome Project (HMP), National Human Genome Research Institute, gives an overview of the HMP program and describes the vast resources produced thus far from the unprecedented study of 300 healthy individuals. Ongoing studies of specific diseases (demonstration projects) and the future directions of human microbiome research are also discussed.
Cell Host Microbe. 2011 Oct 4; 10(4): 287-91
Microbes, including bacteria, inhabit your body in great numbers and impact many aspects of health and disease such as obesity and Crohn's disease. Characterizing the genetic diversity of microbes that live in specific areas of the body is key to understanding the composition and dynamics of microbial communities within individuals, in transmission between individuals, and in transmission between individuals and the environment. The ability to characterize microbial diversity and transmission has been hampered in the past by a lack of high-throughput analysis tools. New computational tools being developed through the Common Fund's Human Microbiome Project (HMP) are accelerating microbiology and biomedical research, and unexpectedly, other fields like forensics.
Dr. Rob Knight, an investigator in the HMP, is developing novel approaches to analyze human microbial communities, and recently contributed to a paper in the Proceedings of the National Academy of Science on the discovery of "microbial fingerprints"; in a person's skin. The skin surface harbors a large number of bacteria that are highly diverse and yet personally unique from individual to individual. The bacteria are easily dislodged from the skin and transferred to objects upon contacting. By analyzing the "microbial fingerprint"; of bacteria left on computer equipment, Dr. Knight and colleagues at the University of Colorado found that the fingerprint could be traced to a specific individual with a high degree of certainty even if the objects had not been touched for two weeks. The approach could be important in forensic investigations to provide independent confirmation of forensic results obtained using more traditional methods such as human DNA analysis or fingerprinting.