人体微生物组计划

人体微生物组计划又称第二人类基因组计划。由美国国立卫生研究院立项资助,2007年正式启动。计划用5年时间耗资1.5亿美元完成900个人体微生物基因组测序。其目标是探索研究人类微生物组的可行性;研究人体微生物组变化与疾病健康的关系;同时为其它科学研究提供信息和技术支持。     

The "most wanted" taxa from the human microbiome for whole genome sequencing

The goal of the Human Microbiome Project (HMP) is to generate a comprehensive catalog of human-associated microorganisms including reference genomes representing the most common species. Toward this goal, the HMP has characterized the microbial communities at 18 body habitats in a cohort of over 200 healthy volunteers using 16S rRNA gene (16S) sequencing and has generated nearly 1,000 reference genomes from human-associated microorganisms. To determine how well current reference genome collections capture the diversity observed among the healthy microbiome and to guide isolation and future sequencing of microbiome members, we compared the HMP's 16S data sets to several reference 16S collections to create a 'most wanted' list of taxa for sequencing. Our analysis revealed that the diversity of commonly occurring taxa within the HMP cohort microbiome is relatively modest, few novel taxa are represented by these OTUs and many common taxa among HMP volunteers recur across different populations of healthy humans. Taken together, these results suggest that it should be possible to perform whole-genome sequencing on a large fraction of the human microbiome, including the 'most wanted', and that these sequences should serve to support microbiome studies across multiple cohorts. Also, in stark contrast to other taxa, the 'most wanted' organisms are poorly represented among culture collections suggesting that novel culture- and single-cell-based methods will be required to isolate these organisms for sequencing.     

Perspectives on human microbiome research ethics

study of ethical, legal, and social implications (ELSI) of human microbiome research has been integral to the Human Microbiome Project (HMP). This study explores core ELSI issues that arose during the first phase of the HMP from the perspective of individuals involved in the research. We conducted semi-structured in-depth interviews with investigators and NIH employees ("investigators") involved in the HMP, and with individuals recruited to participate in the HMP Healthy Cohort Study at Baylor College of Medicine ("recruits"). We report findings related to three major ELSI issues: informed consent, data sharing, and return of results. Our findings demonstrate that investigators and recruits were similarly sensitive to these issues yet generally comfortable with study design in light of current knowledge about the microbiome.     

The Dental Plaque Microbiome in Health and Disease

Dental decay is one of the most prevalent chronic diseases worldwide. A variety of factors, including microbial, genetic, immunological, behavioral and environmental, interact to contribute to dental caries onset and development. Previous studies focused on the microbial basis for dental caries have identified species associated with both dental health and disease. The purpose of the current study was to improve our knowledge of the microbial species involved in dental caries and health by performing a comprehensive 16S rDNA profiling of the dental plaque microbiome of both caries-free and caries-active subjects. Analysis of over 50,000 nearly full-length 16S rDNA clones allowed the identification of 1,372 operational taxonomic units (OTUs) in the dental plaque microbiome. Approximately half of the OTUs were common to both caries-free and caries-active microbiomes and present at similar abundance. The majority of differences in OTU’s reflected very low abundance phylotypes. This survey allowed us to define the population structure of the dental plaque microbiome and to identify the microbial signatures associated with dental health and disease. The deep profiling of dental plaque allowed the identification of 87 phylotypes that are over-represented in either caries-free or caries-active subjects. Among these signatures, those associated with dental health outnumbered those associated with dental caries by nearly two-fold. A comparison of this data to other published studies indicate significant heterogeneity in study outcomes and suggest that novel approaches may be required to further define the signatures of dental caries onset and progression.     

Beyond microbial community composition: functional activities of the oral microbiome in health and disease

The oral microbiome plays a relevant role in the health status of the host and is a key element in a variety of oral and non-oral diseases. Despite advances in our knowledge of changes in microbial composition associated with different health conditions the functional aspects of the oral microbiome that lead to dysbiosis remain for the most part unknown. In this review, we discuss the progress made towards understanding the functional role of the oral microbiome in health and disease and how novel technologies are expanding our knowledge on this subject.     

Statistical Object Data Analysis of Taxonomic Trees from Human Microbiome Data

Human microbiome research characterizes the microbial content of samples from human habitats to learn how interactions between bacteria and their host might impact human health. In this work a novel parametric statistical inference method based on object-oriented data analysis (OODA) for analyzing HMP data is proposed. OODA is an emerging area of statistical inference where the goal is to apply statistical methods to objects such as functions, images, and graphs or trees. The data objects that pertain to this work are taxonomic trees of bacteria built from analysis of 16S rRNA gene sequences (e.g. using RDP); there is one such object for each biological sample analyzed. Our goal is to model and formally compare a set of trees. The contribution of our work is threefold: first, a weighted tree structure to analyze RDP data is introduced; second, using a probability measure to model a set of taxonomic trees, we introduce an approximate MLE procedure for estimating model parameters and we derive LRT statistics for comparing the distributions of two metagenomic populations; and third the Jumpstart HMP data is analyzed using the proposed model providing novel insights and future directions of analysis.     

A Taxonomic Signature of Obesity in the Microbiome? Getting to the Guts of the Matter

Obesity is an important and intractable public health problem. In addition to the well-known risk factors of behavior, diet, and genetics, gut microbial communities were recently identified as another possible source of risk and a potential therapeutic target. However, human and animal-model studies have yielded conflicting results about the precise nature of associations between microbiome composition and obesity. In this paper, we use publicly available data from the Human Microbiome Project (HMP) and MetaHIT, both surveys of healthy adults that include obese individuals, plus two smaller studies that specifically examined lean versus obese adults. We find that inter-study variability in the taxonomic composition of stool microbiomes far exceeds differences between lean and obese individuals within studies. Our analyses further reveal a high degree of variability in stool microbiome composition and diversity across individuals. While we confirm the previously published small, but statistically significant, differences in phylum-level taxonomic composition between lean and obese individuals in several cohorts, we find no association between BMI and taxonomic composition of stool microbiomes in the larger HMP and MetaHIT datasets. We explore a range of different statistical techniques and show that this result is robust to the choice of methodology. Differences between studies are likely due to a combination of technical and clinical factors. We conclude that there is no simple taxonomic signature of obesity in the microbiota of the human gut.     

The human microbiome: at the interface of health and disease

Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.     

The amphibian microbiome: natural range of variation,pathogenic dysbiosis,and role in conservation

Recent research in humans, livestock, and wildlife using high-throughput next-generation sequencing (NGS) has identified that resident microbiota play an essential role in disease resistance, host health, and adaptation to biotic and abiotic stressors. Since amphibians are currently facing population declines and extinctions attributable to anthropogenic pressures and emerging diseases, an understanding of the effects of microbiome dysbiosis and mitigation is a prerequisite for amphibian conservation and disease management. Interest is now growing with regard to understanding the influence of unfavorable environmental conditions on the amphibian microbiome and the effects of dysbiosis on the susceptibility to pathogenic infections. Here, we summarize information on the amphibian microbiome, specifically concerning intrinsic and extrinsic factors that shape the skin and gut microbiome. We explore diverse types of unfavorable environmental perturbations and the ways in which they can impact the microbiota of an individual so that we can better comprehend the consequences of stressors and dysbiosis on pathogen emergence and health. We discuss the role of the microbiome in amphibian conservation and identify gaps of knowledge that need to be filled if we are to achieve a meta-organism conservation approach. NGS studies should be complemented with other high-throughput “-omic” approaches to target microbiome functionality. Understanding the microbiome might be the missing piece in the overall strategy that will help maintain the health of amphibians in a world with highly affected environments and that will prevent/mitigate emerging infectious diseases.     

Phylotyping and Functional Analysis of Two Ancient Human Microbiomes

Background

The Human Microbiome Project (HMP) is one of the U.S. National Institutes of Health Roadmap for Medical Research. Primary interests of the HMP include the distinctiveness of different gut microbiomes, the factors influencing microbiome diversity, and the functional redundancies of the members of human microbiotas. In this present work, we contribute to these interests by characterizing two extinct human microbiotas.

Methodology/Principal Findings

We examine two paleofecal samples originating from cave deposits in Durango Mexico and dating to approximately 1300 years ago. Contamination control is a serious issue in ancient DNA research; we use a novel approach to control contamination. After we determined that each sample originated from a different human, we generated 45 thousand shotgun DNA sequencing reads. The phylotyping and functional analysis of these reads reveals a signature consistent with the modern gut ecology. Interestingly, inter-individual variability for phenotypes but not functional pathways was observed. The two ancient samples have more similar functional profiles to each other than to a recently published profile for modern humans. This similarity could not be explained by a chance sampling of the databases.

Conclusions/Significance

We conduct a phylotyping and functional analysis of ancient human microbiomes, while providing novel methods to control for DNA contamination and novel hypotheses about past microbiome biogeography. We postulate that natural selection has more of an influence on microbiome functional profiles than it does on the species represented in the microbial ecology. We propose that human microbiomes were more geographically structured during pre-Columbian times than today.     

Molecular tools for probing the microbiome

The microbiome plays essential roles in health and disease. Our understanding of the imbalances that can arise in the microbiome and their consequences is held back by a lack of technologies that selectively knock out members of these microbial communities. Antibiotics and fecal transplants, the existing methods for manipulating the microbiota of the gastrointestinal tract, are not sufficiently pinpointed to reveal how particular microbial genes, strains, or species affect human health. A toolset for the precise manipulation of the microbiome could significantly advance disease diagnosis and treatment. Here, we provide an overview of current and future strategies for the development of molecular tools that can be used to probe the microbiome without producing off-target effects.     

Focus: Microbiome: Treating Obesity and Metabolic Syndrome with Fecal Microbiota Transplantation

The worldwide prevalence of metabolic syndrome, which includes obesity and its associated diseases, is rising rapidly. The human gut microbiome is recognized as an independent environmental modulator of host metabolic health and disease. Research in animal models has demonstrated that the gut microbiome has the functional capacity to induce or relieve metabolic syndrome. One way to modify the human gut microbiome is by transplanting fecal matter, which contains an abundance of live microorganisms, from a healthy individual to a diseased one in the hopes of alleviating illness. Here we review recent evidence suggesting efficacy of fecal microbiota transplant (FMT) in animal models and humans for the treatment of obesity and its associated metabolic disorders.     

Targeting friend and foe: Emerging therapeutics in the age of gut microbiome and disease

Mucosal surfaces that line our gastrointestinal tract are continuously exposed to trillions of bacteria that form a symbiotic relationship and impact host health and disease. It is only beginning to be understood that the cross-talk between the host and microbiome involve dynamic changes in commensal bacterial population, secretion, and absorption of metabolites between the host and microbiome. As emerging evidence implicates dysbiosis of gut microbiota in the pathology and progression of various diseases such as inflammatory bowel disease, obesity, and allergy, conventional treatments that either overlook the microbiome in the mechanism of action, or eliminate vast populations of microbes via wide-spectrum antibiotics need to be reconsidered. It is also becoming clear the microbiome can influence the body’s response to therapeutic treatments for cancers. As such, targeting the microbiome as treatment has garnered much recent attention and excitement from numerous research labs and biotechnology companies. Treatments range from fecal microbial transplantation to precision-guided molecular approaches. Here, we survey recent progress in the development of innovative therapeutics that target the microbiome to treat disease, and highlight key findings in the interplay between host microbes and therapy.     

A case study for large-scale human microbiome analysis using JCVI's metagenomics reports (METAREP)

As metagenomic studies continue to increase in their number, sequence volume and complexity, the scalability of biological analysis frameworks has become a rate-limiting factor to meaningful data interpretation. To address this issue, we have developed JCVI Metagenomics Reports (METAREP) as an open source tool to query, browse, and compare extremely large volumes of metagenomic annotations. Here we present improvements to this software including the implementation of a dynamic weighting of taxonomic and functional annotation, support for distributed searches, advanced clustering routines, and integration of additional annotation input formats. The utility of these improvements to data interpretation are demonstrated through the application of multiple comparative analysis strategies to shotgun metagenomic data produced by the National Institutes of Health Roadmap for Biomedical Research Human Microbiome Project (HMP) (http://nihroadmap.nih.gov). Specifically, the scalability of the dynamic weighting feature is evaluated and established by its application to the analysis of over 400 million weighted gene annotations derived from 14 billion short reads as predicted by the HMP Unified Metabolic Analysis Network (HUMAnN) pipeline. Further, the capacity of METAREP to facilitate the identification and simultaneous comparison of taxonomic and functional annotations including biological pathway and individual enzyme abundances from hundreds of community samples is demonstrated by providing scenarios that describe how these data can be mined to answer biological questions related to the human microbiome. These strategies provide users with a reference of how to conduct similar large-scale metagenomic analyses using METAREP with their own sequence data, while in this study they reveal insights into the nature and extent of variation in taxonomic and functional profiles across body habitats and individuals. Over one thousand HMP WGS datasets and the latest open source code are available at http://www.jcvi.org/hmp-metarep.     

Microbes,the gut and ankylosing spondylitis

It is increasingly clear that the interaction between host and microbiome profoundly affects health. There are 10 times more bacteria in and on our bodies than the total of our own cells, and the human intestine contains approximately 100 trillion bacteria. Interrogation of microbial communities by using classic microbiology techniques offers a very restricted view of these communities, allowing us to see only what we can grow in isolation. However, recent advances in sequencing technologies have greatly facilitated systematic and comprehensive studies of the role of the microbiome in human health and disease. Comprehensive understanding of our microbiome will enhance understanding of disease pathogenesis, which in turn may lead to rationally targeted therapy for a number of conditions, including autoimmunity.     

The role of the gut microbiome and its metabolites in metabolic diseases

It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases,while in recent years,accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic dis-eases,including obesity,type 2 diabetes,nonalcoholic fatty liver disease,cardiovascular disease and so on.Numerous microorganisms dwell in the gastrointestinal tract,which is a key interface for energy acquisition and can metabolize dietary nutrients into many bioactive substances,thus acting as a link between the gut microbiome and its host.The gut microbiome is shaped by host genetics,immune responses and dietary fac-tors.The metabolic and immune potential of the gut microbiome determines its significance in host health and diseases.Therefore,targeting the gut microbiome and relevant metabolic pathways would be effective therapeutic treatments for many metabolic diseases in the near future.This review will summarize information about the role of the gut microbiome in organism metabolism and the relationship between gut micro-biome-derived metabolites and the pathogenesis of many metabolic diseases.Furthermore,recent advan-ces in improving metabolic diseases by regulating the gut microbiome will be discussed.     

Colliding and interacting microbiomes and microbial communities - consequences for human health

Living ‘things’ coexist with microorganisms, known as the microbiota/microbiome that provides essential physiological functions to its host. Despite this reliance, the microbiome is malleable and can be altered by several factors including birth-mode, age, antibiotics, nutrition, and disease. In this minireview, we consider how other microbiomes and microbial communities impact the host microbiome and the host through the concept of microbiome collisions (initial exposures) and interactions. Interactions include changes in host microbiome composition and functionality and/or host responses. Understanding the impact of other microbiomes and microbial communities on the microbiome and host are important considering the decline in human microbiota diversity in the developed world – paralleled by the surge of non-communicable, inflammatory-based diseases. Thus, surrounding ourselves with rich and diverse beneficial microbiomes and microbial communities to collide and interact with should help to diminish the loss in microbial diversity and protect from certain diseases. In the same vein, our microbiomes not only influence our health but potentially the health of those close to us. We also consider strategies for enhanced host microbiome collisions and interactions through the surrounding environment that ensure increased microbiome diversity and functionality contributing to enhanced symbiotic return to the host in terms of health benefit.     

Hypothesis Testing and Power Calculations for Taxonomic-Based Human Microbiome Data

This paper presents new biostatistical methods for the analysis of microbiome data based on a fully parametric approach using all the data. The Dirichlet-multinomial distribution allows the analyst to calculate power and sample sizes for experimental design, perform tests of hypotheses (e.g., compare microbiomes across groups), and to estimate parameters describing microbiome properties. The use of a fully parametric model for these data has the benefit over alternative non-parametric approaches such as bootstrapping and permutation testing, in that this model is able to retain more information contained in the data. This paper details the statistical approaches for several tests of hypothesis and power/sample size calculations, and applies them for illustration to taxonomic abundance distribution and rank abundance distribution data using HMP Jumpstart data on 24 subjects for saliva, subgingival, and supragingival samples. Software for running these analyses is available.     

The Human Microbiome Project in 2011 and beyond

The human microbiome comprises the genes and genomes of the microbiota that inhabit the body. We highlight Human Microbiome Project (HMP) resources, including 600 microbial reference genomes, 70 million 16S sequences, 700 metagenomes, and 60 million predicted genes from healthy adult microbiomes. Microbiome studies of specific diseases and future research directions are also discussed.