UBC Faculty Research and Publications

Human microbiome science: vision for the future, Bethesda, MD, July 24 to 26, 2013 Ravel, Jacques; Blaser, Martin J; Braun, Jonathan; Brown, Eric; Bushman, Frederic D; Chang, Eugene B; Davies, Julian; Dewey, Kathryn G; Dinan, Timothy; Dominguez-Bello, Maria; Erdman, Susan E; Finlay, B B; Garrett, Wendy S; Huffnagle, Gary B; Huttenhower, Curtis; Jansson, Janet; Jeffery, Ian B; Jobin, Christian; Khoruts, Alexander; Kong, Heidi H; Lampe, Johanna W; Ley, Ruth E; Littman, Dan R; Mazmanian, Sarkis K; Mills, David A; Neish, Andrew S; Petrof, Elaine; Relman, David A; Rhodes, Rosamond; Turnbaugh, Peter J; Young, Vincent B; Knight, Rob; White, Owen Jul 18, 2014

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MEETING REPORTHuman microbiome scien2owDw1,danfothios rorject (HMP) in 2007 [4,12], the fundamental understand- Maryland School of Medicine, together with corporateRavel et al. Microbiome 2014, 2:16http://www.microbiomejournal.com/content/2/1/16cies including NIH, Environmental Protection Agency(EPA), US Department of Agriculture (USDA), Food andStreet, Baltimore, MD 21201, USAFull list of author information is available at the end of the articleing of the human microbiome has grown at an everaccelerating pace [13]. Together, the HMP healthy co-hort study [14,15], and the many associated studies,which provide more details on methodology, bioinfor-matics analyses, and additional cohorts, have led to over350 publications (http://www.ploscollections.org/hmp).This work has set the stage for rapid advances, somewith high potential for translational studies, in under-standing the mechanisms governing the similarities anddifferences in the microbes we share, their associationsponsors including Roche, Qiagen, Illumina, Life Tech-nologies, MoBio, Metabolon, and the BioMed Centraljournal Microbiome, sought to provide an overview ofcutting-edge work in NIH-supported microbiome re-search, and to identify obstacles as well as opportunitiesfor progress in this challenging field of research. Themeeting was organized by a trans-NIH working group,including 28 participants (programme staff ) from 14 (ofthe 27) NIH Institutes, Centers and Offices, togetherwith four scientific advisory members funded by the Hu-man Microbiome Project. The meeting was attended by269 participants (and an additional 250 with webcast)from academia, national labs, a range of government agen-* Correspondence: jravel@som.umaryland.edu1Institute for Genome Sciences, Department of Microbiology andImmunology, University of Maryland School of Medicine, 801 W. BaltimoreEach of us consists of about 40 trillion human cells [1]and about 22,000 human genes [2], but as many as 100trillion microbial cells [3] (the microbiota) and 2 millionmicrobial genes [4] (the metagenome). Understandingthe microbial side of ourselves may therefore be critic-ally important for understanding human biology, includ-ing drug responses [5-8], susceptibility to infectious [9]and chronic [10] disease, and perhaps even behavior[11]. Since the inception of the Human Microbiome Pro-microbiota play in health and disease.Meeting goals and objectivesTo understand the current state of human microbiomeresearch, and to identify key areas for progress going for-ward, we held a conference in Bethesda, MD from July24 to 26, 2013, entitled ‘Human Microbiome Science:Vision for the Future’. This conference, which was sup-ported in part from a grant by NIH to the University ofBethesda, MD, July 24 toJacques Ravel1*, Martin J Blaser2, Jonathan Braun3, Eric BrJulian Davies7, Kathryn G Dewey8, Timothy Dinan9, MariaWendy S Garrett11, Gary B Huffnagle12,13, Curtis HuttenhoAlexander Khoruts19, Heidi H Kong20, Johanna W Lampe2David A Mills26,27, Andrew S Neish28, Elaine Petrof29, DaviPeter J Turnbaugh33, Vincent B Young12,13, Rob Knight34AbstractA conference entitled ‘Human microbiome science: VisionJuly 24 to 26, 2013. The event brought together experts inproviding a comprehensive overview of the state of microbgaps, challenges and opportunities in this nascent field. Thiwhat is needed for human microbiome research to move fIntroduction© 2014 Ravel et al.; licensee BioMed Central LCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.Open Accessce: vision for the future,6, 2013n4, Frederic D Bushman5, Eugene B Chang6,ominguez-Bello2, Susan E Erdman10, B Brett Finlay5,er14, Janet Jansson15, Ian B Jeffery16, Christian Jobin17,18,Ruth E Ley22, Dan R Littman23,24, Sarkis K Mazmanian25,A Relman30,31, Rosamond Rhodes32,d Owen White35r the future’ was organized in Bethesda, MD frome field of human microbiome research and aimed atme research, but more importantly to identify and discusseport summarizes the presentations but also describesward and deliver medical translational applications.with diseases, but more importantly, the functional rolestd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Ravel et al. Microbiome 2014, 2:16 Page 2 of 11http://www.microbiomejournal.com/content/2/1/16Drug Administration (FDA), US Agency for InternationalDevelopment (USAID), Office of Science and TechnologyPolicy (OSTP), US Army, National Science Foundation(NSF), and National Aeronautics and Space Administra-tion (NASA), and involved 37 speakers from a broadrange of disciplines including microbiology, immunology,medicine, infectious disease, ecology, and computer sci-ence. The broad expertise of the organizing committeeand the participants underscores the way in which mi-crobes pervade the human body and our environment,and microbiome research may soon pervade the biomed-ical research enterprise.Over the course of this 3-day meeting, there were pre-sentations and discussions aimed towards:– Recognizing that the study of the humanmicrobiome, in disease and in health, is of relevanceto the missions of all NIH Institutes and Centers;– Increasing awareness across all NIH Institutes andCenters of gaps, needs, and challenges faced by thebroad microbiome research community to drivefuture research and investments;– Facilitating coordination between the NIH Institutesand Centers to promote coherent oversight forpolicies and approaches that will maximally benefitmicrobiome-related biomedical research;– Identifying areas where common resources orpartnerships would benefit microbiome-related bio-medical research;– Exploring how NIH and other government fundingagencies could collaborate to integrate themicrobiome into studies of human health and morebroadly into studies of human interactions withtheir physical and microbial environment;– Fostering understanding of the current state ofmicrobiome research, and shaping an overall visionfor future directions of the field over the next 10years.Overview: the human microbiome projectIn the first session Dr. Owen White (University ofMaryland School of Medicine, Baltimore, MD, USA)(Figure 1A) set the stage for the conference, noting thatthe meeting was a unique opportunity for microbiome re-searchers both to reflect on past successes and to define thedirection that the field could take going forward. His intro-duction was followed by a presentation by Dr. FrancisCollins (Director of the National Institutes of Health,Bethesda MD, USA) (Figure 1B), who opened with a his-torical perspective of the Human Microbiome Project(HMP). He presented an overview of how the microbiomeis uniquely positioned to enhance the mission of the NIHbecause of the many associations between the state ofthe microbiome and a wide range of diseases fromgastrointestinal diseases and conditions, to cancer and evenmental illnesses. Dr. Eric Green (Director of National Hu-man Genome Research Institute, NHGRI) (Figure 1C)followed with a report on the state and the many accom-plishments of the HMP. The HMP aimed to survey themicrobiome in humans through taxonomic and metage-nomic analyses. He highlighted the central healthy cohortof volunteers who were intensively sampled, and severaldemonstration projects that focused on diseases at sitessuch as the GI track, the skin or the urogenital track. Theseprojects generated over 3.5 Tbp of data and 8 millionunique microbial genes were catalogued. These datasets(sequence data, strains, clinical phenotypes, nucleic acid ex-tracts, and even cell lines) are publicly available through re-positories and coordinated through a Data Analysis andCoordination Center (DACC) hosted at the Institute forGenome Sciences at the University of Maryland School ofMedicine [13]. Overall, the HMP has led to over 350 peer-reviewed scientific publications. The HMP has supportedthe development of new bioinformatics and technologicaltools, which altogether facilitate the study of the humanmicrobiome for the scientific community. Human micro-biome studies’ ethical, legal and social implications (ELSI)were also evaluated, mirroring the Human Genome Project.Dr. David Relman (Stanford University) (Figure 2A) gavethe first of three keynote addresses on ‘Diversity, Stabilityand Resilience of the Human Microbiome’, highlighting thelarger role the human microbiome plays in both health anddisease. He presented recent work from his laboratory onthe profound effects of antibiotics in reshaping the humanmicrobiome, and on the value of applying (and perhaps de-veloping) ecological theory for understanding these com-plex ecosystems and their contributions to human biology[16]. In particular, he raised the issue of resilience, anecological concept that refers to the amount of disturb-ance that a system can withstand without changing itsself-organizing processes or services [17]. He empha-sized the need for better tools to define resilience andevaluate the stability of, and harm to human-associatedmicrobial communities.Dr. Rosamond Rhodes (Icahn School of Medicine atMount Sinai, New York) discussed the ethical, legal, andsocial implications surrounding the study of the humanmicrobiome. In particular, she spoke on issues related tosubject identification from knowledge of microbiome se-quence data - issues that are in so many ways analogousto those faced by scientists studying the human genomesequence. These issues impact the way microbiome sci-ence is and will be performed in the future, especiallybiobanking. Importantly, they highlight the need to bet-ter protect the privacy of subjects involved in micro-biome research.The session was closed by Dr. Robbie Barbero, Office ofScience and Technology Policy, (OSTP), who describedBADinbioMingRavel et al. Microbiome 2014, 2:16 Page 3 of 11http://www.microbiomejournal.com/content/2/1/16the role of OSTP in supporting cross-agency collaborationto meet ‘Grand Challenges’ that address important societalneeds with a combination of research, technology, andpolicy inputs. He described several successful Grand Chal-CFigure 1 Dr. Owen White (A), one of the organizers of the meetingof Health, who gave an historical perspective on the Human MicroGenome Research Institute discussed the many successes of the HumanFood and Drug Administration discussed the regulatory aspects concernfecal transplants.lenges to date, and asked the microbiome community toconsider whether a microbiome-focused Grand Challengemight be appropriate at this point in time, especially giventhe pervasive impact of microbes in the environment andin our bodies.Basic biology of the microbiomeThis session consisted of three exciting talks describingwhat we know about how the microbiome develops andchanges over time, elaborating on the theme developedearlier by Dr. David Relman. Dr. Ruth Ley (Cornell Uni-versity) described the changes in the gut microbiotathroughout pregnancy, as well as those experienced bynewborns in the first few years of life [18]. She presentedA BFigure 2 Keynote speakers. Dr. Jonathan Braun, University of California Lsciences. Dr. David Relman, Stanford University, (B) discussed the larger rolDominguez-Bello, New York University, (C) discussed aspects of the moderexciting new work that aims at linking host genetic vari-ations and the composition of the human microbiome.For example, in a cohort of more than 1,000 twin adults,heritable genera of Bacteria and Archaea were identified.troduced Dr. Francis Collins (B), Director of the National Institutesme Project. Dr. Eric Green (C), Director of the National Humanicrobiome Project. Dr. Jesse Goodman (D), Chief Scientist at the USthe microbiome, including the challenges associated withUnderstanding the contribution of human genetic varibilityin shaping the composition of the human microbiomewill govern the way we will be able to manipulate thesemicrobial communities to maintain or restore healthand cure diseases.Dr. Jacques Ravel (Institute for Genome Sciences, Uni-versity of Maryland School of Medicine) discussed theecological principles that govern the dynamics of the hu-man microbiome (resilience, resistance and persistence)and how one can gain better understanding of these dy-namic systems using descriptive microbial communitycompositional surveys [19], gene composition and wholecommunity gene expression or even metabolite analysis.Each of these analyses often reveals different intrinsicCos Angeles, (A) highlighted the challenges in translating microbiomee the human microbiome plays in both health and disease. Dr. Marian versus ancestral microbiome.Ravel et al. Microbiome 2014, 2:16 Page 4 of 11http://www.microbiomejournal.com/content/2/1/16dynamic patterns when applied to the same community.His presentation stressed the pitfalls that could resultfrom a priori application of principles that might governmicrobial community at a given body site to anothersite. Discussing the vaginal microbiota he introduced anew concept that the intensity of dynamic changes (thatis, frequency and duration of change in microbiota com-position) could represent an increased risk for acquisi-tion and transmission of sexually transmitted infections.Dr. Frederic Bushman (University of Pennsylvania) thenspoke about his work on understanding the dynamics ofthe human gut virome (the set of viruses that targetsbacteria and humans). Although immense progress hasbeen made in understanding the bacteria that inhabitthe human body, especially through 16S rRNA gene se-quencing and reference genome approaches, studies ofthe human virome have lagged behind. Analysis of thecomposition of the gut virome shows that, at least over2.5 years, the dynamics of the virome is subject-specificand may be important for predicting health, and that thevast majority of viral diversity in the human gut is stilluncharacterized and rapidly evolving [20,21]. Thesestudies suggest that a targeted effort to understand viraldiversity may be needed given their likely importance forthe gut ecosystem as a whole.State of the art microbiome tools, technologies, approachesMicrobiome studies rely on the development of noveland robust technologies, approaches and analytical tools.Dr. Janet Jansson (Lawrence Berkeley National Laboratory)described cutting-edge research that combines multi-omicsapproaches for in-depth characterization of gut communityfunction in health and disease. Taking examples from herown work and those of environmental scientists, shedemonstrated the limitations of 16S rRNA gene-basedcommunity survey which often shows high variation be-tween subjects, while functionally the communities aremore similar. She advocated for applying metaproteomicscombined with metabolomics to gain more accurate in-sights into the function of the community and often thehost as well [22,23]. The addition of these multiple layers ofomics data provides substantially greater insight into pos-sible mechanisms, and when joined with time-series datacan be critical for understanding which differences arecauses and which are effects of processes at other levels.However, she stressed that computational tools for func-tional assignment and for omics’ data integration are stillin their infancy and desperately needed. Dr. Dan Littman(New York University) spoke about approaches for study-ing the interaction of the host immune system and themicrobiome, noting the importance of specific commensalsin inducing inflammatory T cell responses [24]. He specific-ally highlighted an association of Prevotella copri colo-nization with the autoimmune response in rheumatoidarthritis [25,26]. Dr. Curtis Huttenhower (Harvard Schoolof Public Health) described novel bioinformatics tools forreconstructing the biomolecular networks driving emer-gent phenotypes in the microbiome and their influenceson human health [27]. These computational methodsprovide the initial steps to integrate multi-omic data,generate mechanistic hypotheses, and identify action-able molecular targets for therapy. He also discussed theneed for improved study designs to effectively scalemicrobiome investigations to epidemiological popula-tions, which along with principled methods for meta-analysis will aid in ensuring reproducible translationalresults.Dr. Rob Knight (University of Colorado at Boulder) de-scribed the challenges in moving from associative studiesthat link microbes to disease towards studies of causalityusing either germ-free mice models or epidemiologicalcriteria for causation. He also discussed the challenges ofintegrating human microbiome datasets that use differentmethodologies and different subject populations. He dis-cussed the critical aspect of the effect size of each meta-data element. For example, because age and body site canhave large effects even in studies that use very differentmethods, it is essential to control for technical variabilitywhen examining serial samples from the same patient orsub-site analysis (for example, stool versus lumen). He alsoshowed the utility of the HMP dataset [14,15] as a dataframe for integrating dynamics of time series datasets suchas during infant development and for understanding re-mission of Clostridium difficile-associated disease afterfecal microbiota transplantation (FMT). Dr. Owen White(University of Maryland School of Medicine) closed thesession by discussing integration of large datasets such asthose from Human Microbiome Project into accessible re-sources such as the HMP DACC, which he leads [13]. Heemphasized the need for adoption of standards such asthose developed by the Genomic Standards Consortiumto enable systematic analysis of these integrated datasets[28]. At present, privacy concerns make it difficult to ob-tain and harmonize data from different projects, especiallybecause a considerable amount of data resides in dbGAP(the access-controlled Database of Genotypes and Pheno-types). He stressed that open resources will go a long waytowards making the controlled-access data more re-usable. Finally, he described OSDF (the Open ScienceData Framework); an open-source project that providesmethods for accessing large volumes of data on distri-buted file systems, including cloud computing resources,which are increasingly gaining importance as the volumeof data expands.The first day concluded with an open discussion facili-tated by Ed Young, a science writer and blogger, betweenthe day’s speakers and the conference participants. A widerange of topics was covered including: the potential ofRavel et al. Microbiome 2014, 2:16 Page 5 of 11http://www.microbiomejournal.com/content/2/1/16microbiome data to impact health; the need for improvedreusability of the resources generated through investmentby NIH and other agencies; and the importance of expand-ing microbiome studies to understand the functional roleof the microbiome in disease. To date, most microbiomestudies have mostly been associative (associate one or moreorganisms with a disease state), and the need for studiesthat are designed to address causality was also discussed.Many audience members were interested in issues of sub-ject identifiability via the microbiome and how a micro-biome can be changed in a specific desired direction; bothof these topics are areas of intense scientific interest, how-ever, at present a clearer picture is still emerging.The modern versus the ancestral microbiomeIn the second keynote, Dr. Maria Gloria Dominguez-Bello(New York University) (Figure 2B) spoke about the mo-dern versus ancestral microbiome [29,30]. She describedhow modern practices including hygiene, antibiotics, andlimited exposure to livestock have likely affected the com-position of the human microbiome. She showed thatpeople living more ancestral lifestyles, without antibioticsand vaccines, such as a previously uncontacted group ofthe Yanomamö Amerindian tribe in Venezuela, have aprofoundly different microbiome as compared to westernpeoples. Their microbiomes exhibit high diversity not justin the gut, but at all body sites surveyed. She concludedher presentation with a description of a fascinating projectthat aims to collect not just biological samples, but envir-onmental samples including household surfaces, water,soil, air, domestic pets and livestock along gradients ofWesternization in both South America and Africa. Suchstudies may be critical for understanding the role of mi-crobes, or their loss, in several so-called ‘Western diseases’which are a high cost burden on the US health system.Host immune system/microbiome interactionsDr. Sarkis Mazmanian (Caltech) discussed how specificbacterial genes control how some gut bacteria colonize theintestinal tract [31]. Focusing on Bacteroides species inmice, he presented data demonstrating that a unique classof microbial polysaccharide utilization loci is responsiblefor species-specific saturable colonization of the crypt chan-nels in the gut. These commensal colonization factors (ccf)loci in Bacteroides fragilis and Bacteroides vulgatus enablespecies-specific physical interactions with the host that me-diate stable and resilient gut colonization; ccf mutants aredefective in horizontal transmission. These studies stressthe importance of species-specific genes that, if absent,could affect the establishment of a healthy microbiome. Dr.Eugene Chang (University of Chicago) discussed the effectsof the gut microbiome on host epithelial functions and re-sponses [32,33], focusing on the pouchitis model that hasbeen extremely informative in his HMP demonstrationproject. Dr. Susan Erdman (Massachusetts Institute ofTechnology) presented her work on animal models show-ing that specific microbial exposures affect host hormones,including oxytocin [34], interrelated with host immunecell functioning. She showed that prior exposures to gutmicrobes alter the immune system and potency of Tregulatory (Treg) lymphocytes, lowering risk for sys-temic diseases including cancer later in life. These stu-dies highlighted microbe-endocrine-immune linkagesand possible mechanisms for transmitting the effects ofmaternal microbial exposures to offspring, including be-havioral benefits such as improved social interactions.Microbiome and disease associationsDr. Heidi H Kong (NIH, NCI, Dermatology Branch) dis-cussed how skin microbiota can influence host skin im-munity and vice versa. For example, Yasmine Belkaidand co-workers [35] showed that applying the skin com-mensal S. epidermidis on germ-free mice can restore theability to control skin infections by the parasite Leish-mania major. These findings have potential implicationsfor the development of rational tissue-specific adjuvantand vaccine approaches. In addition to highlighting theimportance of studying fungal communities as well asbacterial communities, she discussed work demonstrat-ing the alterations of the skin microbiome in patientswith atopic dermatitis (AD) and primary immunodefi-ciencies [36]. The notable differences in the skin micro-biomes of these patient populations may reflect how thehost can modulate its skin microbiome and potentiallyelicit episodes of skin disease. Since AD is often linkedwith asthma and hay fever, understanding the triggers ofAD may allow scientists to develop strategies to preventand treat these other disorders. Dr. Gary Huffnagle(University of Michigan) described the major challengesassociated with sampling the lungs, a body site previ-ously believed to be sterile [37,38]. It is now known thata low-abundance microbiota exists in the lung and thatwhen diseased, the microbial load increases, comprisingnumerous taxa not found in the mouth or throat. Thisindicates that there are selective pressures in the lungsfor bacterial persistence, colonization and growth thatuniquely shape the bacterial community of this bodysite. Dr. Vincent Young (University of Michigan)reviewed Koch’s Postulates and their implications formoving beyond a ‘classical’ infectious disease model andtowards an understanding of the role of both com-mensal and pathogenic microbes in the developmentof inflammatory bowel disease. In particular, unders-tanding the interactions of normal gut bacteria with thehost mucosa is critical to understanding how dysre-gulation of these normal interactions can trigger the ab-normal host response that characterizes inflammatorybowel disease [32].Ravel et al. Microbiome 2014, 2:16 Page 6 of 11http://www.microbiomejournal.com/content/2/1/16Functional interactions between host and microbiomeMicrobes are important modulators of host phenotypes. Itis critical to better understand the mechanisms governingthis modulation. Dr. Andrew Neish (Emory University) dis-cussed how the microbiome controls epithelial cell prolife-ration, focusing on the role of microbes in stimulatingreactive oxygen species (ROS) production in the gut epi-thelium [39,40]. In Nox1 and Frp1 null mice, and dNoxknockout Drosophila, the dynamics of crypt cell prolif-eration are substantially altered, suggesting that signal-ing to host cells via reactive oxygen species stimulatedby commensal bacteria is important. Dr. Peter Turnbaugh(Harvard University) spoke about the impact of gut mi-crobes on drug metabolism; for example, how certainstrains of the gut bacterium Eggertella lenta carry a cyto-chrome operon that causes inactivation of the cardiac drugdigoxin [7]. These and other studies highlight the importantrole of the microbiome in altering the outcome of thera-peutics. A better understanding of these interactions maysomeday allow us to devise strategies to improve drug effi-cacy and reduce side effects. Dr. Wendy Garrett (HarvardSchool of Public Health) discussed how microbial me-tabolites, in particular short-chain fatty acids which arethe major end products of bacterial fermentation ofdietary polysaccharides, regulate the size and function ofthe colonic Treg pool, and can protect mice against colitis[41,42]. Thus, short-chain fatty acids may act as a trans-ducer of the gut microbiome into a reliable signal that canregulate immune homeostasis and function in the colon.Diet and the microbiomeDr. Ian Jeffery (University College Cork, Ireland) presentedthe ElderMet project that studies diet-gut microbiota inter-actions as it relates to the health of the elderly [43]. In thisproject, comparisons of elderly subjects living in the com-munity, residential-care or hospital settings were performedusing a combination of dietary assessment, gut microbialcharacterization using 16S rRNA gene surveys, and NMR-based metabolomic analyses. Differences in diet and livingsituation were highly correlated with differences in the gutmicrobiota composition and function. Within these popula-tions the microbiota was associated with health outcomesin the individuals such as frailty and inflammatory markers.Over the long term, diet was associated with changes in gutmicrobiota and therefore dietary modulation of the micro-biota may have an impact on health of the elderly. Thiswork could lead to carefully designed dietary interventionsto promote healthier aging. Dr. Kathryn Dewey (Universityof California, Davis) reviewed what is known about theinfluence of diet in early life on the microbiome. Shediscussed the key role of breastfeeding, noting that themicrobial composition of breast milk may be influencedby the mother’s weight and mode of delivery, and thatprebiotics in human milk promote the growth of beneficialgut bacteria. Although many studies have compared breast-fed to formula-fed children, it is still unclear which spe-cific aspects of breastfeeding have an effect on the gutmicrobiome. Introduction of solid foods, the types of solidfoods consumed, and certain nutrients such as iron andfatty acids influence the diversity and composition of gutbacteria. However, there is little information on howdietary composition or nutrient intake affects themicrobiome of children and the health consequences ofdifferences in the gut microbiome. A new project enti-tled the Breast Milk, Gut Microbiome, and Immunity(BMMI) Project aims to discover new ways to promotehealthy growth in infants and children, and will addresssome of these important questions. Dr. Johanna Lampe(Fred Hutchinson Research Center and University ofWashington) discussed how a range of dietary compo-nents are metabolized by bacteria, potentially impactinghuman health [44]. For example, bacterial metabolitescan act as nutrients for host cells (for example, short-chain fatty acids), act as signaling molecules, or be gen-otoxic (as in the case of nitrites and hydrogen sulfide)or beneficial to host cells (for example, isothiocyanatesand flavonoids). Of particular interest in studies of car-diovascular disease is the bacterial conversion of cholineto trimethylamine, which is subsequently converted totrimethylamine N-oxide (TMAO) in the liver.Translational research and the microbiomeThe third day was dedicated to strategies for moving be-yond basic association between microbiome and diseaseby exploiting the microbiome to improve humanhealth. The third keynote was given by Dr. JonathanBraun (UCLA) (Figure 2C) who noted that the key totranslating microbiome science was to identify plaus-ible mechanisms to explain how bacteria might affectthe host, as well as therapeutic targets for modulatingbacterial activity. He highlighted a number of diseasesthat were either caused by pathogenic microbes or by a‘pathogenic’ microbial ecosystem, including Clostridiumdifficile-associated colitis, inflammatory bowel disease,Type 1 diabetes, lymphoma, atherosclerosis, and elementsof behavior and cognition. The main challenges are to un-tangle the relationships among the complex networks ofmicrobial species, their functions and products and howthey mediate effects on the host (and vice versa) [45]. Un-derstanding the properties that drive these networks is keyto designing reliable interventions. This presentation wasfollowed by Dr. Jesse Goodman (FDA, Chief Scientist)(Figure 1D) who covered regulatory aspects concerningthe microbiome, in particular the FDA’s decision to re-quire an IND (Investigational New Drug) application ap-proval for all FMT other than those for treating C. difficileinfections. In his presentation he also reviewed the regu-latory issues surrounding probiotics not covered by theRavel et al. Microbiome 2014, 2:16 Page 7 of 11http://www.microbiomejournal.com/content/2/1/16GRAS (Generally Recognized as Safe) guidelines, for ex-ample, microbial strains isolated from traditionally con-sumed fermented foodstuffs. He stressed that the FDA’smission was to get effective therapies and diagnosticsinto the hands of consumers as rapidly as possible, how-ever, within the microbiome space methods for demon-strating safety and efficacy are still in their infancy andvery much evolving.Body/microbiome axisDr. Ted Dinan (University College Cork, Ireland) discussedhis work on the microbiome-gut-brain axis where he usesgerm-free mice to demonstrate that the lack of gut mi-crobes affects sociability, decreases memory, and increasesstress responses. He discussed the role that bacteria playin producing neurotransmitters, such as norepinephrine,serotonin, or dopamine, as well as how certain probioticbacteria can actually modulate the effects of neurotrans-mitters. In particular, he presented data showing how spe-cific strains of Lactobacillus rhamnosus modulate stressand this effect appears to be mediated through the vagusnerve in mice [46]. He cautioned that identifying psycho-biotics (a live organism that, when ingested in adequateamounts, produces a health benefit in patients sufferingfrom psychiatric illness) should involve rationally designedscreening strategies of very large numbers of putative mi-crobial strains, and that, just as is the case with chemicaldrugs, most strains are expected to have no effect on mostdisorders. Dr. Martin Blaser (New York University) spokeabout both epidemiological evidence linking antibiotic useand the risk for obesity [47]. He presented experimentalevidence in mice that sub-therapeutic antibiotic treatmentas well as pulsed full-dose antibiotic treatment modifiesbody composition, growth, and immune status, leading toincreased adiposity. These results, together with the use ofantibiotics as growth promoters in livestock, suggest thatthe obesity epidemic in humans may be in part attribut-able to modifications of the gut microbiota by antibiotics,especially in early in life. Dr. Stanley Hazen (ClevelandClinic) discussed links between microbes and cardiovas-cular disease, and in particular the role of bacteria inconverting choline to TMAO, which in turn promotesatherosclerosis [48]. This model, supported by carefulwork in mice and in human subjects, suggests a directand specific mechanistic link between gut microbes andcardiovascular disease. Dr. Christian Jobin (Universityof Florida School of Medicine) presented his work ongut microbiome and colorectal cancer [49], stressing theimportance of mechanistic studies identifying specificbacterial genes involved in the causal pathway to cancer.Using IL10-/- germ-free mice which develop colitis-associated colorectal cancer after exposure to microbes,he identified the polyketide colibactin, produced by E.coli, which appears to play a substantial inflammation-dependent role in colorectal cancer development inmice and humans. These studies have started to un-tangle the role of inflammation, gut microbiota, andspecific bacterial genes in the development of cancer.Dr. Julian Davies (University of British Columbia, Canada)ended the session with a discussion of the wealth of che-mical products that microbes produce, and of the im-portance of mining this wealth using rational genomicapproaches for identifying microbial secondary meta-bolites with therapeutic activities. He noted that themicrobiome itself represents a great source of novel andpotentially bioactive natural products [50].Probiotics, microbiome vaccines, and fecal transplantsThe final session turned to methods for directly manipulat-ing the microbiome. Dr. Alexander Khoruts (University ofMinnesota) covered the remarkable efficacy (approximately90% remission rates) of fecal microbiota transplantation(FMT) in curing recurrent Clostridium difficile infection(CDI). The potential mechanisms of action are starting tobe elucidated and involve ecological, immunological, andmetabolic (bile acids) components - all are proposed tolead to C. difficile colonization resistance. He noted thatmany challenges remain before widespread implementa-tion of FMT can become a reality in routine clinicalpractice. Dr. Elaine Petrof (Queen’s University, Canada)provided a complementary approach for FMT usingsynthetic stool made of defined communities of bacteriacultured from human feces but grown in the laboratory,rather than samples from donors. She described the suc-cessful treatment of two CDI patients using a definedsynthetic stool comprising 33 bacterial isolates [51].This approach holds substantial promise for improvingpatient and physician acceptability of FMT. Dr. DavidMills (University of California, Davis) discussed the roleof milk-oriented prebiotics and probiotics in identifyingcompounds and bacteria that could form the next gen-eration of rationally-designed prebiotics and probioticsto improve and support infant health. He described therich diversity in oligosaccharides found in human breastmilk and noted that the types of glycans found in breastmilk help to shape the composition of the infant gutmicrobiota, specifically different species of Bifidobacter-ium [52]. This information could be used to design syn-biotic formulations comprised of specific human milkoligosaccharides and bacteria to drive a healthy infantgut. Ultimately, understanding the co-evolution of milkglycans, the immune system, and gut bacteria in infancymay be critical in improving human health in infantsand may be among the first translational models formodulation of the gut microbiota. Finally, Eric Brown(representing the Brett Finlay Lab, University of BritishColumbia, Vancouver, Canada) spoke about gut micro-biota and vaccine efficacy. In developing countries vaccineRavel et al. Microbiome 2014, 2:16 Page 8 of 11http://www.microbiomejournal.com/content/2/1/16efficacy is lower and the gut microbiota is different fromthat in developed countries. He suggested a link betweenthe impact of diet and malnutrition on the composition ofthe gut microbiota and vaccine efficacy. He highlighted aneed for studies to explore ways to manipulate the gutmicrobiota to improve vaccine response, including pro-biotics and/or prebiotics. Understanding the basis forvaccine failure in developing countries is a key issuein global public health. Further, developing tests forthe maturation of the infant microbiota and immunesystem, which could be used to improve public healthstrategies and vaccine efficacy could have a large bene-ficial effect.The meeting closed with another floor discussion mod-erated by Ed Yong, which gave participants a final chanceto share their thoughts about the workshop and about thefuture of human microbiome research. He led discussionson the impact of antibiotics on the gut microbiota andlong-term health, as well as on ways to better understandmechanisms of action driving the benefit associated withmanipulation of the microbiota.Gaps, needs, and challenges: a framework for the futureof human microbiome studiesA key objective of this meeting was to identify gaps,needs and challenges specific to each individual re-search project presented, and the field as a whole.In addition, the meeting organizers aimed to expandmicrobiome research by including specialists in otherdisciplines who could benefit from a microbiomefocus. Not surprisingly, speaker responses to the ques-tions of gaps, needs, and challenges varied, neverthe-less, some themes emerged:Causation and the need for prospective longitudinal studiesA challenge in microbiome research is to move beyondidentification of microbiota community structures thatcorrelate with disease states to establishing a causallink between structural changes and the functions ofmicrobiota in disease. Prospective longitudinal studiesin humans were recommended to help better under-stand the drivers of microbiome dynamics with respectdisease risk and to develop predictive models of sus-ceptibility that could suggest better health practices(Relman, Ravel). Prospective long-term follow up ofintervention trials are also needed to identify the con-sequences of differences in microbiome structure andfunction in early life (Blaser, Dewey, Knight). In mice,multi-generational studies that monitor transfer ofmicrobiota to offspring over generations with changesin diet, antibiotics, or environment are important fortesting cause/effects relationships between allergic,autoimmune, and behavioral disorders and the micro-biome (Mazmanian). Improved clinical phenotypingand clean study design are essential to successful micro-biome studies (Chang). Understanding links between hostgenetics and the microbiome may also require a longitu-dinal component, as some phenotypes develop only atspecific ages (Ley).Improved understanding of microbial ecosystems of thehuman bodyWe need more robust knowledge of ecological networkswithin microbial ecosystems and their stability over timewithin individuals (Braun). Characterization of microbialsuccession and colonization, and of the natural historyof microbes and the disorders they cause, was noted as apotential means to correct dysbiosis or influence meta-bolism of drugs (Mazmanian, Ley, Turnbaugh, Chang).Relman raised several key questions, including: whichaspects of diversity matter most, and do these aspectsmainly occur at the level of organisms, genes, or path-ways, or between communities? He argued that under-standing the fitness landscape of an individual wouldimprove our knowledge of resilience and contribute tostrategies for maintenance and restoration of importantecosystem services. Mazmanian and Knight also notedthat understanding specific and successful colonizationprocesses would be critical to improve disease outcomes.Host-microbiome signals and interactionsPresenters noted our poor understanding of the signal-ing and communication processes between microbiomesand the host. Improved methods and models systemsare needed. While recognizing the limitations of animalmodels, they nevertheless have provided a wealth of in-formation that have led to our current understanding ofthe role of the microbiome in health and disease andcontinue to generate novel hypotheses that can be testedin well-designed human studies. Continued support forthe development of better animal models is critical tothe future of this field. Studies that investigate the mecha-nisms by which the microbiota influences and is influencedby the immune system (Littman, Garrett, Chang), or howhormones, such as estrogen impact the vaginal ecosystems(Ravel), are desperately needed. Exhaustive identifica-tion of small molecule, bioactive metabolites, secretedand cell surface peptides that can influence microbe-to-host interactions, would be highly desirable (Hutten-hower, Mills, Jobin).Analysis approaches and toolsMany concerns regarding the lack of tools for the analysisof ’omic datasets being generated by the microbiome com-munity were expressed during the meeting. Researchersneed improved methods to perform quantitative measure-ments of transcripts, proteins, and metabolites (Braun,Ravel). There is also a lack of consensus as to how muchRavel et al. Microbiome 2014, 2:16 Page 9 of 11http://www.microbiomejournal.com/content/2/1/16diverse ‘omics’ data is needed for robust scientific in-terpretation (Knight). The need for better methods tointegrate large and diverse ‘omics’ datasets was fre-quently mentioned (Young, Jeffrey, Lampe, Jansson,Huttenhower, Knight) and the sheer volume of infor-mation should be considered to be ‘big data’ problem(Jansson). The lack of procedures to integrate multipleomics data types in longitudinal studies was also iden-tified (Knight). The overall need for increased interdis-ciplinary collaboration to generate and interpret datawas noted (Mills, Lampe, Jansson), mainly because of thedifferent expertise needed to analyze such datasets ex-ceeds what any individual lab can do. Presenters pointedout that tools for the analysis, visualization, and manipu-lation of these large datasets are also needed. Userswould like, for example, to ‘make meta’omics analysisas easy as microarray analysis’ (Huttenhower). Specificsystems for analysis of metabolomic, genetic, glycomicdatasets (Mills), or sequences from low-biomass sam-ples (Kong), and mass spectrometry data (Davies) arealso lacking. Many presentations at the meeting thusrevolved around the generation of diverse ‘omics’ data-sets, and the challenges associated with integrating thatinformation.StandardsSeveral presenters expressed that more standards areneeded in microbiome research. Standardized protocolsimprove reproducibility of microbiome experiments andensure translation of results from independent expe-riments (Braun, Huttenhower, White, Knight). White sug-gested that software could be developed to improve theuniformity of data submissions to the NCBI Short ReadArchive and dbGaP. Further, uniform clinical and la-boratory procedures such as sampling methods atdifferent body sites, PCR protocols, and DNA/RNA ex-traction methods would also improve our ability tocompare data from different research projects (Kong).It was also noted that non-standardized diets for modelorganisms could account for phenotypic differencesbetween experiments (Mazmanian). Presenters alsocited the challenges associated with non-standard meta-data associated with microbiome work. Most sampleinformation is not in a standardized format (Knight),and standardized clinical description of phenotypes islacking (Kong). A solution to these metadata issueswould be to utilize software systems similar to thePhenX toolkit for describing common clinical data ele-ments [53], in combination with standardized meta-data deposition practices being enforced by scientificjournals (White). There was a clear need expressed forcollection of data and tools in a single accessible site,much as the HMP DACC provided for the HumanMicrobiome Project.ConclusionsThe meeting was clearly a success, in that it highlighted theamazing progress in microbiome research funded across arange of NIH Institute and Centers, focusing on a widearray of diseases. Additionally, while the speakers re-sponses to the needs, gaps, and challenges varied, themesfocusing on a few key areas emerged: studies of causality(mechanistic studies in model organisms and prospectivelongitudinal studies), need to integrate more complexomics and phenotype data, and better standardization ofmethods and data. Overall, the diversity and excellence oftalks underscored how much has been done in this field,in just the past 6 years, and the potential for microbiomescience to produce a revolution in human health.AbbreviationsAD: Atopic Dermatitis; DACC: Data Analysis and Coordination Center;dbGaP: The Database of Genotypes and Phenotypes; ELSI: Ethical, Legal andSocial Implications; EPA: Environmental Protection Agency; FDA: Food andDrug Administration; FMT: Fecal Microbiota Transplantation; GRAS: GenerallyRecognized as Safe; HMP: Human Microbiome Project; NASA: NationalAeronautics and Space Administration; NHGRI: National Human GenomeResearch Institute; NIH: National Institutes of Health; NSF: National ScienceFoundation; OSTP: Office of Science and Technology Policy; USAID: USAgency for International Development; USDA: US Department of Agriculture.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsOW, JR, and RK wrote the paper. All authors read, edited and approved thefinal manuscript.AcknowledgementsThe authors would like to thank Lita Proctor (NHGRI/NIH), for conceiving thisidea to evaluate the status of microbiome research across the NIH, as well asChristopher Wellington, Nicholas Digiacomo, Sue Dilli, and Michele Giglio fortheir invaluable contributions to the organization of the scientific programand the logistics of the meeting. The conference was supported in part bygrant U01HG004866 from the National Human Genomics Research Institute,National Institutes of Health. The conference organizers are grateful toRoche, Qiagen, Illumina, Life Technologies, MoBio, Metabolon, and theBioMed Central journal Microbiome for their financial support of the meeting.Author details1Institute for Genome Sciences, Department of Microbiology andImmunology, University of Maryland School of Medicine, 801 W. BaltimoreStreet, Baltimore, MD 21201, USA. 2Department of Microbiology, HumanMicrobiome Program, New York University Langone Medical Center, 550 FirstAvenue, Bellevue CD 689, New York, NY 10016, USA. 3Department ofPathology and Laboratory Medicine, David Geffen School of Medicine atUCLA, Los Angeles, CA 90095, USA. 4The Michael Smith Laboratories andDepartment of Microbiology and Immunology, University of BritishColumbia, Vancouver, BC V6T 1Z4, Canada. 5Department of Microbiology,Perelman School of Medicine at the University of Pennsylvania, Philadelphia,PA 19104, USA. 6Knapp Center for Biomedical Discovery, University ofChicago, 900 E. 57th Street, Chicago IL 60637, USA. 7Department ofMicrobiology and Immunology, University of British Columbia, 2350 HealthSciences Mall, Life Sciences Centre, Vancouver BC V6T 1Z3, Canada.8Department of Nutrition, University of California, One Shields Avenue, Davis,CA 95616, USA. 9Department of Psychiatry, GF Unity, Cork University Hospital,Cork, Wilton, Ireland. 10Division of Comparative Medicine, MassachusettsInstitute of Technology, One Massachusetts Avenue, Cambridge, MA 02139,USA. 11Department of Immunology and Infectious Diseases, Harvard Schoolof Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.12Department of Internal Medicine/Infectious Diseases, ImmunologyUniversity of Michigan Medical School, 1500 W. Medical Center Drive, AnnBiological Engineering, California Institute of Technology, 1200 E. CaliforniaBl, Pasadena, CA 91125, USA. 26Department of Food Science and Technology,Ravel et al. Microbiome 2014, 2:16 Page 10 of 11http://www.microbiomejournal.com/content/2/1/16University of California, One Shields Avenue, Davis, CA 95616, USA.27Department of Viticulture and Enology, University of California, One ShieldsAvenue, Davis, CA 95616, USA. 28Department of pathology, Emory UniversitySchool of Medicine, 105H whitehead bldg., 615 Francis Street, Atlanta, GA30322, USA. 29Department of Medicine/Infectious Diseases, GastrointestinalDiseases Research Unit, Queens University and Kingston General Hospital, 76Stuart Street, GIDRU wing, Kingston ON K7L 2V7, Canada. 30Department ofMicrobiology & Immunology, Stanford University, Stanford, CA 94305, USA.31Department of Medicine, Stanford University, Stanford, CA 94305, USA.32Department of Medical Education, Icahn School of Medicine at MountSinai, One Gustave Levy Place, Box 1076, Annenberg 12-42, New York, NY10029, USA. 33FAS Center for Systems Biology, Harvard University, 52 OxfordSt, Cambridge, MA 02138, USA. 34Department of Chemistry and Biochemistry,Howard Hughes Medical Institute, University of Colorado, 215 UCB, Boulder,CO 80309, USA. 35Institute for Genome Sciences, Department ofEpidemiology and Public Health, University of Maryland School of Medicine,660 W. 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