annurevpathol.7(2012)99 human microbiome in health and disease

PM07CH04-Versalovic ARI 15 December 2011 10:43

Human Microbiome in Healthand DiseaseKathryn J. Pughoeft1 and James Versalovic1,21Department of Pathology and Immunology, Baylor College of Medicine, Houston,Texas 77030; email: [email protected], [email protected] of Pathology, Texas Childrens Hospital, Houston, Texas 77030

Annu. Rev. Pathol. Mech. Dis. 2012. 7:99122

First published online as a Review in Advance onSeptember 9, 2011

The Annual Review of Pathology: Mechanisms ofDisease is online at pathol.annualreviews.org

This articles doi:10.1146/annurev-pathol-011811-132421

Copyright c 2012 by Annual Reviews.All rights reserved

1553-4006/12/0228-0099$20.00

Keywords

metagenomics, microbiota, probiotics, pathogens, dysbiosis, diversity

Abstract

Mammals are complex assemblages of mammalian and bacterial cellsorganized into functional organs, tissues, and cellular communities.Human biology can no longer concern itself only with human cells:Microbiomes at different body sites and functional metagenomics mustbe considered part of systems biology. The emergence ofmetagenomicshas resulted in the generation of vast data sets of microbial genes andpathways present in different body habitats. The profound differencesbetween microbiomes in various body sites reveal how metagenomescontribute to tissue and organ function. As next-generation DNA-sequencing methods provide whole-metagenome data in addition togene-expression proling, metaproteomics, and metabonomics, differ-ences in microbial composition and function are being linked to healthand disease states in different organs and tissues. Global parameters ofmicrobial communitiesmay provide valuable information regarding hu-man health status and disease predisposition. More detailed knowledgeof the human microbiome will yield next-generation diagnostics andtherapeutics for various acute, chronic, localized, and systemic humandiseases.

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Metagenomics:identication of taxaby use of sequence-based culture-independent methods

Microbiome: acollection of microbialgenomes

Microbiota: acollection of microbes

ABOUT THE HUMANMICROBIOME

Cell-rich bacterial communities outnumberhuman cells in each person by an estimated ra-tio of 10 bacterial cells to each human cell (1). Inother words, approximately 90% of the cells inand on the human body are microbial cells. Tounderstand human metagenomics, the HumanMicrobiome Project was launched as part of theNational Institutes of Health RoadMap version1.5 in 2007 (2). Microbial diversity varies byanatomic site, and the complexity and aggregatefunctions of bacterial communities may corre-late with an individuals health status, genotype,diet, and hygiene (3, 4). The numbers of dif-ferent microbes (richness) at a body site, andthe genetic diversity of microbiomes (5), areregulated partly by the local environment andbiology of each body habitat. Although yeastsand viruses also form part of the human micro-biome, the majority of published studies havefocused on host-associated bacterial commu-nities. Therefore, this review mainly discussesbacterial communities in the context of humananatomy and disease states. With respect toviruses and the human virome, diverse bacterio-phage populations in the human microbiomeare an additional source of biological diver-sity in human- and animal-associated bacterialcommunities (6).

Each human individual houses diversemicrobial communities that reside in differentbody habitats, and these microbiomes differgreatly in terms of composition and function.The majority of human-associated bacteria fallwithin four phyla, Actinobacteria, Firmicutes,Proteobacteria, and Bacteroidetes (4, 79);each phylum contains many different bacterialspecies. The distribution and ratios of phyladiffer with respect to body site (10). Bodysitespecic communities of bacteria vary tosuch a degree that the communities at each site(e.g., intestine) are more similar across the hu-man population than they are to communitiespresent at other sites within the same individual(4). The implication of these ndings is thatanatomical sites and tissues coevolved with

microbiomes that contain different functionalrepertoires. Whereas the predominant micro-bial phyla and classes have been described, themicrobiome is a uctuating collection of genesand gene products; environmental perturba-tions, such as antibiotic treatment and infection,can readily alter the microbial compositionand function of each community (9, 11). Thehuman metagenome is relatively plastic ormalleable, which makes the microbiome an at-tractive target for manipulation by cell or genetherapy.

The rst year of human life provides anattractive window of opportunity to alter thecomposition and function of the microbiota ininfants. Colonization of the newborn beginsduring the birth process, and relatively complexbacterial communities have been documentedby the end of the rst week of life (12, 13).The complexity of the bacterial communityincreases during infancy so that an adult-likecomplexity is attained by the end of the rstyear of life, and large uctuations of bacterialpopulations occur during this rst year (12, 13).Specic microorganisms within the commu-nity depend, in part, on environmental factors,including family size, nutrition, and water qual-ity (3). The importance of diet was recentlyrevealed in a study comparing the intestinal mi-crobiomes of children froma village in theWestAfrican country of Burkina Faso with thoseof children in Florence, Italy. Although twobacterial phyla, Bacteroidetes and Firmicutes,dominated the microbiota of the population ineach environment, there was a dramatic shift interms of the relative percentages of these twodominant phyla: 73% and 12%, respectively,in Burkina Faso to 27% and 51%, respectively,in Italy (Figure 1) (14). Major differences indiet presumably shaped the microbiomes inthese two pediatric populations in fundamentalways, possibly contributing to differences inwhole-body metabolism (e.g., differences infecal quantities of short-chain fatty acids) anddevelopment of organs and tissues.

The humanmicrobiome may be a vast, mal-leable genome that can be modied by dietary,medical, and hygienic practices. Antibiotics

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a 15%

20%

53%

4%4%

4%

PrevotellaXylanibacterAcetitomaculumFaecalibacteriumSubdoligranulumOthers

Bacteroidetes

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4%23%

12%

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9%

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AlistipesBacteroidesAcetitomaculumFaecalibacteriumRoseburiaSubdoligranulumOthers

Bacteroidetes

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Figure 1Bacterial taxa of the intestinal microbiota differ depending on diet. Taxa identied using 16S ribosomal RNA sequencing of DNA fromfecal samples of children from (a) Burkina Faso and (b) Italy. The colors indicate differential distribution of classes of bacteria, includingFirmicutes (red ) and Bacteroidetes ( green). Figure reproduced from Reference 14.

Taxon: phylogeneticclassication of anidentied orunidentied organism(plural: taxa)

Pathogen:an organism that isdetrimental to the hostor causes disease

have potent effects by suppressing up toone-third of the gut microbiome with a simpleve-day course of a single antimicrobial agent,ciprooxacin. Gut communities are dynamicin nature such that most microbes returned tobaseline levels within weeks posttreatment, butseveral bacterial taxa remained undetectable(11, 15). Such differences in microbial compo-sition that arise from diet or medication historymay contribute to different patterns of humandisease predisposition and to the prevalence ofvarious systemic and organ-specic disorders.Changes in human microbial populations havebeen linked to localized diseases [e.g., dentalcaries, bacterial vaginosis (BV)], as well as sys-temic disorders (e.g., autoimmune diseases) (9,16). Alterations of the host environment (e.g.,pH or nutrition) result in shifts in the relativeabundance of pathogenic bacteria or upreg-ulation of virulence genes in opportunisticpathogens, leading to disease states (7, 17, 18).

The yield of bacteriologic culture is limitedbecause only 20%60% of the microbes iden-tied in different body sites have been cultured

(2). Uncultured microbes can be identiedby 16S ribosomal RNA gene sequencing(16S metagenomics), and entire genomes andmetabolic pathways may be reconstructed bywhole-genome shotgun (WGS) metagenomics(19). The reference genomes initiative withinthe Human Microbiome Project has facilitatedidentication of novel microbes and microbialgenes (20), and such ongoing efforts willexpand microbial sequence databases for mi-croorganism identication and gene/functionalannotation efforts. In addition to microbialDNA/RNA sequencing, metaproteomics andmetabonomics strategies will enable investiga-tors to identify microbial biomarkers that maybe directly tied to differences in metabolic orphysiologic functions in mammals. Databasesthat include microbial proteins and metabolitesand newer bioinformatic tools that describebiochemical pathways in various bacteria (e.g.,KEGG BRITE, U.S. Department of EnergyIntegrated Microbial Genomes) are providingnew opportunities for human systems biologyinclusive of metagenomics.

www.annualreviews.org Human Microbiome in Health and Disease 101

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Regulation of virulence factors

Supplementation of nutrients

Modulation of community composition by bacteriaderivedantimicrobials

Modulation of immune response

Regulation of transcription factors

Supplementation of nutrients

Transfer of antibiotic resistanceencoding genes

Transfer of virulence factorencoding genes

Transfer of metabolismrelated genes

IntrakingdomcommunicationIntrakingdom

communicationInterkingdom

communicationInterkingdom

communicationGene transferGene transfer

Figure 2Basic modes of interspecies communication. Small molecules secreted by bacteria are used to communicate with other bacteria or thehost, which results in the regulation of virulence factors or bacterial community composition, the regulation of gene expression in thehost, or the supplementation of nutrients in the community as a whole. Communication can also occur via genetic exchange, in which agene or genes, represented by the red region of DNA in the chromosome, are transferred between one species of bacteria and another.Genes involved in such transfer include genes involved in antibiotic resistance, virulence, and metabolism (26, 27, 31, 34, 44,111114).

Quorum sensing:chemical signaling bymicrobes via secretedmolecules

Probiotic: anorganism that elicitshealth benets to thehost

INTERMICROBIALCOMMUNICATION ANDGENE TRANSFER

Bacteria are social microorganisms that com-municate and interact with one another aswell as with the mammalian host (Figure 2).Individual bacterial species use small moleculesto assess numbers of self (intraspeciescommunication) and to determine whetherother bacterial species are present in thecommunity (interspecies communication) bya mechanism termed quorum sensing (21).Signaling through quorum sensing enablesgroup-specic behaviors, which cause changesin bacterial gene expression; some of theseregulatory changes are potentially benecial ordetrimental to the host (22, 23). Probiotics canbenet the host bymodulating quorum-sensing

pathways in pathogenic bacteria. Such changesin quorum-sensing pathways by differentspecies of Lactobacillus may result in the inhi-bition of toxin production (2426). Quorumsensingindependent bacterial communicationmay result in the production of nutrients (e.g.,vitamins) utilized by the human host and fellowmicrobes. Bacteria that produce cobalamin (orvitamin B12) and folate can supplement thehuman host and nutrient-dependent bacteriain the community (2730). In addition to pro-ducing vitamins and nutrients, various bacterialspecies modulate mucosal signaling pathways,resulting in changes in host gene expression andimmune cell responses (Figure 3) (31). Thesedata highlight the need for more researchin bacteriahost interactions that will allowus to develop rened microbiome-deriveddiagnostics and therapeutics.


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MicrobesIgA

Macrophage/dendritic cell


SCFAs(butyrate,

propionate)

Vitamins(B12,

folate)

Lymphocyte

Lymphocyte

TGF-APRILBAFF

TGF-

IL-8IL-6

IL-12

Lymphocyte IFN-IL-17IL-23

TNFIL-1IL-6

IL-23IL-12TNFIL-6

IL-10

Inflammatoryresponse

MicrobesIgA

ImmunomodulinsImmunomodulinsImmunomodulinsImmunomodulins

ImmunomodulinsImmunomodulins



SCFAs(butyrate,

propionate)

Vitamins(B12,

folate)

Lymphocyte

Lymphocyte

TGF-APRILBAFF

TGF-

IL-8IL-6

IL-12

Lymphocyte

Proinflammatory Anti-inflammatory

IFN-IL-17IL-23

TNFIL-1IL-6

IL-23IL-12TNFIL-6

IL-10

Inflammatoryresponse

Figure 3Intestinal bacteria produce nutrients and molecules that modulate mucosal immunity. Microbe-derived immunomodulins, short-chain fatty acids (SCFAs), and vitamins modulate host signaling, whichleads to changes in cytokine and immune cell activity. Abbreviations: BAFF, B cellactivating factor; IFN,interferon; IgA, immunoglobulin A; IL, interleukin; TGF, transforming growth factor; TNF, tumornecrosis factor. Figure reproduced from Reference 115.

Gene transfer:transfer of a novelgenetic element fromone organism toanother

Commensal: acolonizing organismthat is neitherbenecial nordetrimental to the host

In addition to bacterial signaling via smallmolecules and nutrients, interspecies commu-nication may include the lateral movementof genes between bacterial species and strainsin microbial communities. Studies of genetransfer and acquisition within the oral cavityindicate that 5%45% of genes present inbacteria with sequenced genomes are acquiredthrough gene transfer (18). Gene transfer maybe bidirectional such that virulence genes maybe transferred from pathogens to commensals,and commensals may also serve as reservoirsof genes that encode antibiotic resistanceand other genes that may facilitate digestion(Figure 2) (30, 32, 33). A recent study (34)described the transfer of gene(s) involved in

carbohydrate utilization from bacteria presenton seaweed to the gut microbiota of Japaneseconsumers. Presumably, this additional capa-bility in Japanese gut microbiomes enhancedthe ability of these individuals to digest andabsorb dietary seaweed and associated algalcarbohydrates. Spatial relationships betweenmicrobes facilitate genetic exchange and sig-naling among microbes within these complexcommunities.

ORAL MICROBIOME: INSIGHTSINTO DENTAL CARIES ANDPERIODONTAL DISEASE

The oral cavity contains a diverse set of niches,including the soft tissues of the tongue and


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Biofilm: a three-dimensional bacterialcommunity encasedwithin anexopolysaccharide

tonsils, saliva, and the hard surfaces of the teeth.Despite this range in habitats, a similar arrayof bacteria constitutes the oral microbiome ineach niche of a healthy oral cavity (3537). Thiscore microbiome is consistent throughout thehuman population, as the extent of interpop-ulation variation of the microbiome is similarto the extent of intrapopulation variation (38).The formation of biolms on the supragingivalsurface of teeth constitutes what is commonlytermed dental plaque (18, 39). Such biolmsconsist predominantly of various combinationsof streptococcal species (60% of the bacteriain dental plaque), and metabolism of carbohy-drates by streptococci and other bacteria resultsin degradation of tooth enamel via pH reduc-tion at the tooth surface (18, 39). This reduc-tion in pH is partially attributable to organicacid production by streptococci and other lac-tic acid bacteria. Differences between the mi-crobiota of healthy and diseased oral cavities ofchildren in China and the United States wererecently assessed in culture-independent stud-ies (40). Species of the genusGranulicatellaweremore abundant in the plaque samples of caries-prone children from the United States and lessabundant in a similar population from China(40, 41). The data suggest that changes in themicrobiota of dental plaque predispose suscep-tible individuals to dental caries, and ethnic dif-ferences may account for the impact of speciccomponents of themicrobiome.This concept isconsistent with the so-called ecological plaquehypothesis, which states that changes in the mi-crobiota from a healthy state shape the environ-ment in a way that leads to dental plaque anddecay (42).

Inammatory lesions within the subgingivalcrevice and degradation of periodontal tissueassociated with subgingival biolms are charac-teristics of periodontal disease (43, 44). Severalbacterial pathogens, including Porphyromonasgingivalis and Aggregatibacter actinomycetem-comitans, are associated with periodontaldisease. These bacteria interact with epithelialcells, which leads to an alteration of theepithelial cell transcriptional prole, includingbacteria-specic changes in the apoptotic

and cell cycleprogression pathways (44, 45).Infection of human immortalized gingivalkeratinocytes (HIGKs) with the oral pathogenP. gingivalis causes the induction of HIGKgenes involved in cell-cycle regulation, specif-ically cyclin-dependent kinases (44). Becausethe subgingival crevice is not colonized solelyby P. gingivalis, the pathogen is found in com-munities with various commensal microbes,including several streptococcal species, and thecollective regulation imposed upon host cellsby these communities of bacteria may differsignicantly from that observed by a singlespecies. Studies of gene-expression proles ofHIGKs infected with cocultures of P. gingivalisand Streptococcus gordonii found that S. gordoniisignicantly modulated host cell responses toP. gingivalis, including the downregulation ofgenes involved in cell-cycle regulation (44).

Differences between the microbiota presentin the gingival crevice of healthy and diseasedtissue from 49 individuals were recently in-vestigated (43). The data indicated that sev-eral species of oral streptococci, as well as Veil-lonella parvula, were associated with the healthystate. Although no major differences in the ra-tios of bacterial species were observed betweenhealthy and disease states, greater numbers ofbacteria were associated with periodontal le-sions (43).Overgrowth ofmultispecies bacterialcommunities at specic infection sites, ratherthan changes in ratios of bacterial species, maydrive the pathogenesis of periodontal disease.

MICROBIOMES ANDMETABOLISM: DIABETESAND OBESITY

The human diet plays a role in shaping thecomposition of the human microbiome, andthe microbiome, in turn, affects the ability ofthe individual to absorb and metabolize nutri-ents. Differences in gut microbial compositionbetween lean and obese individuals stimulatedample interest in commensal microbes and inhow the humanmicrobiomemay be relevant tohuman health and disease. In fundamental stud-ies using mouse models, obese mice containeda relative abundance of Firmicutes, in contrast


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spp.: several species

to the relative preponderance of the phylumBacteroidetes in lean mice (46, 47). The gutmicrobiomes of lean mice, when transplantedinto ob/ob (obese) mice, normalized the bodyweights of the latter, indicating that differencesin microbial composition could affect bodymetabolism and energy harvest and inuencethe predisposition of mammals to obesity.Micedecient in the microbial pattern-recognitionreceptor Toll-like receptor 5 (TLR5) displayedhyperphagia, became obese, and developed fea-tures of the metabolic syndrome, including hy-pertension, hypercholesterolemia, and insulinresistance (48). When gut microbiomes fromthese mice were transplanted into germ-freemice with an intact TLR5 gene, recipient micedeveloped similar features of themetabolic syn-drome, which suggests that the intestinal mi-crobiome, and not murine TLR genetics, wasthe key determinant of this disease phenotype.

Studies in mouse models were correlatedwith similar ndings in human individuals andstimulated interest in how the gut microbiomemay affect predisposition to metabolic disor-ders. Long-term dietary trends shape the in-testinal microbiota and metabolic activity ofthe host. In a study that compared shifts inthe gut microbiota of lean and obese but oth-erwise healthy men in the United States, a20% increase in bacteria of the phylum Fir-micutes was observed in association with in-creased caloric absorption and energy harvestby bomb calorimetry (49). Prior data suggestedthat Fiaf (fasting-induced adipocyte factor) isa contributing factor to enhanced fat deposi-tion by mammals with a conventional gut mi-crobiome (50). The suppression of this gutepitheliumderived lipoprotein lipase inhibitoris essential for gut microbiotainduced deposi-tion of triglycerides in adipocytes.RecentWGSmetagenomics data uncovered the predomi-nance of three basic enterotypes or human gutmicrobiomeproles in a group of 39 individualsrepresenting six nationalities (51). Through themining of whole-metagenome data, twomicro-bial ATPase complexes were identied as po-tential biomarkers of the microbiome that cor-relate stronglywith bodymass index in humans;

such biomarkers support the potential link be-tween the capacity of the gut microbiome forenergy harvest and obesity. In other words, anenhanced ability to harvest energy may be as-sociated with a tendency toward fat depositionand obesity in individuals.

An individuals predisposition to harvestand store fat may be determined in utero be-cause changes in the mothers gut microbiomemay translate into alterations of the intestinalmicrobiomes of their infants; the verticaltransmission of microbiomes associated withincreased energy harvest may result in infantswith inherited tendencies to excessive weightgain. A recent study by Collado et al. (52)highlighted the abundance of Clostridiumhistolyticum, C. difcile, and Akkermansia spp.in overweight mothers and their infants.The transition from development in utero toinfancy emphasizes the potential role of humannutrition, combined with human development,in shaping the human microbiome early in life.Dynamic uctuations in the human micro-biome have been detected at both macroscopicand microscopic levels, and diet and mam-malian development inuence the compositionand function of the human microbiome.

The gut microbiome can affect whole-bodymetabolism and alter physiological parametersin multiple body compartments (53). Gutmicrobial communities fundamentally alterthe metabolite composition of body uids,the liver, and the kidneys. In one study (53),gnotobiotic mice had increased quantitiesof phosphocholine and glycine in the liverand increased quantities of bile acids in theintestine. The gut microbiome also inuenceskidney homeostasis bymodulating quantities ofkey cell-volume regulators such as betaine andcholine (53). A more recent study showed spe-cic differences in the patterns of bile acids andoverall bile acid diversity in germ-free versusconventional rats (54). Germ-free animals con-tain greater quantities of conjugated bile acidsin the heart and liver and greater quantities oftaurine, compared with conventional animals.Because bile acids are now recognized as im-portant cell-signaling molecules, as evidenced


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by effects on farnesoid X receptorregulatedpathways, such differences in microbial bileacid cometabolite patterns may have importantconsequences for whole-body metabolism.

Intestinal microbiomes have also beenstudied in the context of insulin resistancein adult patients with type 2 diabetes. Inone study using relatively deep tag-encodedsequencing (55), the relative abundance of thephylum Firmicutes and the class Clostridiawas signicantly reduced in adults with type2 diabetes (55). Additionally, the ratios ofBacteroidetes to Firmicutes and BacteroidesPrevotella to C. coccoidesEubacterium rectalegroups were correlated with plasma glucoseconcentrations in adult patients. Such ndingsare intriguing and prompt questions regardinghow microbial composition and correspond-ing metabolites may inuence whole-bodymetabolism in humans. Intestinal bacterial taxadiffer with respect to their abilities to utilizedietary carbohydrates and host-derived car-bohydrates (e.g., mucus components) (47, 56).Bacteroides species contain a rich collectionof carbohydrate-utilization pathways, and suchgut bacteria can easily assimilate dietary car-bohydrates. However, in situations of dietarycarbohydrate starvation, the gut bacteria turn tomucus in the gastrointestinal tract as a source ofcarbohydrate, thereby compromising the mu-cus barrier. Such uctuations in diet may havefunctional consequences for bacteria and thehost so that the cannibalization of indigenousmammalian carbohydratesmay result in predis-position to invasion or inammation. Insightsinto the metabolic pathways of indigenous mi-crobes with respect to carbohydrate utilizationand metabolism may provide an explanation ofthe mechanisms of differential energy harvestand endocrine/metabolic disorders in humans.

THE MICROBIOME ANDGASTROINTESTINAL DISEASES

The Esophagus and Stomach

Until recently, the esophagus and stomachwere considered to contain relatively simple

microbial communities, with the occasionalpresence of specic pathogens. Advances inmetagenomics resulted in widespread appreci-ation of the presence of rich microbial com-munities in these body habitats, and shifts inthese populations may be associated with an in-creased risk of disorders of chronic inamma-tion and neoplasia. With respect to the loweresophagus, two basic types of esophageal mi-crobiomes were associated with different phys-iological states (57). The type I microbiomewas dominated by the genus Streptococcus, andthis community class was found mostly in indi-viduals lacking evidence of esophageal disease.The type II microbiome was characterized bygreater phylogenetic diversity, including vari-ous gram-negative anaerobic and microaerobicbacteria. The type II microbiome was corre-lated with esophagitis and Barretts esophagusin one group of patients. This report includeda relatively supercial data set of only 200 se-quenced clones per sample, and unsupervisedcluster analysis of these limited data sets yieldedtwo basic microbiome types in the esophagus(57). Deeper sequencing studies will be neededto ascertain the signicance of these ndings,but the ability to stratify patients on the ba-sis of classication of human microbiomes isan important observation. The association ofincreased microbial diversity and human dis-ease phenotypesmay hinge on the relative com-plexity of the microbiome at a specic bodysite. Body sites that have coevolved with rel-atively simple microbial communities such asthe esophagus may not be capable of sustainingmore complex communities in the absence ofdisease.

The discovery of Helicobacter pylori in thehuman stomach by Warren & Marshall (58)in the 1980s fueled interest in bacterial colo-nization and infection of the human stomach.Subsequent studies and clinical trials with an-timicrobial agents conrmed the importance ofH. pylori in atrophic gastritis, peptic ul-cer disease, and susceptibilities to gastricMALT (mucosa-associated lymphoid tissue)lymphoma and gastric adenocarcinoma (59).Following a period of exuberance regarding the


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apparent success of antimicrobial therapy in pa-tientswith peptic ulcer disease, Blaser&Falkow(3) emphasized the potential danger of elimi-nation of one long-time component of the hu-man gastric microbiome. Deciencies of H. py-lori in modern human communities have beenassociated with an increased risk of Barrettsesophagus and esophageal adenocarcinoma inthese populations. Studies of the gastric mi-crobiome documented the presence of multi-species microbial communities in the humanstomach, indicating that many species, in addi-tion to gastric Helicobacter, apparently colonizethe stomach (15, 60). The removal of H. pylorifrom the gastric microbiome may reduce therisk of peptic ulcer disease and gastric adeno-carcinoma, but conversely, the absence of thisspecies may cause changes to the esophagealmicrobiome that increase the risk of chronicesophageal inammation and cancer. The ef-fects in the esophagus may arise from alter-ations in the nature of esophageal microbiomes(type I or type II) due to the presence or absenceof H. pylori.

Acute Gastroenteritisand Infectious Colitis

Acute gastroenteritis includes diarrheal diseasescaused by various infectious agents, includingviruses, bacteria, and protozoal pathogens. Di-agnosis of the causative agent of acute gastroen-teritis may defy routine methods in microbi-ology. Viral agents are more predominant inchildren younger than three years of age, witha shift to a predominance of bacterial pathogensin children older than three years of age (61). Inone study, only 47% of stool samples that un-derwent complete diagnostic testing yielded aspecic etiologic agent (61). The pathobiologyof acute gastroenteritis includes effacement ofintestinal villi, enhanced intestinal permeabilitydue to interactions between pathogens and thegut epithelium, and toxin production that me-diates disruption of the intestinal barrier andimmune cell inltration.

Studies in mouse models of acute gastroen-teritis suggest that microbial richness may be

markedly diminished in the gastrointestinaltract during episodes of disease, and such a com-promisedmicrobiomemay enhance disease sus-ceptibility and pathogenesis. Reduced diversitymaymean that specic components that protectthe host from pathogenic invaders are absent.In amousemodel of hemorrhagic colitis arisingfrom Escherichia coli 0157:H7, bidobacterialspecies protect the host by providing genes thatencode specic ATP-binding cassette-typecarbohydrate transporters (62). Protection bybidobacteria appears to be mediated, at leastin part, by the production of acetate and byacetates ability to inhibit Shiga toxin translo-cation across the intestinal epithelium. Thecommensal bacteria in the intestine may inhibitthe ability of toxins and virulence factors topenetrate themucosa, thereby preventing acuteinfection and leading to mucosal pathology.

Antimicrobial therapy, especially specicclasses of agents such as -lactams and uoro-quinolones, predisposes subsets of patients toantibiotic-associated diarrhea and colitis due tospecic pathogens. Treatment with antibiotics,including single-agent therapy, may yield pro-found effects on the composition and functionof the gastrointestinal microbiome. A ve-daycourse with a single uoroquinolone resulted inthe eliminationor suppressionof approximatelyone-third of the fecal microbiome within threeto four days of antibiotic treatment (11). Gutmicrobial populations mostly recovered withinone week of completion of a course of antibi-otics, but the recovery of the microbiome wasincomplete (15). Similarly, diminished bacterialdiversity in the respiratory tract due to antimi-crobial therapy was associated with ventilator-associated pneumonia during the treatmentcourse (63). Antimicrobial-associated disor-ders, part of a new class of disorders ofmicrobialecology, result from the short- and long-termimpact of antibiotics on the composition andfunction of the human microbiome.

Toxigenic C. difcile is the primary etiologicagent of antimicrobial-associated diarrhea(AAD), and it accounts for an estimated15%25% of cases. Other clostridial etiologiesinclude enterotoxin-producing strains of


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Dysbiosis: loss ofbalance within ananimal-associatedmicrobial community

C. perfringens and possibly C. spiroforme,a species known to cause disease in rabbits,which inhabits the human gastrointestinal tract.Enterotoxin-producing strains of Staphylococcusaureus have been implicated as another possiblemicrobial etiology of AAD (64). Clearly, per-turbations of the gastrointestinal microbiotacreate opportunities for multiple bacterialspecies to proliferate and cause disease. Diseasemay be secondary to production of sufcientamounts of toxin such that a threshold is passed,resulting in symptomatic diarrheal illness. Re-duced diversity of the intestinal microbiome isassociated with recurrent C. difcileassociateddisease in adults (65). Patients with restrictedphylogenetic diversity appear to be predis-posed to recurrent disease, which supports therole of the intestinal microbiome as a protec-tive barrier to colonic infection. Sufcientlydiverse microbial communities are presumablyable to effectively suppress the proliferationof pathogens and subsequent production ofenterotoxins by pathogens such as toxigenicC. difcile in the intestine.

Healthy Healthy

Ulcerative colitis Ulcerative colitis

P value: 0.031

Crohn's diseaseCrohn's disease

PC2

PC1

Figure 4Inammatory bowel disease states are correlated with microbiomecomposition. Principal components analysis of bacterial species representing1% of the microbiome of fecal samples from healthy subjects (n = 14),patients with ulcerative colitis (21 subjects) or Crohns disease (4 subjects). Firstcomponents 1 and 2 (PC1 and PC2) are plotted on the x and y axes,respectively. Figure reproduced from Reference 75.

Fecal transplantation is a microbiome-based strategy to restore microbial balanceand species richness in patients with recurrentC. difcile disease (66, 67). Greater phylo-genetic diversity is associated with reducedrisk of C. difcileassociated disease, and fecaltransplantation via colonoscopy demonstratedthat diverse donor microbial communities cansupplant disease-associated microbiomes (68).Such introduction of phylogenetic diversity ina diseased human individual is associated withclinical recovery and amelioration of symp-toms. Instead of microbiome transplantation,the simultaneous addition of specic benecialmicrobes to treatment regimens offers new op-portunities to promote microbial diversity andresilience of the host. A series of systematic re-views reported evidence recommending probi-otic preparations to treat C. difcileassociateddiarrhea in children or adults (69) or to preventantibiotic-associated diarrhea in children (70).

Inflammatory Bowel Disease

Inammatory bowel disease (IBD), includingCrohn disease and ulcerative colitis, probablyhas multifactorial etiologies including humangene- andmicrobiome-associated components.Mutations in human genes such as NOD2 af-fect the recognition of microbial patterns orsignals, and NOD2 alleles are associated withCrohn disease in a subset of individuals (7173). In addition to human genetic defects, mi-crobial dysbiosis has been implicated in inam-matory bowel disease (74). In one study, a setof 155 bacterial species of the fecal microbiomeseparately clustered patients with Crohn dis-ease, patientswith ulcerative colitis, and healthycontrols into different groups by principal com-ponents analysis (Figure 4) (75); a prior studyhad shown that patients with IBD can be effec-tively distinguished from healthy controls onthe basis of qualitative interpretation of globalmicrobiome data (76). The segregation of pa-tient populations according to bacterial DNAsequences in the human microbiome withouthuman DNA-sequence information highlightsthe potential importance of metagenomics in


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human pathology. In addition to differencesbetween patients with IBD and healthy indi-viduals, different disease phenotypes of Crohndisease are associated with differences in gutbacterial populations (77). Human metage-nomics may lead to new diagnostic strategiesthat will rene disease stratication in combi-nation with histopathologic assessment of IBD.

The bacterium Faecalibacterium prausnitziiis a member of the C. leptum group commonlyfound in the fecal microbiomes of healthy adultindividuals (78), and deciency of F. prausnitziiappears to be relatively specic for ileal Crohndisease (79). Deciencies of F. prausnitziiare associated with increased frequency inendoscopic recurrence of active Crohn diseasein adult patients (80). Intraperitoneal injectionof soluble components of F. prausnitzii intomice subsequently exposed to trinitrobenzene

a

b

a

b

100 m100 m

Figure 5Bacterial abundance correlates with the severity ofappendicitis, as demonstrated by uorescence in situhybridization. (a) Fusobacterium necrophorum and(b) F. nucleatum associated with suppurativeappendicitis. Figure reproduced from Reference 83.

sulfonate, a chemical agent that induces a lethalacute colitis, protected mice from intestinalinjury and mortality. The protective effects invivo were associated with anti-inammatoryactivities through the use of human intestinalepithelial cell culture models, and they appearto be due to small, unidentied organiccompounds, or immunomodulins, producedby gut bacteria. Deciencies of Firmicutessuch as F. prausnitzii may determine suscepti-bility to Crohn disease (81) and suggest newdirections for microbiome-targeted therapies(82). Interestingly, intraperitoneal inoculationof this organism is associated with remoteeffects such as the modulation of eight ormore metabolites in the urinary compartmentalone. The presence of F. prausnitzii in hu-mans causes the modulation of eight urinarymetabolites of diverse structure and stressesthe potential multicompartment effects of gutbacteria (82). In terms of diagnostic utility,bacterial features such as the amounts ofF. prausnitzii in fecal specimens have been usedto diagnose active Crohn disease and ulcerativecolitis (81). The presence of F. prausnitzii andother commensals in fecal specimens is alsoinversely correlated with appendicitis, whichindicates that certain bacteria may suppressinammation in susceptible individuals (83). Inthe same study, the presence of Fusobacteriumspp. correlated positively with the severity ofappendicitis, and the bacteria were visualizedin cecal biopsy specimens by uorescence insitu hybridization (Figure 5) (83).

Patients with IBD and other diseases ofthe intestine may undergo surgical proceduresto address refractory disease phenotypes.Patients who have undergone small-boweltransplantation and postsurgical ileostomyprocedures undergo dramatic transformationsof the human microbiome, and such changes incomposition within the ileal uid are associatedwith environmental factors such as oxygen con-centration (84). The local ambient atmospheremay affect the ileal uid directly, allowingfacultative anaerobes to dominate the intesti-nal microbiota. Obligate anaerobes of theClostridium and Bacteroides genera have been


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detected in ileal samples immediately followingileostomy closure, which suggests that restora-tion of anaerobiosis in the intestine follows thisprocedure. Restoration of the microbiome mayrepresent an important component of futureimprovements in intestinal rehabilitation andtransplantation outcomes following abdominalsurgery.

Recurrent Abdominal Pain andIrritable Bowel Syndrome

Recurrent abdominal pain (RAP) is widelyprevalent in children and adults and accountsfor approximately 30% of health care visits forchildren aged 416 years (85). RAP includestwo primary disorders known as functionalabdominal pain (pain only) and irritablebowel syndrome (IBS; pain plus diarrhea orconstipation). Clinical trials with probiotics,or benecial bacteria, in adults and childrenprovided evidence that microbial dysbiosissomehow contributes to the disease phenotypeof chronic abdominal pain and that differencesin gut microbial communities may contributeto differences in pain signaling and nociception(86). In another study (87), germ-free micedemonstrated increased motor activity andreduced anxiety early in life, and these changesin behavior were correlated with changes ingene expression in the brain. These studiesindicate that the gut microbiome inuencesearly brain development in mice with effectson mammalian behavior (87) and that theaddition of lactobacilli may affect visceral painsensitivity in rodents (88). Fluctuations in thegut microbiome may affect pain signaling inthe enteric nervous system and visceral painperception.

In addition to differences in the gut micro-biomes of patients with IBS, subtypes of IBSmay also be distinguished by differences in gutmicrobiome composition. IBS with diarrhea isassociated with reductions in Lactobacillus spp.,and IBS with constipation is associated withelevated abundance of Veillonella spp. (89). Aseparate study also found increased abundance

ofVeillonella spp. in adult patients with IBS, andthis difference was associated with increasedproduction of acetate and propionate in theseindividuals (90). The rst 16S metagenomicsstudy of adults with IBS documented en-richment of the phyla Proteobacteria andFirmicutes (especially Lachnospiraceae) inthese patients (91). Published results withProteobacteria, especially -Proteobacteria,are consistent with our own ndings (91a),demonstrating greater proportions of thesebacteria in children with IBS. Specic bacteria,notably taxa of the genus Alistipes, are moreabundant in the gut microbiomes of childrenwith moderate-to-severe abdominal pain (91a).Patients who had IBS with diarrhea yieldeddiminished quantities of the genera Bacteroidesand Bidobacterium (91). The latter ndingis intriguing because Bidobacterium species,and not Lactobacillus species, were effectivein diminishing the symptoms of IBS in oneclinical trial (92). Differences in the intestinalmicrobiome may be exploited to rene strate-gies for microbial manipulation therapies andnutritional management of patients with RAP.Metagenomics-based diagnostic tests may bedeveloped to rene the ability of the patholo-gist and gastroenterologist to dene subtypesof IBS that can be effectively managed.

VAGINAL AND URETHRALMICROBIOMES: DISEASEIMPLICATIONS

The vaginal microbiome in women has im-plications for pregnancy and preterm birth,sexually transmitted diseases (STDs), andconditions such as vaginitis and BV. Inhealthy women of reproductive age, the genusLactobacillus predominates; it includes speciessuch as L. iners, L. crispatus, L. gasseri, and L.jensenii (93). Although these four Lactobacillusspecies dominate the composition of the vagi-nal microbiome, the relative proportions of dif-ferent bacterial species vary with ethnicity andvaginal pH. Interestingly, one group of womenhad a phylogenetically diversemicrobiomewith


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different anaerobic bacteria and a relative de-ciency of lactobacilli (93), and women withdifferent vaginal microbiomes may differ withrespect to predisposition to STDs or BV. Tounderstand how maternal microbiomes inu-ence neonatalmicrobiomes, a vertical transmis-sion study described the phenomenon in whichthe composition of oral and gut microbiomesin neonates depends on the mode of delivery atbirth. Infants delivered vaginally acquire bacte-rial communities in their skin, oral cavity, andnares that resemble their mothers vaginal mi-crobiota, dominated by Lactobacillus, Prevotella,and Sneathia spp. (94). Infants delivered by Ce-sarean section harbor microbial communitiessimilar to those found on human skin, dom-inated by Staphylococcus, Corynebacterium, andPropionibacterium spp.Howbabies are bornmaypartly determine the composition of bacterialcommunities in different body habitats early inlife, and these differencesmayhave implicationsfor early susceptibility to disease (e.g., sepsis,necrotizing enterocolitis).

In contrast to studies implicating reduc-tions of microbial diversity associated withdifferent disease states (e.g., disorders of thegastrointestinal tract), studies of BV suggestthat increased bacterial diversity may be asso-ciated with disease. As in the esophagus, bodysites with restricted microbial diversity in thehealthy state may not tolerate increased micro-bial diversity without adverse consequences.Through the use of next-generation sequencingin a population of Chinese women, increasedphylogenetic diversity and the presence ofmany low-abundance bacterial taxa have beenassociated with BV (Figure 6) (95). This studywas consistent with prior publications (96) indi-cating that increased bacterial species richnessand diversity correlate with the disease pheno-type ofBV.L. iners is the predominant species inBV-negative women but is markedly reduced inBV-positive women (95). Genera such asGard-nerella, Sneathia, and Megasphaera have beendetected at higher prevalence and relativelygreater abundance in BV-positive women.Next-generationDNApyrosequencing found a

number of low-abundance bacterial genera thathad not previously been detected, and particu-lar species may be useful microbial biomarkersfor disease. The genus Atopobium is present in84% of women diagnosed with BV, in contrastto 22% of women in the control group. Theabsence or relative deciency of indigenous,nonpathogenic lactobacilli in the vagina maypredispose women to recurrent urinary tractinfections (97), and urinary tract pathogensmay displace indigenous lactobacilli by theproduction of natural antibiotics such as bacte-riocins (98). Dysbiosis of the vagina apparentlypredisposes women to various disorders, suchas BV, and recurrent infections. More recent16Smetagenomics data of vaginal microbiomesindicate that the microbial composition of thevagina fundamentally differs between pregnantand nonpregnant women (K. Aagaard, K.Riehle, T.A. Mistretta, J. Ma, C. Coarfa, C.Huttenhower, D. Gevers, S. Rosenbaum, I.Van den Veyver, A. Milosavljevic, J. Petrosino& J. Versalovic, manuscript submitted). Suchdifferences may yield insights into the vagi-nal microbiome, predisposition to pretermbirth, and susceptibility to infections inpregnancy.

The urethra and surrounding skin serve asprimary sites for genitourinary tractassociatedmicrobial communities in men. The male uri-nary microbiome differs between men withoutevidence of infection and men with evidenceof asymptomatic sexually transmitted infection(STI) (99). Men with STIs caused by thebacteria Chlamydia, Neisseria, Mycoplasma, orUreaplasma have urinary microbiomes withdiverse, fastidious, and uncultured bacteria thatare rare in STI-negative men. Phylogeneticclustering methods such as Unifrac clearlyseparated STI-positive and STI-negative menon the basis of principal components analysis.Uncultured bacteria associated with pathologyof the female genital tract are abundant inurine specimens of STI-positivemen, and thesendings suggest that the male urethra containspathogenic bacteria that cause infections wheninoculated into the female vagina.


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Other BV-positive genera identified (relative abundance < 0.25%)OlsenellaArcanobacteriumSlackiaMobiluncusBifidobacteriumCryptobacteriumMicromonosporaTessaracoccusCorynebacteriumCouchioplanesOkibacteriumPropioniferaxBacteroides

PorphyromonasTannerellaKaistellaOwenweeksiaFluviicolaXylanibacterCrocinitomixFlavobacteriumFlectobacillusMariniflexilePersicivirgaCapnocytophagaCloacibacterium

DysgonomonasWinogradskyellaPeptoniphilusPseudobutyrivibrioLachnospiraceae

genera incertae sedis

AlloiococcusVeillonellaAnaerococcusCoprococcusSubdoligranulumAnaeroglobus

FastidiosipilaTuricibacterAbiotrophiaMoryellaPediococcusPropionispiraBulleidiaCatonellaButyrivibrioGracilibacterLactovumParalactobacillusPelospora

MitsuokellaPaucisalibacillusRoseburiaSporobacterAcetivibrioAcidaminococcusDolosigranulumFinegoldiaGranulicatellaCaloranaerobacterCerasibacillusDesulfonisporaEremococcus

IsobaculumMarinilactibacillusAnaerobacterAnaerobaculumBrevibacillusFaecalibacteriumLachnobacteriumAtopococcusAtopostipesTwo Clostridiaceae


Ignavigranum

SporacetigeniumStaphylococcusTissierellaUreibacillusVagococcusPropionigeniumStreptobacillusCetobacteriumLeptotrichiaAcinetobacterUreaplasmaTM7 genera

incertae sedis

CaldilineaCycloclasticusHaemophilusSutterellaSerratiaCampylobacterErythrobacterNeisseriaComamonasHylemonellaSphingomonasSphingopyxis

EggerthellaOlsenellaArcanobacteriumSlackiaMobiluncusBifidobacteriumCryptobacteriumMicromonosporaTessaracoccusCorynebacteriumCouchioplanesOkibacteriumPropioniferaxPrevotellaHallella

BacteroidesPorphyromonasTannerellaKaistellaOwenweeksiaFluviicolaXylanibacterCrocinitomixFlavobacteriumFlectobacillusMariniflexilePersicivirgaCapnocytophagaCloacibacteriumDysgonomonas

WinogradskyellaShuttleworthiaMegasphaeraPapillibacterStreptococcusDialisterGemellaAerococcusParvimonasPeptostreptococcusPeptoniphilusPseudobutyrivibrioLachnospiraceae


VeillonellaAnaerococcusCoprococcusSubdoligranulumAnaeroglobusFastidiosipilaTuricibacterAbiotrophiaMoryellaPediococcusPropionispiraBulleidiaCatonellaButyrivibrioGracilibacter

LactovumParalactobacillusPelosporaMitsuokellaPaucisalibacillusRoseburiaSporobacterAcetivibrioAcidaminococcusDolosigranulumFinegoldiaGranulicatellaCaloranaerobacterCerasibacillusDesulfonispora

EremococcusIsobaculumMarinilactibacillusAnaerobacterAnaerobaculumBrevibacillusFaecalibacteriumLachnobacteriumAtopococcusAtopostipesTwo Clostridiaceae


IgnavigranumSporacetigenium

StaphylococcusTissierellaUreibacillusVagococcusSneathiaFusobacteriumPropionigeniumStreptobacillusCetobacteriumLeptotrichiaAcinetobacterMycoplasmaUreaplasmaTM7 genera

incertae sedis

CaldilineaCycloclasticusHaemophilusSutterellaSerratiaCampylobacterErythrobacterNeisseriaComamonasHylemonellaSphingomonasSphingopyxis

GardnerellaAtopobiumEggerthellaPrevotellaHallellaLactobacillusShuttleworthiaMegasphaeraPapillibacterStreptococcusDialisterGemellaAerococcusParvimonasPeptostreptococcusAlloiococcusSneathiaFusobacteriumMycoplasma

BV positive

BV negative

Other BV-negative genera identified (relative abundance < 0.25%)


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SKIN MICROBIOME ANDDERMATOLOGIC DISEASES

Many factors, including climate, occupation,and hygiene, shape the human skin micro-biome, and intrinsic factors such as physiology,genotype, or disease state (100) and skinmicrobiomes provide unique informationabout individuals that may be used in forensicpathology (101). Themicrobiota of the skin arecharacterized by the same four predominantphyla as in other body sites: Actinobacteria,Firmicutes, Proteobacteria, and Bacteroidetes(4, 102, 103). However, the relative distri-butions of bacterial phyla and families differsignicantly among skin sites throughout thehuman body (103, 104). Human skin at differ-ent body sites varies in terms of temperature,humidity, glandular distribution, and envi-ronmental exposure (103). Areas of the bodythat are enriched with sebaceous glands haveprominent populations of Actinobacteria (e.g.,Corynebacterineae, Propionbacterineae), incontrast to relatively dry areas, such as the volarforearm, that are enriched for Proteobacteria.Despite bacterial diversity at different sites,human skinassociated microbial compositionis more similar between skin sites than amongother body habitats (103). Interestingly, whenbacteria characteristic of the tongue or fore-arm were transplanted to the forehead, thecharacteristic forehead bacteria were able tooutcompete the bacteria from the tongue orforearm (4), which highlights the importanceof the biology of the body habitat in shapingthe composition and function of microbiomes.Even when the skin surface is compromised, asin a diabetic wound, bacterial populations onthe skin may have a profound impact on theability of wounds to heal, and they reepithelial-

ize the skin surface by unknown mechanisms(105).

Skin colonization by pathogens such asS. aureus is a prerequisite for subsequentS. aureus infection of the skin and other bodysites. The nasal microbiome contains S. aureusin approximately 50% of the adult population,and the composition of the microbiome maypredispose individuals to bacterial infections(106). The nasal microbiomes of hospital-ized patients are decient in Actinobacteria,especially Propionibacterium acnes, and thesebacterial deciencies are inversely correlatedwith the relative abundance of staphylococcalspecies in inpatients (106). Persistent infectionshave been associated with changes in the skinmicrobiota, such as diminished abundance ofthe genus Propionibacterium and the phylumActinobacteria (106). Additionally, the relativeabundance of S. aureus is inversely corre-lated with the abundance of the commensalS. epidermidis. These shifts or differences inmicrobiomes at skin surfaces may yield im-portant prognostic information related to riskof infection in vulnerable patient populations.S. epidermidis is a common skin commensalthat can participate in remodeling microbialcommunities by production of antibacterialpeptides (107).Relative distributions of bacteriamay have implications for the relative abun-dance of drug-resistant bacteria. Nasal carriageof methicillin-resistant S. aureus (MRSA) hasbeen associated with MRSA infection, andthe relative preponderance of drug-resistantbacteria may depend on skin microbiomecomposition.

Dermatologic disorders are beginning to belinked to changes in the skin microbiome. Inaddition to infections of the skin and otherbody sites, the presence of S. aureus has been

Figure 6Bacterial vaginosis (BV) is associated with a different and more complex vaginal microbiome. This gure depicts the relative abundanceof bacteria identied by 16S ribosomal RNA from vaginal swabs of 50 healthy (BV-negative) subjects and 50 BV-positive subjects.Figure reproduced from Reference 95.


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associated with persistent dermatologic disor-ders such as atopic dermatitis (107). However,more information is needed to determine therelative contribution of S. aureus versus otherbacteria in triggering atopic dermatitis. Fluctu-ations in skin bacterial populations have beenassociated with psoriasis, a chronic inamma-tory disorder that may be induced by pathogenssuch as S. aureus and S. pyogenes (102). Targetedpolymerase chain reaction strategies highlightdifferences in the distribution of specic bacte-rial genera at skin sites, and these approachesmay be useful for monitoring disease progres-sion and the management of psoriasis (102). Inaddition to changes in bacterial communities,differences in fungal communities may con-tribute to skin disorders such as seborrheic der-matitis and tinea versicolor. The fungal genusMalassezia is the most widely prevalent fungaltaxon on human skin, andMalassezia species aredifferentially distributed (108, 109).Knowledgeregarding uctuations of specic yeasts may beuseful for disease prevention and managementin dermatology.

POTENTIAL MECHANISMS

The human microbiome has emerged as a corecomponent of human systems biology and ge-nomics, and serious consideration of differencesand uctuations in the human microbiomewill be important for one to fully understandbasic mechanisms of human pathology. Globalfeatures such as excessive bacterial numbers ordiversity at specic body sites may contributeto inammation and pathologic host responses.Conversely, reduced richness of bacteria atbody sites such as the intestine may diminishthe ability of individuals to resist infection,assimilate nutrients, or maintain aggregatefunction of a healthy microbiome. In additionto these global features, specic differencesor uctuations of bacterial species may causeenhanced predisposition to disease. The com-binations of human genotypes and microbiometypes (e.g., enterotypes) may cause increased

predisposition to disease and increased riskof recurrent chronic diseases. The site ofpathology may depend partly on the nature ofmicrobiomes at specic body sites when com-bined with local patterns of gene expressionand epigenomics. The presence or relativeabundance of specic bacteria may protectindividuals from disease phenotypes throughthe production of signals or compounds thatcounteract abnormalities of human physiol-ogy. The timing and spatial development ofmicrobiomes early in life may have lastingconsequences on differentiation and matu-ration of different mucosal surfaces, organs,and tissues. In addition to local effects, micro-biomes contribute to whole-body metabolismand may have remote effects on humanphysiology.

Once the specic composition of the mi-crobial community and interactions within themicrobiota are identied, this information canbe utilized to manipulate microbial communi-ties either by antibiotics, diet, or applicationsof specic biologicals or by supplementationwith natural or engineeredmicrobes (Figure 7)(110). By performing microbial manipulationwith antibiotics, probiotics, or dietary inter-ventions, microbiomes may be shifted or re-modeled such that these microbial communi-ties could help tilt the balance from a diseasedstate to a healthy state (Figure 8).

SUMMARY AND FUTUREDIRECTIONS

The conceptual framework of human diseasemust accommodate the composition andfunction of human-associated microbiomes.Differences among and uctuations in humanmicrobiomes in various body habitats will pro-vide key insights into mechanisms of disease,and such ndings will result in next-generationdiagnostics and therapeutics. Prior to devel-oping applications in human medicine, inves-tigators must acquire more mechanistic infor-mation regarding the biology of the humanmicrobiome and its relevance to pathology.


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a Healthy microbiota c Treatment of dysbiosis

b Dysbiotic (diseased) microbiota

Diagnosis

400 450

m/z

500

M U C U S

I N T E S T I N E

L U M E NMutualisticmicrobes

Dietaryglycans

Probiotic Engineeredmicrobe

Microbiota-targeteddrug

Prebiotic

Pathogen

Figure 7Microbial manipulation and treatment of dysbiosis. Differences found between (a) healthy and (b) diseased microbiota may lead tofactors that can be exploited (c) to treat dysbiosis. Figure reproduced from Reference 110.

Specic microbes or bacterial species dis-tributions are still being dened in healthycohorts and compared with those of patientswith various disease phenotypes. A paucity ofmechanisms, coupled with many intriguingndings, highlights the urgency of this eldof biomedical research. Recent publicationssuggest that identication of specic microbesmay be a sensitive barometer of temporaluctuations in human disease because thevariation in microorganisms vastly exceeds the

extent of variation in known metabolic genesand pathways. For applications such as forensicpathology, 16S metagenomics or organismidentication may be more useful. By contrast,functional and WGS metagenomics, with afocus on specic pathways and mechanismsof disease, will probably be a more robustapproach for most diagnostic and therapeuticapplications.

Applications of metagenomics may includethe incorporation of microbial sequencing data


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Metagenome alteration

Metabonomealteration

Diseased state Healthy statePrebiotics regulation

Probiotics regulation

Antibiotics regulation

2

1

0

1

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Figure 8Restoring the metabonome to a healthy state by microbial manipulation. Alterations of the composition ofthe microbiota and subsequent metabonomic prole by microbial manipulation with antibiotics, probiotics,or nutritional interventions that may include prebiotics. Figure reproduced from Reference 116.

in the diagnostic workup of chronic immune-mediated and inammatory diseases thatpreviously relied only on histopathologic or im-munologic assessment. In addition to microbialDNA and RNA targets, microbial biomarkerssuch as proteins and metabolites may emergeas useful diagnostic features and indicators ofdisease progression versus successful diseasemanagement. For some disorders, convenientspecimens such as oral or skin swabs andself-collected stool may be sufcient to providerelevant information in the diagnostic labora-tory. In other cases, deeper body sampling suchas endoscopy or surgery may be required toobtain specimens with the requisite microbialgenes and biologics for clinical evaluation.The remote effects of microbiomes in distantor multiple body compartments must alsobe considered in future investigations andapplications of human microbiome research.

The remote effects of the human micro-biome may be especially important whenconsidering the prognosis and managementof systemic disorders. For example, metabo-nomics of urinary specimens may yield a robustsignal-to-noise ratio when exploring distanteffects of the gut microbiome on whole-bodymetabolism.

In addition to development of new diagnos-tic strategies, next-generation probiotics andmicrobe-derived biotherapeutics based on ad-vances in compositional and functionalmetage-nomics may be important for future manage-ment of gastrointestinal, skin, oral, and otherdisorders. Intentional manipulation of the hu-man microbiome may facilitate the recovery ofpatients by effects on diverse physiologic pa-rameters such as pain signaling, systemic im-mune responses, energy harvest, and whole-body metabolism.


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SUMMARY POINTS

1. The human microbiome is an integral component of the human body.

2. The human microbiome represents a plastic metagenome that varies according to bodysite, environmental exposure, and health status within and between individuals.

3. Pathologic alterations, or dysbioses, of site-specic bacterial communities can shift mi-crobiomes from healthy states to disease-associated states.

4. Bacteria produce signals and compounds that affect local microbial populations and localtissue compartments.

5. Human-associated bacterial communities may affect multiple remote body compart-ments and may yield systemic effects on energy harvest, immunity, and whole-bodymetabolism.

6. Increased diversity of the microbiome may be associated with disease at body sites thatnormally have restricted diversity. Conversely, reduced diversity of the microbiome maybe associated with disease at body sites with greater indices of diversity.

7. Microbial manipulation strategies, including human nutrition, antibiotics, and microbialsupplementation (probiotics), may provide new strategies for disease management andprevention.

FUTURE ISSUES

1. A greater understanding of the signaling mechanisms of the human microbiome, includ-ing intra- and interkingdom interactions, may result in a rened approach to humansystems biology.

2. Explorations of global features of the microbiome, such as richness, evenness, diversity,and how they inuence disease predisposition, may be useful for disease management.

3. Investigations of specic features anddiscriminant taxa of themicrobiomeprovide oppor-tunities for important discoveries of microbial genes and microorganisms. Such classesof microbes may affect diagnosis and treatment strategies.

4. Metagenomics and an improved understanding of the dynamism of microbiomes at dif-ferent body sites can be translated into rational manipulations by diet, probiotics, andnew drug combinations.

DISCLOSURE STATEMENT

The authors are not aware of any afliations, memberships, funding, or nancial holdings thatmight be perceived as affecting the objectivity of this review.

LITERATURE CITED

1. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, et al. 2006. Metagenomic analysis of thehuman distal gut microbiome. Science 312:135559

2. Peterson J, Garges S, Giovanni M, McInnes P, Wang L, et al. 2009. The NIH Human MicrobiomeProject. Genome Res. 19:231723


Ann

u. R

ev. P

atho

l. M

ech.

Dis.

201

2.7:

99-1

22. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

Uni

vers

ity o

f Upp

sala

on

03/0

9/15

. For

per

sona

l use

onl

y.


3. Blaser MJ, Falkow S. 2009. What are the consequences of the disappearing human microbiota? Nat.Rev. Microbiol. 7:88794

4. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. 2009. Bacterial communityvariation in human body habitats across space and time. Science 326:169497

5. Lozupone CA, Knight R. 2008. Species divergence and the measurement of microbial diversity. FEMSMicrobiol. Rev. 32:55778

6. Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, et al. 2010. Viruses in the faecal microbiota ofmonozygotic twins and their mothers. Nature 466:33438

7. Dethlefsen L, McFall-Ngai M, Relman DA. 2007. An ecological and evolutionary perspective onhuman-microbe mutualism and disease. Nature 449:81118

8. Grice EA, Kong HH, Renaud G, Young AC, Bouffard GG, et al. 2008. A diversity prole of the humanskin microbiota. Genome Res. 18:104350

9. Reid G, Younes JA, Van derMei HC, Gloor GB, Knight R, Busscher HJ. 2011.Microbiota restoration:natural and supplemented recovery of human microbial communities. Nat. Rev. Microbiol. 9:2738

10. Spor A, Koren O, Ley R. 2011. Unravelling the effects of the environment and host genotype on thegut microbiome. Nat. Rev. Microbiol. 9:27990

11. Dethlefsen L, Huse S, Sogin ML, Relman DA. 2008. The pervasive effects of an antibiotic on thehuman gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6:e280

12. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. 2007. Development of the human infantintestinal microbiota. PLoS Biol. 5:e177

13. Eggesbo M, Moen B, Peddada S, Baird D, Rugtveit J, et al. 2011. Development of gut microbiota ininfants not exposed to medical interventions. Acta Pathol. Microbiol. Immunol. Scand. 119:1735

14. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, et al. 2010. Impact of diet in shapinggut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl.Acad. Sci. USA 107:1469196

15. Dethlefsen L, Relman DA. 2010. Microbes and Health Sackler Colloquium: incomplete recovery andindividualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc.Natl. Acad. Sci. USA 108:455461

16. Proal AD, Albert PJ, Marshall T. 2009. Auto. disease in the era of the metagenome. Autoimmun. Rev.8:67781

17. Hanin A, Sava I, Bao Y, Huebner J, Hartke A, et al. 2010. Screening of in vivo activated genes inEnterococcus faecalis during insect and mouse infections and growth in urine. PLoS ONE 5:e11879

18. Kolenbrander PE, Palmer RJ Jr, Periasamy S, Jakubovics NS. 2010. Oral multispecies biolm devel-opment and the key role of cell-cell distance. Nat. Rev. Microbiol. 8:47180

19. Petrosino JF, Highlander S, Luna RA, Gibbs RA, Versalovic J. 2009. Metagenomic pyrosequencingand microbial identication. Clin. Chem. 55:85666

20. NelsonKE,WeinstockGM,Highlander SK,WorleyKC,CreasyHH, et al. 2010. A catalog of referencegenomes from the human microbiome. Science 328:99499

21. Bassler BL, Losick R. 2006. Bacterially speaking. Cell 125:2374622. AndreyDO,Renzoni A,MonodA, LewDP,CheungAL,KelleyWL. 2010.Control of the Staphylococcus

aureus toxic shock tst promoter by the global regulator SarA. J. Bacteriol. 192:60778523. Lupp C, Ruby EG. 2005. Vibrio scheri uses two quorum-sensing systems for the regulation of early

and late colonization factors. J. Bacteriol. 187:36202924. Laughton JM, Devillard E, Heinrichs DE, Reid G, McCormick JK. 2006. Inhibition of expression

of a staphylococcal superantigen-like protein by a soluble factor from Lactobacillus reuteri. Microbiology152:115567

25. Li J, Wang W, Xu SX, Magarvey NA, McCormick JK. 2011. Lactobacillus reuteriproduced cyclicdipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proc.Natl. Acad. Sci. USA 108:336065

26. Medellin-Pena MJ, Wang H, Johnson R, Anand S, Grifths MW. 2007. Probiotics affect virulence-related gene expression in Escherichia coli O157:H7. Appl. Environ. Microbiol. 73:425967

27. Goodman AL, McNulty NP, Zhao Y, Leip D, Mitra RD, et al. 2009. Identifying genetic determinantsneeded to establish a human gut symbiont in its habitat. Cell Host Microbe 6:27989


Ann

u. R

ev. P

atho

l. M

ech.

Dis.

201

2.7:

99-1

22. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

Uni

vers

ity o

f Upp

sala

on

03/0

9/15

. For

per

sona

l use

onl

y.


28. Lebeer S, Vanderleyden J, De Keersmaecker SC. 2008. Genes and molecules of lactobacilli supportingprobiotic action. Microbiol. Mol. Biol. Rev. 72:72864

29. Strozzi GP, Mogna L. 2008. Quantication of folic acid in human feces after administration of Bi-dobacterium probiotic strains. J. Clin. Gastroenterol. 42(Suppl. 3):17984

30. van Reenen CA, Dicks LM. 2011. Horizontal gene transfer amongst probiotic lactic acid bacteria andother intestinal microbiota: What are the possibilities? A review. Arch. Microbiol. 193:15768

31. Hord NG. 2008. Eukaryotic-microbiota cross talk: potential mechanisms for health benets of prebi-otics and probiotics. Annu. Rev. Nutr. 28:21531

32. Kelly BG, Vespermann A, Bolton DJ. 2009. Horizontal gene transfer of virulence determinants inselected bacterial foodborne pathogens. Food Chem. Toxicol. 47:96977

33. Sommer MO, Church GM, Dantas G. 2010. The human microbiome harbors a diverse reservoir ofantibiotic resistance genes. Virulence 1:299303

34. Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G. 2010. Transfer ofcarbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464:90812

35. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. 2005. Dening the normal bacterial ora of theoral cavity. J. Clin. Microbiol. 43:572132

36. Lazarevic V, Whiteson K, Hernandez D, Francois P, Schrenzel J. 2010. Study of inter- and intra-individual variations in the salivary microbiota. BMC Genomics 11:523

37. Zaura E, Keijser BJ, Huse SM, Crielaard W. 2009. Dening the healthy core microbiome of oralmicrobial communities. BMC Microbiol. 9:259

38. Nasidze I, Li J, Quinque D, Tang K, Stoneking M. 2009. Global diversity in the human salivarymicrobiome. Genome Res. 19:63643

39. JenkinsonHF, Lamont RJ. 2005.Oralmicrobial communities in sickness and in health.TrendsMicrobiol.13:58995

40. Ling Z, Kong J, Jia P, Wei C, Wang Y, et al. 2010. Analysis of oral microbiota in children with dentalcaries by PCR-DGGE and barcoded pyrosequencing. Microb. Ecol. 60:67790

41. Kanasi E, Dewhirst FE, Chalmers NI, Kent R Jr,Moore A, et al. 2010. Clonal analysis of the microbiotaof severe early childhood caries. Caries Res. 44:48597

42. Marsh PD. 2003. Are dental diseases examples of ecological catastrophes? Microbiology 149:2799443. Colombo AV, Silva CM, Haffajee A, Colombo AP. 2006. Identication of oral bacteria associated with

crevicular epithelial cells from chronic periodontitis lesions. J. Med. Microbiol. 55:6091544. Mans JJ, von Lackum K, Dorsey C, Willis S, Wallet SM, et al. 2009. The degree of microbiome

complexity inuences the epithelial response to infection. BMC Genomics 10:38045. Handeld M, Mans JJ, Zheng G, Lopez MC, Mao S, et al. 2005. Distinct transcriptional proles

characterize oral epithelium-microbiota interactions. Cell Microbiol. 7:8112346. Hooper LV, Gordon JI. 2001. Commensal host-bacterial relationships in the gut. Science 292:11151847. Sonnenburg ED, Zheng H, Joglekar P, Higginbottom SK, Firbank SJ, et al. 2010. Specicity of

polysaccharide use in intestinal Bacteroides species determines diet-induced microbiota alterations.Cell 141:124152

48. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, et al. 2010. Metabolic syndromeand altered gut microbiota in mice lacking Toll-like receptor 5. Science 328:22831

49. Jumpertz R, Le DS, Turnbaugh PJ, Trinidad C, Bogardus C, et al. 2011. Energy-balance studies revealassociations between gut microbes, caloric load, and nutrient absorption in humans. Am. J. Clin. Nutr.94:5865

50. Backhed F,DingH,WangT,HooperLV,KohGY, et al. 2004.The gutmicrobiota as an environmentalfactor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101:1571823

51. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, et al. 2011. Enterotypes of the human gutmicrobiome. Nature 473:17480

52. ColladoMC, Isolauri E, Laitinen K, Salminen S. 2010. Effect of mothers weight on infants microbiotaacquisition, composition, and activity during early infancy: a prospective follow-up study initiated inearly pregnancy. Am. J. Clin. Nutr. 92:102330

53. Claus SP, Tsang TM, Wang Y, Cloarec O, Skordi E, et al. 2008. Systemic multicompartmental effectsof the gut microbiome on mouse metabolic phenotypes. Mol. Syst. Biol. 4:219


Ann

u. R

ev. P

atho

l. M

ech.

Dis.

201

2.7:

99-1

22. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

Uni

vers

ity o

f Upp

sala

on

03/0

9/15

. For

per

sona

l use

onl

y.


54. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, et al. 2011. Systemic gut microbial modulationof bile acid metabolism in host tissue compartments. Proc. Natl. Acad. Sci. USA 108(Suppl. 1):452330

55. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, et al. 2010. Gut microbiota inhuman adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 5:e9085

56. Sonnenburg JL, Xu J, Leip DD, Chen CH, Westover BP, et al. 2005. Glycan foraging in vivo by anintestine-adapted bacterial symbiont. Science 307:195559

57. Yang L, Lu X, Nossa CW, Francois F, Peek RM, Pei Z. 2009. Inammation and intestinal metaplasiaof the distal esophagus are associated with alterations in the microbiome. Gastroenterology 137:58897

58. Warren JR, Marshall BJ. 1983. Unidentied curved bacilli on gastric epithelium in active chronicgastritis. Lancet 1:127375

59. Versalovic J. 2003. Helicobacter pylori. Pathology and diagnostic strategies. Am. J. Clin. Pathol. 119:40312

60. Morowitz MJ, Denef VJ, Costello EK, Thomas BC, Poroyko V, et al. 2011. Strain-resolved commu-nity genomic analysis of gut microbial colonization in a premature infant. Proc. Natl. Acad. Sci. USA108:112833

61. Klein EJ, Boster DR, Stapp JR, Wells JG, Qin X, et al. 2006. Diarrhea etiology in a childrens hospitalemergency department: a prospective cohort study. Clin. Infect. Dis. 43:80713

62. Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y, et al. 2011. Bidobacteria can protect fromenteropathogenic infection through production of acetate. Nature 469:54347

63. Flanagan JL, Brodie EL, Weng L, Lynch SV, Garcia O, et al. 2007. Loss of bacterial diversity duringantibiotic treatment of intubated patients colonized with Pseudomonas aeruginosa. J. Clin. Microbiol.45:195462

64. Boyce JM, Havill NL. 2005. Nosocomial antibiotic-associated diarrhea associated with enterotoxin-producing strains of methicillin-resistant Staphylococcus aureus. Am. J. Gastroenterol. 100:182834

65. Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT, et al. 2008. Decreased diversity of thefecal microbiome in recurrent Clostridium difcileassociated diarrhea. J. Infect. Dis. 197:43538

66. Aas J,GessertCE, Bakken JS. 2003. RecurrentClostridium difcile colitis: case series involving 18 patientstreated with donor stool administered via a nasogastric tube. Clin. Infect. Dis. 36:58085

67. Yoon SS, Brandt LJ. 2010. Treatment of refractory/recurrent C. difcileassociated disease by donatedstool transplanted via colonoscopy: a case series of 12 patients. J. Clin. Gastroenterol. 44:56266

68. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. 2010. Changes in the composition of the humanfecal microbiome after bacteriotherapy for recurrent Clostridium difcileassociated diarrhea. J. Clin.Gastroenterol. 44:35460

69. Pillai A, Nelson R. 2008. Probiotics for treatment of Clostridium difcileassociated colitis in adults.Cochrane Database Syst. Rev. CD004611

70. JohnstonBC, SupinaAL,OspinaM,Vohra S. 2007. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst. Rev. CD004827

71. Hampe J,CuthbertA,CroucherPJ,MirzaMM,Mascheretti S, et al. 2001.Associationbetween insertionmutation in NOD2 gene and Crohns disease in German and British populations. Lancet 357:192528

72. Hugot JP, ChamaillardM, ZoualiH, Lesage S, Cezard JP, et al. 2001. Association ofNOD2 leucine-richrepeat variants with susceptibility to Crohns disease. Nature 411:599603

73. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, et al. 2001. A frameshift mutation in NOD2associated with susceptibility to Crohns disease. Nature 411:603606

74. Sartor RB. 2008. Microbial inuences in inammatory bowel diseases. Gastroenterology 134:5779475. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, et al. 2010. A human gut microbial gene catalogue

established by metagenomic sequencing. Nature 464:596576. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. 2007. Molecular-

phylogenetic characterization of microbial community imbalances in human inammatory bowel dis-eases. Proc. Natl. Acad. Sci. USA 104:1378085

77. Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, et al. 2010. A pyrosequencing study intwins shows that gastrointestinal microbial proles vary with inammatory bowel disease phenotypes.Gastroenterology 139:184454, e1841


Ann

u. R

ev. P

atho

l. M

ech.

Dis.

201

2.7:

99-1

22. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

Uni

vers

ity o

f Upp

sala

on

03/0

9/15

. For

per

sona

l use

onl

y.


78. Tap J,Mondot S, Levenez F, Pelletier E, CaronC, et al. 2009. Towards the human intestinal microbiotaphylogenetic core. Environ. Microbiol. 11:257484

79. Willing B, Halfvarson J, Dicksved J, Rosenquist M, Jarnerot G, et al. 2009. Twin studies reveal specicimbalances in the mucosa-associated microbiota of patients with ileal Crohns disease. Inamm. BowelDis. 15:65360

80. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, et al. 2008. Faecalibacteriumprausnitzii is an anti-inammatory commensal bacterium identied by gut microbiota analysis of Crohndisease patients. Proc. Natl. Acad. Sci. USA 105:1673136

81. Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y. 2008. Active Crohns disease and ul-cerative colitis can be specically diagnosed and monitored based on the biostructure of the fecal ora.Inamm. Bowel Dis. 14:14761

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