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Microbiota
Until recently, the properties of the microbiota of humans systems with strong phenotypes is essential for mak-
The microbial organisms that (formerly called the normal flora) were largely a black ing progress in this field of applied genetics. Although
constitute the microbiome. The box. Cultivation invitro, which has been the cornerstone a focus on bacteria is important, inquiries aimed at
composition of the microbiota of microbiology since the nineteenth century, cannot be archaea, viruses and retroviruses are alsoneeded.
in a community can vary
applied to many of the most densely populated micro- The purpose of this Review is to develop the theoreti-
substantially between
environmental sites, among bial communities1. However, DNA-based analyses have cal basis for investigating how microbiome composition
host niches and between expanded our horizon by generating enormous new data and function affect human health. We provide examples
health and disease. sets that can be mined for information on the composi- of applying this knowledge to better understand human
tion and functional properties of vastly greater numbers health, and we discuss how microbiome changes could
of microbial communities. For example, the Human alter hostmicrobiome interactions to mitigate disease.
Microbiome Project (HMP)2 by the US National Institutes We also consider the next steps in the development of
of Health has produced a 2.3 terabyte 16S ribosomal this field, particularly regarding the need to focus on the
RNA metagenomic data set of over 35 billion reads taken inheritance of the microbiome and on its involvement in
from 690 samples from 300 US subjects, across 15 body modulating complextraits.
sites. Large-scale endeavours (for example, the HMP
1
Department of Medicine, and also the European project, MetaHIT3) are already Characterizing the microbiome
NYU Langone Medical Center,
providing a preliminary understanding of the biol- Animals have had residential microbes carrying out met-
New York, New York 10016,
USA. ogy and medical significance of the human microbiome abolic functions for at least 500 million years, at a con-
2
New York Harbor and its collective genes (the metagenome). servative estimate6,7. Extensive congruent phylogenies of
Department of Veterans The aim of these projects, particularly the HMP, is animal hosts and their microbiota, involving both indi-
Affairs Medical Center to characterize the compositional range of the normal vidual organisms and whole microbial populations1,8,9,
(Manhattan), New York,
New York 10010, USA.
microbiome of healthy individuals. Important ques- suggest the existence of specific selection based on co-
3
Department of Microbiology, tions concerning the commonalities and differences adaptation. Cooperative interactions between microbes
NYU Langone Medical Center, among healthy individuals in both microbial taxa and and their hosts typically involve microbial participation
New York, New York 10016, functional pathways are being addressed. The presence in host functions such as defence, metabolism and repro-
USA.
of major clustering patterns at body sites such as the duction10. For example, comparing germ-free and normal
4
Department of Biology,
New York University, New vagina4 and the gastrointestinal tract 5 provide new ways mice indicates that microbiota are responsible for most
York, New York 10003, USA. to classify individuals and possibly their disease risks. of the metabolites that are detected in plasma11.
Correspondence to I.C. Substantial progress has been made in developing the Below we describe the efforts to categorize the com-
e-mail: tools for inquiry and in defining the overarching con- position and complex dynamics of our microbiota.
Ilseung.Cho@nyumc.org
doi:10.1038/nrg3182
cepts that advance the field. However, the subject is vast, Functional variation of host microbiota can be mediated
Published online and the implications for human health and disease are by the introduction or extinction of particular microbial
13 March 2012 wide-ranging. The study of humans and model animal groups or by a change in population structure1214. Such
Metagenome Among all mammals, the microbiota composition is generations per human generation, is omnivorous and
The genetic information of extensively conserved at high taxonomic levels7, but vari- has accumulated genetic and epigenetic diversity as a
a complex population ation increases at progressively lower taxonomic levels30. host species for >1 million years. Indicator organisms
typically from microbes in an Consequently, 85% of the sequences obtained from the such as Helicobacter pylori 32 and Streptococcus mutans 33
environmental or host niche
sample that is constituted
distal gut of the mouse represent genera that are not highlight some differences across the microbiota34 and
by the genomes of many detected in humans31. Furthermore, intraspecies vari- metagenome35 among human ethnic groups; however,
individual organisms. The ability of the microbiota among human populations is the extent of ethnic variation in overall metagenomic
metagenome provides substantial5. This degree of variation was unanticipated composition is unknown. The microbiomes of monozy-
information about the
apriori. In retrospect, however, extensive taxonomic var- gotic twins are more closely related to one another
functional genetic potential
of the aggregate population.
iation is unsurprising: a human harbours a climax popu- than to those of unrelated individuals36,37 but not strik-
lation of ~1014 bacterial cells, can host 105106 bacterial ingly so, indicating important postnatal influences on
composition.
T2 B
F4 OB
T1 B
T B
F5 2OB
F6 OV
T B
M B
B
F4 1O
F5 O
F5 O
F6 O
F6 2O
O
T2
M
T1
M
M
T
T
T
T
T2 B
F4 OB
T1 B
T B
F5 2OB
F6 OV
F4 1O
F5 O
F5 O
F6 O
F6 2O
O
M
T1
M
M
T
T
T
T
T
T
T
F1
agents. Such usage has been based on the implicit belief In summary, as with other complex ecosystems, the
that the human microbiome is completely resilient and microbiomes that populate specific human anatomical
returns to the pretreated composition after antibiotic- niches are species-rich, but possess particular overall
induced perturbation. However, studies of indicator community characteristics at higher organizational
organisms, such as H.pylori, show that individual levels. All are subject to perturbation in the course of
hosts can experience extirpations of bacterial species40. normal development and ageing, and especially with
Medium- and long-term selection of resistant organ- disease. As our knowledge of the fundamental char-
isms and the destabilization of the microbiome with acteristics and biology of the human microbiome
new species compositions are also seen, even in the grows, so will our ability to understand disease-related
absence of further antibiotic exposure28,41. Thus, despite variation.
the extensive resilience that is inherent in a complex
ecosystem, there may be loss of recovery from contin- Influences on the microbiota during host life cycles
ued perturbations29, which has important implications As described in the previous section, differences in
for human health42. microbiota composition exist across body sites and
Medical scientists are familiar with Kochs postu- among individuals. However, changes are also evident
lates, which are used as criteria to determine whether across the human lifespan. Important questions in
Extinction a microbe causes disease43. However, when consider- this field involve determining whether such temporal
The loss of an organism or
ing the pathogenicity of the microbiome it might be changes are life-stage-specific, and whether they are
group of organisms (usually of
a species) from an ecosystem. better to focus on community characteristics, which predetermined by host genetic characteristics or by
are largely governed by richness, composition and environmentalfactors.
Enterotype interactions among the constituent members 7,16,44.
A recently proposed Substantial perturbation (community disturbance45) Inheritance of microbiota. The congruent phylogenies
classification unit of animals
that is based on the
tests the resilience of the community, such as its ability of mammals and their microbiota8 provide strong evi-
bacteriological composition of to resist invasion by exogenous microbes; stable diverse dence for the inheritance of the microbiota7. Although
their gut microbiome. There communities resist pathogens46. At present, 16S rRNA inheritance of the microbiota from the father is presently
are reported to be at least analyses focus on taxonomic differences at or above little studied, increasing evidence supports inheritance
three distinct enterotypes,
the species level. However, examinations below the from the mother 34,53. Until the amniotic sac ruptures,
which are independent of
ethnic background and diet. subspecies level, relating to strains or even alleles, may a fetus is considered to be sterile, or essentially sterile.
be more informative. However, the technology (par- Immediately after vaginal delivery, founding microbial
Nash equilibria ticularly the informatics tools) are not yet sufficiently populations in the baby closely resemble that of their
Concepts from game theory developed for these applications. mothers vagina54, with lactobacilli predominating.
in which players know the
strategies of the others, and in
Because lactic-acid-producing bacteria dominate in
which any change from their Extinctions. The human microbiome represents one both the mothers vagina and milk, the initial bloom of
strategy puts them in a less or more complete ecosystems. The trophic organiza- lactobacilli in the babys gastrointestinal tract cannot be
favourable position. tion of species-rich communities is similar to other considered accidental. Lactobacilli represent the pioneer
complex network topologies, in that it shows extreme community in mice55 and humans39, in which they pre-
Resilience
A term in ecology indicating heterogeneity and is dominated by a few highly con- pare the gastrointestinal tract for subsequent microbial
the capacity of a system to nected nodes47. Such communities may resist random successions until microbial maturity isreached.
absorb disturbance and perturbations but if keystone species48 are lost, effects The repeated opportunities for the microbiota to
to reorganize itself while may cascade, causing secondary extinctions; high bio- be transferred from a mother to her baby may be dis-
undergoing change, so as to
retain essentially the same
diversity diminishes this risk12. The substantial nonlin- rupted by modern lifestyles. The availability of delivery
function, structure and identity. ear interactions present in complex, co-evolved systems by Caesarean section, as opposed to vaginal delivery,
ensure that ecological networks are robust against is an obvious example of the potential impact of medi-
Extirpations random removals49. However, if a system is repeatedly cal practice on microbiota composition; substantial
The loss of species in a
perturbed, the effects of gene loss can be amplified by differences in the founding microbiota population 54
locality (for example, an
individual host). downstream effects on co-colonizing microbes and on can persist for months56 (FIG. 3). In many host species,
the host. Because of allelopathy, the effects of extinc- paternal contributions to offspring traits have been
Allelopathy tions may be magnified50. In the short-term, functional well documented 57,58; these observations have been
A phenomenon in which a redundancy may mask extinction effects but in the extended to the microbiome, in which paternal contri-
microbe uses chemical means
to aid its competition within a
longer-term, extinctions lead to losses of contingency butions to H.pylori allele composition in the offspring
group of microbes. Allelopathy responses and cause ecological crashes49. Considering have been shown59. In any event, there is evidence for
may involve manipulation of the importance of guilds of bacteria that exploit parallel extensive horizontal transfer of microbial genes within
third parties (for example, the and sequential metabolic pathways, these concepts are human populations, involving microbes in different
host) to favour competition.
relevant to the human metagenome. As a result of mod- functional classes and inhabiting different ecological
Mating preference ern lifestyles, horizontal microbial transmission has niches60, indicating the site-specificity and dynamism
The selection or choice of been diminishing, and there has been unprecedented of selection on the human microbiome. Even so, micro-
sexual partners that is often selection against existing, long-present microbes40. An bial inheritance can provide important confirmation of
based on traits of a potential example is provided by the loss of a dominant species, human ancestry 61.
mate. Genetic differences
between selected and
H.pylori, from the human stomach51,52, which has led In Drosophila melanogaster, microbial influences
non-selected hosts are a to this body site harbouring alternative, stable states have an effect on mating preference for >30 generations62.
source of selectable variation. characterized by the presence or absence of H.pylori. Could microbiome composition therefore affect mating
The cutaneous microbiome. The cutaneous microbiome accounts for >90% of sequence reads from the gastric
is an obvious target in specific diseases such as psoriasis, microbiota93, markedly reducing the overall diversity of
a chronic, idiopathic inflammatory dermatological con- this microbiota. The ability of H.pylori to dominate the
dition87. In studies predating HTS, the use of PCR and gastric microbiota indicates an evolved fitness for that
cloning led to observations that Firmicute species were specialized niche. H.pylori is a classical amphibiont; the
significantly over-represented and that Actinobacteria presence (or absence) of an H.pylori-dominated gastric
were significantly under-represented in psoriatic lesions microbiota is strongly associated with particular diseases
compared with both unaffected skin in patients with that show important age-related differences85. Its pres-
psoriasis and in unaffected controls88. Studies to explore ence increases risks for developing peptic ulcer disease,
these findings using HTS are currently underway 89. gastric mucosa-associated lymphoid tissue (MALT)
Atopic dermatitis, another chronic inflammatory condi- tumours, and gastric adenocarcinomas94. Conversely,
tion, has increased in incidence approximately threefold it is also associated with a decreased risk of reflux
over the last 30years in industrialized countries, suggest- oesophagitis95 and childhood-onset asthma96, thus dem-
ing a potential role for microbiome alterations. Classic onstrating the complex biological interactions between
atopic dermatitis occurs in skin regions, such as the ante- hosts and microbiota.
cubital fossae and the popliteal fossae, that have similar
microbial populations89, suggesting a microbiome role. The colonic microbiota and colorectal cancer. The
Similarly, Propionibacterium acnes has been implicated colonic microbiota has been suspected for a long time
in the common dermatological condition, acne. P.acnes to be involved in the development of colorectal cancers97,
thrives in the cutaneous pilosebaceous units, secretes possibly by synthesizing short-chain fatty acids (SCFAs)
enzymes that cause local injury and inflammation, and and other metabolites. SCFAs, in particular butyrate, may
is widely accepted to have a function in acne develop- induce apoptosis, cell cycle arrest and differentiation,
ment90. However, investigations are ongoing to examine through WNT signalling 98. Microbes may also be geno-
the involvement of other microbes in the development toxic to colonic epithelial cells, as demonstrated by the
Antecubital fossae
The triangular areas on the
of acne. Chronic skin ulcers, which are often secondary induction of aneuploidy and tetraploidy by Enterococcus
anterior (flexor) aspects of to venous stasis or diabetes, lead to substantial morbid- faecalis 99. The colonic microbiota might also promote
elbow joints. ity. Cutaneous microbiome shifts have been noted in colorectal cancer by eliciting host responses, for exam-
these conditions, such as an increased abundance of ple, by stimulating exaggerated immune responses,
Popliteal fossae
Pseudomonadaceae in patients with chronic ulcers that potentially through T helper 17 (Th17)cells99.
The shallow depressions
that are found on the flexor were treated with antibiotics, and an increased abun- Further evidence of a link between colonic microbiota
aspects of knee joints. dance of Streptococcaceae in diabetic ulcers91. Such shifts and colorectal cancer is suggested by the ability of antibi-
may interact with aberrantly expressed host cutaneous otic administration to not only alter the composition of
Pilosebaceous units defence response genes92, thereby increasing diseaserisk. the colonic microbiota but also to affect the expression
The anatomic structure around
each hair shaft that consists
of host genes that are involved in cell cycle regulation,
of the hair shaft and follicle, The gastric microbiome. The discovery that H.pylori thus reducing epithelial proliferation100. Early studies
the sebaceous gland and the was adapted to survive in the acidic gastric environment evaluating specific microbes were limited to identifying
erector pili muscle. overturned the dogma that the stomach is sterile. In culture-dependent species, such as Streptococcus bovis,
H.pylori-negative individuals, gastric microbiota diver- but could not adequately assess anaerobic constituents.
Amphibiont
An organism (for example, sity is high; most of the prominent gastric phylotypes However, members of the anaerobic genus Fusobacterium
a microbe) that may have a (Streptococcus, Actinomyces, Prevotella and Gemella) also have recently been associated with colorectal cancer:
pathogenic or symbiotic are abundant in the oropharynx of these individuals93; whole-genome sequences of Fusobacterium species were
relationship with another this indicates either that many constituents are swal- compared between tumour tissue and matched normal
organism (for example, its
host), depending on context.
lowed from more proximal sites, or that close relatives of colon tissue using both quantitative PCR analysis and
This is a more specific term the oral microbiota colonize more distally. By contrast, HTS101,102. Fusobacterium nucleatum is a mucosally
than commensal. among H.pylori-positive individuals, H.pylori usually adherent, pro-inflammatory microbe that was first
identified in the mouth103. In colorectal cancer samples, lipase; this microbiome-mediated effect consequently
F.nucleatum sequences were significantly enriched com- increases downstream triglyceride accumulation in the
pared with samples obtained from control tissue, while hepatic parenchyma and adipocytes117. Chronic expo-
both Bacteroidetes and Firmicutes were depleted relative sure to ethanol disturbs the gut microbiome118,119, but
to other bacteria in Fusobacterium-rich malignancies102. roles for the microbiome in steatosis are unresolved.
The enrichment of Fusobacterium species (not limited to Particular colonic commensals of the mouse (for exam-
F.nucleatum) was confirmed when evaluating the mucosal ple, Helicobacter hepaticus) promote the development of
microbiome of colorectal cancers compared to adjacent hepatocellular carcinoma120. Patients with cirrhosis have a
normal tissues in an expanded collection of 99 biop- substantially altered microbiome, including community-
sies101. However, the causal direction of the association wide changes at multiple taxonomic levels, with enrich-
has not yet been ascertained. ment of Proteobacteria and Fusobacteria phyla, and of
Enterobacteriaceae, Veillonellaceae and Streptococcaceae
The colon microbiota and inflammatory bowel disease. families 121. Although many observations suggest
The microbiome is essential for the activation of host links between microbiome composition and liver
immune responses104. For example, Th17 cell differentia- disease, definitive associations in humans arelacking.
tion in the mouse lamina propria requires the presence of
segmented filamentous bacteria (SFB)105, and polysac- The gut microbiota and obesity. Genetically obese
charide A produced by Bacteroides fragilis mediates the (ob/ob) mice have decreased Bacteroidetes/Firmicutes
conversion of CD4+ Tcells into regulatory Tcells106. The ratios compared with their lean (ob/+ and +/+ wild-
inflammatory bowel diseases have long been considered type) siblings31. Transplantation of gut microbiota from
Lamina propria to reflect interactions between microbes and the host. the obese (ob/ob) to germ-free mice conferred an obese
A thin layer of loose connective IBD susceptibility is associated with host polymorphisms phenotype, demonstrating the transmissibility of meta-
tissue that lies underneath the
epithelium; collectively these
in bacterial sensor genes such as nucleotide-binding oli- bolic phenotypes17; the transferred microbiomes had
tissues constitute the mucosa gomerization domain-containing 2 (NOD2; also known increased capacities for energy harvest. In humans, the
that line various lumens in the as caspase recruitment domain-containing protein 15 relative proportions of members of the Bacteroidete phy-
body. The lamina propria is (CARD15))107,108 and Toll-like receptor 4 (TLR4)109, and lum increase with weight loss122. In studies of monozy-
densely populated by
symptoms in patients with IBD sometimes improve fol- gotic and dizygotic twins, obesity was associated with
immunological and
inflammatory cells. lowing antibiotic treatment110. Early childhood exposure smaller populations of Bacteroidetes, diminished bacte-
to antibiotics has been associated with a significantly rial diversity and enrichment of genes related to lipid
Steatosis increased risk for Crohns disease111, suggesting that gut and carbohydrate metabolism. Despite substantial
The pathological accumulation microbiome perturbations are important for disease taxonomic variation, functional metagenomic differ-
and retention of lipids in liver
parenchymal cells. Substantial
risk. Microbial diversity is significantly diminished in ences were minor 37. Modern lifestyles that change the
steatosis can compromise Crohns disease112, suggesting a decreased gut microbi- selection pressures on microbiomes could alter expo-
cellular functions and is ome resilience that could affect immune interactions. sures to bacteria during the early lives of hosts and thus
associated with disease Gut microbiome population structures in patients with may contribute to the development of obesity. Antibiotic
processes, including
ulcerative colitis or Crohns disease19 depart from nor- use in human infancy (before the age of 6months) was
alcoholism, diabetes and
hyperlipidaemia. mality, but remain clustered by disease within their significantly associated with obesity development 123.
characteristic deviated patterns. Specific bacteria of the By contrast, perinatal administration of a Lactobacillus
Commensals Enterobacteriaceae family may act together with a disor- rhamnosus probiotic decreased excessive weight gain dur-
Organisms (for example, dered microbiome to increase the risk of ulcerative coli- ing childhood124. These early studies provide support for
microbes) that are involved in a
form of symbiosis in which one
tis113. Between twins that are discordant for ulcerative the concept that perturbations in microbiota could lead
organism derives a benefit colitis, those affected had significantly reduced bacterial to childhood-onset obesity, which might be modifiable.
while the other is unaffected. diversity, but increased proportions of Actinobacteria Alterations in the gut microbiome also occur when
and Proteobacteria114. Patients with Crohns disease interventions are used to treat obesity. Roux-enY surgery
Probiotic
have over-representation of Enterococcus faecium and of significantly increases levels of Proteobacteria and alters
Living microorganisms
that are thought to confer several Proteobacteria compared with controls115. The specific metabolic markers, such as the production of
a benefit to the host. microbial patterns observed for the conditions described urinary amines and cresols125.
above are preliminary, and their specificity and causal
Roux-enY surgery direction have not been established. The gut microbiota and rheumatoid arthritis.
A type of gastric bypass
surgery that is primarily used
Dysregulation of host responses as a consequence of
for the treatment of morbid The gut microbiota and diseases of the liver. The gut dysbiosis in the gut lumen could affect distant anatomical
obesity. In Roux-enY surgeries, microbiota may be involved in hepatological con- sites through the activation of host immune responses.
a portion of the small bowel ditions, including non-alcoholic fatty liver disease This could be the mechanism that contributes to rheu-
is bypassed to decrease the
(NAFLD)116, alcoholic steatosis and hepatocellular car- matoid arthritis, which is another chronic idiopathic
absorption of nutrients.
cinoma. The liver is the first solid organ to be exposed inflammatory condition. In mice, the presence of SFBs
Dysbiosis to the metabolic products that are generated by the in the gut microbiome causes the local expansion of
A condition in which the gut microbiome, including acetaldehyde, ammonia Th17 cells126, which then migrate to peripheral immune
normal microbiome population and phenols. Compared with germ-free mice, the compartments and activate B cells into antibody-
structure is disturbed, often
through external pressures
presence of a microbiome in normal mice leads to producing plasma cells. Antibody production leads
such as disease states or the suppression of intestinal epithelium angiopoietin- to the immune-mediated destruction of joints, which
medications. related protein 4, which normally inhibits lipoprotein occurs in rheumatoid arthritis127.
restoration could be therapeutic, when the aetiological solutions. For example, in analyses of 16SrRNA-defined
extinctions and imbalances are recognized. This scien- operational taxonomic unit (OTU) populations in mice
tific frontier will require an understanding of the biol- that received either traditional or Western-type diets,
ogy of re-introductions, as well as developing microbial Reshef etal.132 examined top-scoring nonlinear abun-
breeding programmes. In addition to the technical prob- dance relationships. These often involved non-coexistence
lems that are associated with restoring particular organ- that was sometimes related to known factors (for exam-
isms in specific hard-to-reach niches (such as the distal ple, diet or host gender) but was often unexplained.
ileum), there also will be substantial biological problems Although incomplete, such work leads to new approaches
related to understanding how re-introductions affect the for understanding the underlying complexity.
population structure of the extant organisms and their We also will need new tools to implement the find-
interactions with thehost. ings of metagenomic analyses that are relevant to
To better understand the implications of microbiota human health. Although the known principles of evolu-
and metagenome variation in human health and disease, tion and genetics apply, studies of microbiomes provide
the field needs improved informatics tools, including new applications, and will lead to new understandings
new approaches for understanding the complexity of the of complex traits. Important questions to pursue are
metadata60. The multidimensionality of the human and listed in BOX 1. As such, this is a frontier for human
microbial phenotypes (and the dynamic, nonlinear inter- preventive medicine and for the medical management
actions) creates challenges for identifying deterministic of chronic diseases.
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