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The Human Microbiome and the Future Practice
of Medicine

David A. Relman, All animals coexist in intimate, dependent relation- at distinct body sites, as well as priority effects on com-
MD ships with microbes. Humans are no exception. Host- munity succession, rates of dispersal, and local micro-
Departments of associated microbes, like nearly all others on this bial diversification. The subtle distinguishing features be-
Medicine and of
planet, form communities in which the overall compo- tween microbial communities may teach us about
Microbiology and
Immunology, sition, structure, and function are explained by ecologi- important, underlying variation in both normal and ab-
Stanford University, cal processes and environmental factors. Evidence of normal human physiology and cell biology. For ex-
Stanford, California; coadaptation and mutual benefit are key features of ample, distinct types of epithelium, temperatures, and
and Veterans Affairs
Palo Alto Health Care
these symbioses between hosts and their microbial com- other environmental conditions are associated with dif-
System, Palo Alto, munities, or microbiotas.1 The human microbiota is a fun- fering bacterial communities between the anterior na-
California. damental component of what it means to be human. ris of the nose and the middle meatus and sinoeth-
Recent work suggests that the benefits derived by moidal recess and associated with distinct competitive
humans from their microbiotas may have profound interactions among community members of interest, like
consequences for health. These benefits include differ- Staphylococcus aureus.3
entiation of host mucosa, food digestion and nutrition, From high-diversity oral habitats to low-diversity
regulation of metabolism, processing and detoxifica- vaginal habitats, microbial biogeography suggests dis-
tion of environmental chemicals, development and tinct ecological zones across the human landscape
ongoing regulation of the immune system, and preven- (Figure). On the skin, there are 3 types of microbial com-
tion of invasion and growth of pathogens. Conversely, munities, each characteristic of either dry, moist, or se-
disturbance and alterations of the human microbiota baceous environments.4 Propionibacterium acnes, com-
and its collective genes and genomes, ie, the micro- mensal staphylococci, Corynebacterium species, and
biome, are associated with a wide variety of human dis- Propionibacterium phage explain the greatest amount
eases, such as chronic periodontitis, inflammatory of variation between these community types; fungi and
bowel disease, and antibiotic-associated diarrhea. other eukaryotic microbes are relatively rare. P acnes
The first direct observations and measurements of strains tend to be specific to an individual, whereas
the human microbiota were made more than 300 years Staphylococcus epidermidis strains tend to be specific to
ago with the advent of the microscope and scrapings body site. DNA viruses, especially bacterial viruses
from teeth. Since then, the tools for studying the hu- (phage), vary considerably in number and type be-
man microbiota have expanded in scope, sophistica- tween individuals on the skin and elsewhere across hu-
tion, and availability. The current surge of interest in this man body mucosa and are relatively abundant in the
topic reflects in part recent advances in DNA sequenc- nose and vagina. Because they can kill bacteria or modify
ing technology and its use in characterizing the micro- them by carrying in new genes, phages help shape the
bial world directly from environmental samples, as well structure and function of the human microbiota.
as a renewed appreciation for ecological principles, in- Site-specific features of microbiota structure and
cluding the importance of interactions among organ- function may serve as early markers of future local dis-
isms; the formation, activities, and stability of commu- ease. Focal processes such as chronic periodontitis, den-
nities of microbes; and the relationships between tal caries, atopic dermatitis, and Crohn disease are at-
communities and their environment. The study of the tractive settings for the identification of such features.
human microbiota has substantial potential for improv- Smallmoleculesmediateawidevarietyofinteractions
ing the management of human health and disease. among members of microbial communities, and in so do-
Body site is one of the strongest determinants of ing, promote community stability; with regard to the hu-
variation in human microbiota compositional diversity.2 man microbiota, small molecules also mediate and facili-
For example, microbial communities on the exposed tate host adaptation. With the advent of computational
tooth surfaces of a healthy individual generally have tools for identifying the putative products of complex
Corresponding more similar taxonomic compositions to those on the mixed communities based on their meta-genomes, a
Author: David A. teeth of another healthy individual than they do to those wealth of new molecules have been discovered within the
Relman, MD, on the tongue of the same individual. In contrast, when human microbiota. A number of them have demonstrated
VA Palo Alto Health
Care System 154T,
specimens from the same body site are compared among drug-like activities with significant medical potential.5
3801 Miranda Ave, a group of different healthy individuals, individual- A recent examination of metagenomic sequence
Palo Alto, CA 94304 specific microbiota features are apparent. Biogeo- data obtained directly from human microbiota samples
graphic patterns in microbiota taxonomic and genomic at 5 body sites identified more than 3000 biosynthetic
composition reflect differing selective pressures found gene clusters, each predicted to produce a small mol- (Reprinted) JAMA September 15, 2015 Volume 314, Number 11 1127

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Opinion Viewpoint

Figure. Microbial Biogeography and Community Stability in the Human Body

Microbial ecological zones Stability landscape of the human

microbial ecosystem
Stable state 1
Stable state 2

Left, Each zone is distinguished

by a distinct microbial community
composition and function.4
Landscape Right, A stable state, depicted as a
depression in the landscape, may be
associated with health or disease. The
Skin position of the ball indicates the
change Stable
Moist current state of the ecosystem. For a
given individual, the landscape
Sebaceous Stable state 1 Stable state 2
topology reflects host genetics,
Dry immune status, lifestyle, prior
exposures to drugs, chemicals, and
Oral pathogens, and microbiota
Small intestine composition. With time, the topology
may change, for example, as a result
Large intestine
of immune system impairment
prompting a shift to a different state.

ecule with biological activity.6 Oral and gut communities contained Familiarity with an individuals microbial ecosystem stability land-
more of these gene clusters (roughly 1100 and 600 per site, respec- scape might provide an understanding of their vulnerability to desta-
tively) than communities at other, less diverse sites (such as skin and bilizing factors such as antibiotics, as well as the likelihood of
urogenital tract). Some of the most common types of predicted small restoring their ecosystem to a health-associated state, for example,
molecules in the human microbiome are ribosomally synthesized and using a defined personalized synthetic community and complemen-
posttranslationally modified peptidesincluding lantibiotics, bac- tary set of nutrients. Thus, a future clinical test might include a small,
teriocins, and thiopeptides. A predicted thiopeptide that was com- standardized short-lived disturbance with which to assess stability, as
putationally identified as originating from the common vaginal com- well as the response characteristics of the microbiota.8
mensal Lactobacillus gasseri (and called lactocillin) has been purified, Among the most important unanswered questions and press-
characterized, and demonstrated to have potent antigram- ing issues about the human microbiome are the following: What
positive bacterial activity, but no activity against the commensal are the most effective approaches for measuring human microbial
Lactobacillus species of the vagina. ecosystem beneficial services? What are the most important pro-
All ecosystems display multiple, alternative stable states. In the cesses and factors that determine human microbiota assembly
case of the human microbial ecosystem, some stable states are as- after birth, do different community assembly trajectories deter-
sociated with health, others with disease (Figure). Given the known mine health and disease later in life, and if so, how? What are the
and suspected benefits that humans derive from their microbiota, most important determinants of microbiome stability and resil-
the stability and resilience of this ecosystem are critical properties.7 ience? How can the stability and resilience of health-associated
Few longitudinal studies have been performed with dense tempo- ecosystem states be strengthened, and how can health-associated
ral and spatial sampling and detailed clinical data from a large num- ecosystem states be restored? Whether and how the microbiome
ber of research participants. Available data, albeit sparse, suggest might contribute to disease are critical questions at the present
that changes in diet, immunological function, and the use of antibi- time. Carefully designed clinical studies that assess multiple, possi-
otics can trigger shifts from one state to another that are tempo- bly interacting disease factorsincluding the microbiomeand that
rary or persistent. parse cause from effect are desperately needed.

ARTICLE INFORMATION REFERENCES Biogeography and individuality shape function in

Conflict of Interest Disclosures: The author has 1. Dethlefsen L, McFall-Ngai M, Relman DA. the human skin metagenome. Nature. 2014;514
completed and submitted the ICMJE Form for An ecological and evolutionary perspective on (7520):59-64.
Disclosure of Potential Conflicts of Interest and human-microbe mutualism and disease. Nature. 5. Donia MS, Fischbach MA. Human microbiota.
reported serving on the scientific advisory boards 2007;449(7164):811-818. Science. 2015;349(6246):1254766.
for Cepheid, Seres Health, Second Genome, 2. Costello EK, Lauber CL, Hamady M, et al. 6. Donia MS, Cimermancic P, Schulze CJ, et al.
Identify Genomics, and Karius. Bacterial community variation in human body A systematic analysis of biosynthetic gene clusters
Funding/Support: Dr Relmans research is habitats across space and time. Science. 2009;326 in the human microbiome reveals a common family
supported by the National Institutes of Health, (5960):1694-1697. of antibiotics. Cell. 2014;158(6):1402-1414.
March of Dimes Foundation, Gates Foundation, 3. Yan M, Pamp SJ, Fukuyama J, et al. Nasal 7. Shade A, Peter H, Allison SD, et al. Fundamentals
Helmsley Foundation, and the Thomas C. and Joan microenvironments and interspecific interactions of microbial community resistance and resilience.
M. Merigan Endowment at Stanford University. influence nasal microbiota complexity and S aureus Front Microbiol. 2012;3:417.
Role of the Funder/Sponsor: The funders/ carriage. Cell Host Microbe. 2013;14(6):631-640. 8. Lemon KP, Armitage GC, Relman DA, Fischbach
sponsors had no role in the preparation, review, or 4. Oh J, Byrd AL, Deming C, Conlan S, Kong HH, MA. Microbiota-targeted therapies: an ecological
approval of the manuscript. Segre JA; NISC Comparative Sequencing Program. perspective. Sci Transl Med. 2012;4(137):137rv5.

1128 JAMA September 15, 2015 Volume 314, Number 11 (Reprinted)

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