The Human Microbiome and the Future Practice of Medicine.

All animals coexist in intimate, dependent relationships with microbes. Humans are no exception. Hostassociated microbes, like nearly all others on this planet, form communities in which the overall composition, structure, and function are explained by ecological processes and environmental factors. Evidence of coadaptation and mutual benefit are key features of these symbioses between hosts and their microbial communities, or microbiotas.1 The human microbiota is a fundamental component of what it means to be human. Recent work suggests that the benefits derived by humans from their microbiotas may have profound consequences for health. These benefits include differentiation of host mucosa, food digestion and nutrition, regulation of metabolism, processing and detoxification of environmental chemicals, development and ongoing regulation of the immune system, and prevention of invasion and growth of pathogens. Conversely, disturbance and alterations of the human microbiota and its collective genes and genomes, ie, the microbiome, are associated with a wide variety of human diseases, such as chronic periodontitis, inflammatory bowel disease, and antibiotic-associated diarrhea. The first direct observations and measurements of the human microbiota were made more than 300 years ago with the advent of the microscope and scrapings from teeth. Since then, the tools for studying the human microbiota have expanded in scope, sophistication, and availability. The current surge of interest in this topic reflects in part recent advances in DNA sequencing technology and its use in characterizing the microbial world directly from environmental samples, as well as a renewed appreciation for ecological principles, including the importance of interactions among organisms; the formation, activities, and stability of communities of microbes; and the relationships between communities and their environment. The study of the human microbiota has substantial potential for improving the management of human health and disease. Body site is one of the strongest determinants of variation in human microbiota compositional diversity.2 For example, microbial communities on the exposed tooth surfaces of a healthy individual generally have more similar taxonomic compositions to those on the teeth of another healthy individual than they do to those on the tongue of the same individual. In contrast, when specimens from the same body site are compared among a group of different healthy individuals, individualspecific microbiota features are apparent. Biogeographic patterns in microbiota taxonomic and genomic composition reflect differing selective pressures found at distinct body sites, as well as priority effects on community succession, rates of dispersal, and local microbial diversification. The subtle distinguishing features between microbial communities may teach us about important, underlying variation in both normal and abnormal human physiology and cell biology. For example, distinct types of epithelium, temperatures, and other environmental conditions are associated with differing bacterial communities between the anterior naris of the nose and the middle meatus and sinoethmoidal recess and associated with distinct competitive interactions among community members of interest, like Staphylococcus aureus.3 From high-diversity oral habitats to low-diversity vaginal habitats, microbial biogeography suggests distinct ecological zones across the human landscape (Figure). On the skin, there are 3 types of microbial communities, each characteristic of either dry, moist, or sebaceous environments.4 Propionibacterium acnes, commensal staphylococci, Corynebacterium species, and Propionibacterium phage explain the greatest amount of variation between these community types; fungi and other eukaryotic microbes are relatively rare. P acnes strains tend to be specific to an individual, whereas Staphylococcus epidermidis strains tend to be specific to body site. DNA viruses, especially bacterial viruses (phage), vary considerably in number and type between individuals on the skin and elsewhere across human body mucosa and are relatively abundant in the nose and vagina. Because they can kill bacteria or modify them by carrying in new genes, phages help shape the structure and function of the human microbiota. Site-specific features of microbiota structure and function may serve as early markers of future local disease. Focal processes such as chronic periodontitis, dental caries, atopic dermatitis, and Crohn disease are attractive settings for the identification of such features. Smallmoleculesmediateawidevarietyof interactions among members of microbial communities, and in so doing, promote community stability; with regard to the human microbiota, small molecules also mediate and facilitate host adaptation. With the advent of computational tools for identifying the putative products of complex mixed communities based on their “meta-genomes,” a wealth of new molecules have been discovered within the human microbiota. A number of them have demonstrated drug-like activities with significant medical potential.5 A recent examination of metagenomic sequence data obtained directly from human microbiota samples at 5 body sites identified more than 3000 biosynthetic gene clusters, each predicted to produce a small molVIEWPOINT