screens is gene expression. Success generally depends on expression, in a laboratory strain of E. coli, of exotic genes from exotic organisms. The differences in gene-expression mechanisms among species are likely to prevent detection of many genes by this method. Using multiple host species and tweaking the gene expression machinery of E. coli are mechanisms for achieving expression of a wider array of genes that deserve further study to enhance the utility of the function-based approach to metagenomics.

The Human-Microbiome Project

Microbes thrive on us: we provide wonderfully rich and varied homes for our 100 trillion microbial (bacterial and archaeal) partners. Considering that we contain perhaps 10 times more microbial than human cells and at least 100 times more microbial than human genes, it is inescapable that we are superorganisms composed of both microbial and human parts. Bacterial communities play an important role in health and disease in a variety of anatomical locations, such as the female reproductive tract, the skin, the oral cavity, and the respiratory tract. Even after completion of the first reference human genome, our view of the “human” genetic landscape is quite incomplete. We know little about how our microbial component has evolved or about the forces that are shaping it as our biosphere, our lifestyles, and our technologies change. What aspects of our microbiome are uniquely “human,” or mammalian? Are we undergoing a form of “micro-evolution” because of changes in our microbial ecology that is affecting our biology and our predispositions to diseases?

Because the human microbiota has not yet been extensively explored, much of what is known of the contributions of organisms’ microbial partners has come from comparisons of germ-free animals (reared with no microbes) with their counterparts that have been colonized with defined components of the mouse or human microbiota (Turnbaugh et al. 2006, 2006; Samuel and Gordon 2006). Comparisons of germ-free and colonized animals have shown, for example, that the gut microbiota regulates energy balance, directs myriad biotransformations (including detoxification of carcinogens), modulates the maturation and activity of the innate and adaptive immune systems, and affects the cardiovascular system. On the basis of these and other observations, the gut microbiota has been invoked as a factor that determines susceptibility to diseases ranging from obesity and diabetes to gastrointestinal and other malignancies, atopic disorders (such as asthma), infectious diarrhea, and various immunopathologic states, including inflammatory bowel diseases.

Initial results of 16S rRNA gene-based enumerations of the microbial communities of a small number of humans have revealed remarkable diversity in a number of habitats, including the gut (Eckburg et al. 2005; Ley et

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