The human intestinal microbiota is composed of 10 13 to 10 14 microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own genome. We analyzed ~78 million base pairs of unique DNA sequence and 2062 polymerase chain reactionamplified 16S ribosomal DNA sequences obtained from the fecal DNAs of two healthy adults. Using metabolic function analyses of identified genes, we compared our human genome with the average content of previously sequenced microbial genomes. Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-Derythritol 4-phosphate pathway-mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.Our body surfaces are home to microbial communities whose aggregate membership outnumbers our human somatic and germ cells by at least an order of magnitude. The vast majority of these microbes (10 to 100 trillion) inhabit our gastrointestinal tract, with the greatest number residing in the distal gut, where they synthesize essential amino acids and vitamins and process components of otherwise indigestible contributions to our diet such as plant polysaccharides (1). The most comprehensive 16S ribosomal DNA (rDNA) sequencebased enumeration of the distal gut and fecal microbiota published to date underscores its highly selected nature. Among the 70 divisions (deep evolutionary lineages) of Bacteria and 13 divisions of Archaea described to date, the distal gut and fecal microbiota of the three ‡

The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise indigestible dietary polysaccharides. The products of polysaccharide fermentation include shortchain fatty acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41؊/؊ and Gpr41؉/؉ mice that were either conventionally-raised with a complete gut microbiota or were reared germ-free and then cocolonized as young adults with two prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methanobrevibacter smithii. Both conventionallyraised and gnotobiotic Gpr41؊/؊ mice colonized with the model fermentative community are significantly leaner and weigh less than their WT (؉/؉) littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic studies of germ-free and cocolonized Gpr41؊/؊ and ؉/؉ littermates disclosed that Gpr41-deficiency is associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet. These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent upon the gut microbiota.host-microbial interactions ͉ energy balance ͉ enteroendocrine cells ͉ nutrient sensing ͉ polysaccharide fermentation O ur ability to effectively digest food reflects the combined activities of enzymes encoded in our primate genome and in the genomes of the trillions of microbes that reside in our distal guts. This microbial community, or microbiota, affects both sides of the energy-balance equation, influencing both the harvest of calories and the activity of host genes involved in the metabolism and storage of absorbed energy (e.g., ref.

Danio rerio ͉ symbiosis ͉ host-microbial cross-talk ͉ mice ͉ DNA microarrays