Small molecules from the human microbiota

Microbial bioactive molecules Human cells are outnumbered by the microbial cells of our commensals by an order of magnitude. All of these organisms are metabolically active and secrete multiple bioactive molecules. Genomics has unveiled a remarkable array of biosynthetic gene clusters in the human microbiota, which encode diverse metabolites. Donia et al. review how molecules ranging from lantibiotics and microcins to indoxyl sulfate and immunemodulatory oligosaccharides and lipids could affect the health and physiology of the whole organism, depending on the composition of an individual's microbial community. Science, this issue p. 10.1126/science.1254766 BACKGROUND Two developments in distinct fields are converging to create interest in discovering small molecules from the human microbiome. First, the use of genomics to guide natural product discovery has led to the unexpected discovery of numerous biosynthetic gene clusters in genomes of the human microbiota. Second, the microbiome research community is moving from a focus on “who’s there?” to “what are they doing?” with an accompanying emphasis on understanding microbiota-host interactions at the level of molecular mechanism. This merger has sparked a concerted hunt for the mediators of microbe-host and microbe-microbe interactions, including microbiota-derived small molecules. ADVANCES Numerous small molecules are known that are produced by the human microbiota. The microbiota-derived ribosomally synthesized, posttranslationally modified peptides (RiPPs) include widely distributed lantibiotics and microcins; these molecules have narrow-spectrum activity and are presumptive mediators of interactions among closely related species. Another notable RiPP is Escherichia coli heat-stable enterotoxin, a guanylate cyclase 2C agonist from which the recently approved gastrointestinal motility drug linaclotide was derived. Fewer amino acid metabolites are synthesized by the microbiota, but they are produced at very high levels that vary widely among individuals (e.g., indoxyl sulfate at 10 to 200 mg/day). Gut bacterial species convert common dietary amino acids into distinct end products, such as tryptophan to indoxyl sulfate, indole propionic acid, and tryptamine—indicating that humans with the same diet but different gut colonists can have widely varying gut metabolic profiles. Microbially produced oligosaccharides differ from other natural products because they are cell-associated (i.e., nondiffusible) and because many more biosynthetic loci exist for them than for other small molecule classes. Well-characterized examples, such as Bacteroides polysaccharide A, show that oligosaccharides may not simply play a structural role or mediate adhesion; rather, they can be involved in highly specific ligand-receptor interactions that result in immune modulation. Similarly, the (glyco)lipids α-galactosylceramide and mycolic acid can play roles in immune signaling. The most prominent microbiota-derived terpenoids are microbial conversion products of the cholic acid and chenodeoxycholic acid in host bile. These secondary bile acids can reach high concentration (mM) in the gut and vary widely in composition among individuals. Several canonical virulence factors from pathogens are derived from nonribosomal peptides (NRPs) and polyketides (PKs), but less is known about NRPs and PKs from the commensal microbiota. A recent computational effort has identified ~14,000 biosynthetic gene clusters in sequenced genomes from the human microbiota, 3118 of which were present in one or more of the 752 metagenomic sequence samples from the NIH Human Microbiome Project. Nearly all of the gene clusters that were present in >10% of the samples from the body site of origin are uncharacterized, highlighting the potential for identifying the molecules they encode and studying their biological activities. OUTLOOK There are two central challenges facing the field. The first is to distinguish, from among thousands of microbiota-derived molecules, which ones drive a key phenotype at physiologically relevant concentrations. Second, which experimental systems are appropriate for testing the activity of an individual molecule from a complex milieu? Meeting these challenges will require developing new computational and experimental technologies, including a capacity to identify biosynthetic genes and predict the structure and target of their biological activity, and systems in which germ-free mice are colonized by mock communities that differ only by the presence or absence of a biosynthetic gene cluster. Small-molecule–mediated microbe-host and microbe-microbe interactions. Commensal organisms of the human microbiota produce many diverse small molecules with an equally diverse array of targets that can exacerbate or modulate immune responses and other physiological functions in the host. Several act as antibacterials to remove competing organisms, but many other products have unknown targets and effects on commensals and the host. Developments in the use of genomics to guide natural product discovery and a recent emphasis on understanding the molecular mechanisms of microbiota-host interactions have converged on the discovery of small molecules from the human microbiome. Here, we review what is known about small molecules produced by the human microbiota. Numerous molecules representing each of the major metabolite classes have been found that have a variety of biological activities, including immune modulation and antibiosis. We discuss technologies that will affect how microbiota-derived molecules are discovered in the future and consider the challenges inherent in finding specific molecules that are critical for driving microbe-host and microbe-microbe interactions and understanding their biological relevance.