HUMAN MICROBIOTA. Small molecules from the human microbiota

Abstract

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.

Figure 1. Structurally diverse small molecules from the human microbiota

The diversity of chemical classes produced by the human microbiota rivals that of microorganisms from any ecological niche. Representative molecules are shown for each of the major molecular classes discussed: the RiPPs lactocillin and linaclotide; the amino acid metabolites indolepropionic acid and tryptamine; the oligosaccharide polysaccharide A; the lipids/glycolipids mycolic acid and α-galactosylceramide; the terpenoid deoxycholic acid, in which carbons 3, 7, and 12 of the bile acid scaffold are labeled; the nonribosomal peptides corynebactin, tilivalline, and mutanobactin; and the polyketide mycolactone.

Figure 2. Small-molecule mediated microbe-host and microbe-microbe interactions

The microbiota produce a range of small molecules from various classes with distinct targets. Four examples are shown: the nonribosomal peptide tilivalline, whose host target is unknown; the ribosomally synthesized and post-translationally modified peptide microcin E492 (MccE492), a narrow spectrum antibacterial; lipid A, the glycolipid core of lipopolysaccharide, which targets TLR4 in host immune cells; and indole propionic acid, a reductive metabolite of tryptophan that enters host circulation but whose biological activity is poorly understood. These metabolites are each produced by different species of the microbiota, but are shown here in a single cell for schematic purposes. The following are abbreviations for domains in the nonribosomal peptide synthetase that produces tilivalline: A = adenylation domain, T = thiolation domain, C = condensation domain, R = terminal reductase domain.

Figure 3. Approaches to discovering small molecules from the microbiota

(A) Samples from germ-free and colonized mice can be analyzed by untargeted metabolomics to identify molecules that are present in a microbiota-dependent fashion. (B) A mouse harboring a reference gut community can be subjected to antibiotic treatment, a dietary shift, or another perturbation. Comparative metabolomics can be used to identify microbiota-derived molecules whose abundance changes as a consequence of the perturbation. (C) Candidate bacterial gene clusters or bacterial species can be selected by metagenomic profiling (e.g., for gene clusters or species that are widely distributed, or differ in abundance between cases and controls). Comparative metabolomics can then be used to identify molecules produced by a gene cluster or bacterial species of interest. (D) Subsets of bacteria from a fractionated complex community or designed synthetic communities can be used to colonize mice in order to identify specific bacterial species whose presence correlates with the production of a molecule of interest.