Deciphering Human Microbiota-Host Chemical Interactions

Abstract

Our gut harbors more microbes than any other body site, and accumulating evidence suggests that these organisms have a sizable impact on human health. Though efforts to classify the metabolic activities that define this microbial community have transformed the way we think about health and disease, our knowledge of gut microbially produced small molecules and their effects on host biology remains in its infancy. This Outlook surveys a range of approaches, hurdles, and advances in defining the chemical repertoire of the gut microbiota, drawing on examples with particularly strong links to human health. Progress toward understanding and manipulating this chemical language is being made with diverse chemical and biological expertise and could hold the key for combatting certain human diseases.

Figure 1

Gut microbial metabolism produces bioactive small molecules that influence host biology. Gut microbiota-derived metabolites are produced by the transformation of compounds ingested by the host, by modification of host metabolites, and de novo.

Figure 2

A multiomics approach leveraged a cholesterol metabolizing environmental bacterium to understand this metabolic activity in the human gut microbiota. Hog sewage lagoon bacterium E. coprostanoligenes converts cholesterol to coprostanol. Characterization of this activity in cultures revealed the chemical logic of this pathway and led to the discovery of a critical enzyme, IsmA. Homologs of ismA were classified phylogenetically and identified in as-yet-uncultured human gut bacteria. Paired metagenomic–metabolomic samples revealed that ismA+ encoders have less fecal cholesterol and more coprostanol than nonencoders. ismA is inversely correlated with serum cholesterol levels, suggesting that gut bacterial cholesterol metabolism may reduce host cholesterol levels and risk for cardiovascular disease.

Figure 3

Chemical knowledge and approaches helped to elucidate the structure and activity of colibactin, a DNA alkylating gut bacterial genotoxin that is associated with colorectal cancer. (A) pks+ E. coli induce cell cycle arrest and DNA damage in neighboring eukaryotic cells. Mutagenesis revealed that an NRPS-PKS biosynthetic gene cluster is required for genotoxicity. An understanding of assembly line biosynthetic logic guided in vitro biochemical experiments and isolation efforts that ultimately led to a proposed chemical structure. (B) The potential reactivity of cyclopropanes found in metabolites isolated from pks mutants suggested that colibactin was a DNA alkylating agent and inspired efforts to identify colibactin-derived DNA adducts. DNA adductomics revealed adenine adducts that were proposed to derive from larger, interstrand cross-links. Injection of organoids with pks+ and pks– E. coli revealed a mutagenic signature specific to colibactin. This signature further suggests that colibactin forms interstrand cross-links to deoxyadenosine residues and is found in human colorectal cancer patients.