Microbiome-derived small molecules and host resistance against Vibrio cholerae

The human body is colonized by a complex microbial community with critical roles for health. This microbiota
educates the immune system, helps digest our food, and protects us against pathogens. The diversity of
microbes and encoded functions is significant. Our group showed that the gut microbiota is also a source of
great chemical diversity, and that most of the compounds produced are unknown. Bacteria produce and
respond to small molecules to communicate and adapt to their environment. Chemical signaling controls
functions that are critical for host adaptation in most pathogens. Therefore, small-molecule signaling is an
attractive target for the development of anti-infectives. Given the chemical complexity of the gut, microbiotapathogen
crosstalk must be common. In fact, we previously showed that an organic extract of human feces
elicits a significant transcriptional response in Salmonella enterica, with ~100 regulated genes. Interestingly,
virulence genes were abundant among those repressed by the extract, suggesting that microbiota-derived
metabolites can dampen virulence. We then determined that a single commensal, Enterocloster citroniae,
can repress S. enterica virulence gene expression. More recently, we studied the transcriptional impact of
the human fecal metabolome on other pathogens. In Vibrio cholerae, the causative agent of cholera, the
effect was even more pronounced, with ~900 genes being regulated. Motility was the main category of
repressed genes, and the effect was confirmed by phenotypic assays. As with S. enterica, the effect could
be recapitulated with E. citroniae. Given the importance of V. cholerae as a human pathogen and the critical
role played by motility in its pathogenesis, it is our goal to determine the impact of microbiota-derived
metabolites on V. cholerae pathogenicity. We will generate a collection of gut commensals with anti-motility
properties to characterize the genetic and chemical nature of the bioactivity. Genomes and transcriptomes
of active and inactive strains will be compared, giving insights into the synthetic apparatus involved.
Bioactivity-guided purification will be performed, and compound characterization using mass spectrometry
and nuclear magnetic resonance will ensue. Lastly, we will study the impact of active strains and compounds
on host resistance to V. cholerae using infection models. Results from this work will shed light on the chemical
biology of microbiota-pathogen interactions and may reveal strains and compounds with potential therapeutic
applications.

Grant Number: 5P20GM113117-10
NIH Institute/Center: NIH
Principal Investigator: Luis Caetano Antunes