P-326 Systematic Discovery of Human Microbial Small Molecule Effectors

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Abstract

Background:

Bacteria are increasingly believed to have an important role in the pathogenesis of human disease, especially inflammatory bowel disease (IBD). Despite evidence directly linking bacteria to IBD phenotypes in mice and correlative evidence in humans, the mechanisms by which specific bacterial functions affect host cellular functions (i.e., effector functions) remain largely ill-defined. Bacteria from environmental microbiomes are known to rely heavily on small molecules as signaling molecules to interact with their environment. It is likely that human microbiota also rely on small molecules to interact with their human hosts but the characterization of these effector molecules and their cellular receptors remains largely undefined. Bacterial small molecules have provided a tremendous reservoir for therapeutic discovery over the last 70 years and the study small molecules produced by human microbiota should not only help to define host-microbial interactions important to disease pathogenesis but also provide a novel resource for small molecule therapeutic discovery. We recently reported on the discovery of a human microbial GPCR active long chain N-acyl amide that suggests convergence between human and bacterial small molecules.

Methods:

We will discuss here the expansion of our discovery platform for the identification of human microbial small molecules and their cellular targets. This platform incorporates functional metagenomics with bioinformatics and synthetic biology to (1) isolate small molecule effectors and identify host cellular targets (2) target biosynthetic genes in human microbiota and (3) expand newly identified effector molecule families to systemically explore host-microbial interactions in the human microbiome.

Results:

This work has led to the identification of new small molecule families that are able to regulate important aspects of gastrointestinal mucosal functions related to wound healing, immune cell differentiation and metabolism that may have important implications for IBD pathogenesis. Furthermore, we will discuss how small molecule effectors identified in this platform can be translated into novel therapeutic strategies for the targeted manipulation of host phenotypes in vivo.

Conclusions:

The systematic characterization of human microbial small molecule effectors helps elucidate potential mechanisms of disease pathogenesis involving host-microbial interactions and identifies novel therapeutic strategies.

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