Emerging targetome and signalome landscape of gut microbial metabolites

The gut microbiome produces chemically diverse small molecules to interact with the host, conveying signals from the gut to the whole system. The microbial metabolites feature several unique modes of interaction with host targets, which fits well into the balanced and networked fashion of biological regulation. Hence, fully unveiling the targetome of signaling microbial metabolites may offer new insights into host health and disease, expand the repertoire of druggable targets, and enlighten a bioinspired path to drug design and discovery. In this review, we present an updated understanding of how microbial metabolite interaction with host targets finely orchestrates and integrates multiple signals to pathophysiological phenotypes, contributing new insights into organ crosstalk and holistic homeostasis maintenance in biological systems. We discuss strategies and open questions for mining and biomimicking the microbial metabolite-targetome interactions for pharmacological manipulation, which may lead to a new paradigm of drug discovery.