An atlas of small molecules in the human microbiome

Abstract

The human microbiome produces an atlas of biologically active yet mostly unexplored small molecules encoded by biosynthetic gene clusters (BGCs). Understanding the small molecule biosynthetic landscape in the human microbiome holds the key to deciphering the numerous cryptic microbe-microbe and microbe-host interactions. We herein provided a holistic view of the biosynthetic capacity of the human microbiome, by integrating human-derived isolate genomes, metagenomes, and metagenomic bins from various studies. We observed from metagenomes that biosynthetic profiles are not a simple reflection of taxonomical profiles, which can be potentially explained by variability of BGCs within the same genus or species and horizontal gene transfer of the same BGC between distant taxa. We then demonstrated how biosynthetic profiles can be employed to generate hypotheses and uncover microbe-microbe interactions on the molecular level: using association analysis across multiple studies for the human gut, we identifed more than a hundred BGCs encoding potential antibacterial small molecules, together with their possible targets. Next, we focused on the small molecule biosynthetic landscape of the human skin and a skin disease. Using the aforementioned approach, we identifed BGCs associated with healthy controls and disease state, some of which are not reflected by taxonomical analysis. Machine learning models also suggest that BGCs are predictive of the disease, better than traditional taxonomical and high-level functional biomarkers. Our approach to study small molecules in the human microbiome can be used to guide experiments as well as elucidate molecular mechanisms underlying microbiome-associated diseases.