A Metabolome- and Metagenome-Wide Association Network Reveals Microbial Natural Products and Microbial Biotransformation Products from the Human Microbiota.

The human microbiome consists of thousands of different microbial species, and tens of thousands of bioactive small molecules are associated with them. These associated molecules include the biosynthetic products of microbiota and the products of microbial transformation of host molecules, dietary components, and pharmaceuticals. The existing methods for characterization of these small molecules are currently time consuming and expensive, and they are limited to the cultivable bacteria. Here, we propose a method for detecting microbiota-associated small molecules based on the patterns of cooccurrence of molecular and microbial features across multiple microbiomes. We further map each molecule to the clade in a phylogenetic tree that is responsible for its production/transformation. We applied our proposed method to the tandem mass spectrometry and metagenomics data sets collected by the American Gut Project and to microbiome isolates from cystic fibrosis patients and discovered the genes in the human microbiome responsible for the production of corynomycolenic acid, which serves as a ligand for human T cells and induces a specific immune response against infection. Moreover, our method correctly associated pseudomonas quinolone signals, tyrvalin, and phevalin with their known biosynthetic gene clusters.IMPORTANCE Experimental advances have enabled the acquisition of tandem mass spectrometry and metagenomics sequencing data from tens of thousands of environmental/host-oriented microbial communities. Each of these communities contains hundreds of microbial features (corresponding to microbial species) and thousands of molecular features (corresponding to microbial natural products). However, with the current technology, it is very difficult to identify the microbial species responsible for the production/biotransformation of each molecular feature. Here, we develop association networks, a new approach for identifying the microbial producer/biotransformer of natural products through cooccurrence analysis of metagenomics and mass spectrometry data collected on multiple microbiomes.

Dereplication of microbial metabolites through database search of mass spectra.

Natural products have traditionally been rich sources for drug discovery. In order to clear the road toward the discovery of unknown natural products, biologists need dereplication strategies that identify known ones. Here we report DEREPLICATOR+, an algorithm that improves on the previous approaches for identifying peptidic natural products, and extends them for identification of polyketides, terpenes, benzenoids, alkaloids, flavonoids, and other classes of natural products. We show that DEREPLICATOR+ can search all spectra in the recently launched Global Natural Products Social molecular network and identify an order of magnitude more natural products than previous dereplication efforts. We further demonstrate that DEREPLICATOR+ enables cross-validation of genome-mining and peptidogenomics/glycogenomics results.