Gene-level metagenomics identifies genome islands associated with immunotherapy response

Researchers must be able to generate experimentally testable hypotheses from sequencing-based observational microbiome experiments to discover the mechanisms underlying the influence of gut microbes on human health. We describe a novel bioinformatics tool for identifying testable hypotheses based on gene-level metagenomic analysis of WGS microbiome data (geneshot). By applying geneshot to two independent previously published cohorts, we identified microbial genomic islands consistently associated with response to immune checkpoint inhibitor (ICI)-based cancer treatment in culturable type strains. The identified genomic islands are within operons involved in type II secretion, TonB-dependent transport, and bacteriophage growth. These results, as well as the underlying methodology, inform further mechanistic studies and facilitate the development of microbiome-enhanced therapeutics.