CRISPR-Cas immune repertoires as an ecological record of bacterial interactions with mobile genetic elements in the human gut

Bacteria in the human gut influence host physiology and disease risk, but their ecology is strongly shaped by mobile genetic elements (MGEs) such as phages and plasmids. Past interactions between bacteria and MGEs can be inferred from CRISPR-Cas cassettes, which contain short DNA fragments derived from invading elements. To lay the groundwork for research on the impact of such interactions on the human host, we examined bacteria, MGEs, and CRISPR-Cas in the gut microbiome. Using fecal shotgun metagenomes from 1034 Norwegians, we constructed an extended microbiome resource comprising 1.7K prokaryotic mOTUs, 19.5K viral vOTUs and 24.2K plasmid PTUs. We also recovered 74.2K unique CRISPR-Cas cassettes to map past bacteria-MGE interactions and assessed their associations with human diet and lifestyle factors. CRISPR-Cas spacers, and which viruses and plasmids they targeted, varied substantially within bacterial species, but were predominantly directed towards cohort-specific MGEs. Moreover, bacteria were more likely to target MGEs present in the same sample, consistent with local exposure. Bacteria also shared more targets within taxonomic families than across families, where mobilizable plasmids were more frequent among the targets. We did not find evidence that CRISPR-Cas spacers were related to characteristics of the human host, beyond the host-bacteria associations. Together, this research provides a large-scale resource and a structured analysis of bacteria-MGE interactions in the gut microbiome, and their contribution to microbial ecosystem dynamics.