Sub-genomic variation in the gut microbiome associates with host metabolic health

Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences such as virulence, antibiotic resistance, and even host longevity, yet exploring variation at this sub-genomic level across people's gut microbiome is challenging, possibly owing to difficulties in correct metagenomic read assignment. Here, we devised algorithms that improve the assignment accuracy of metagenomic reads to reference sequences and systematically identify variability in microbial sub-genomic regions. We find Sub-Genomic Variation (SGV) to be prevalent in the microbiome and to span multiple microbial phyla. SGVs are associated with bacterial fitness and their member genes are enriched for CRISPR-associated and antibiotic producing functions and depleted from housekeeping genes, suggestive of a role in microbial adaptation. We find over 100 novel associations between SGVs and host disease risk factors, demonstrating that SGVs constitute a new layer of metagenomic information. Finally, by exploring genes clustered in the same SGV, we uncover possible mechanistic links between the microbiome and its host, as in the case of a 41kbp region in Anaerostipes hadrus encoding a composite inositol catabolism-butyrate biosynthesis pathway, whose existence is associated with significantly lower host body weight and metabolic disease risk. Overall, our results uncover a nascent layer of variability in biological systems that is associated with microbial adaptation and host health.