Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota

Abstract

Reversible genomic DNA-inversions control expression of numerous bacterial molecules in the human gut, but how this relates to disease remains uncertain. By analyzing metagenomic samples from six human Inflammatory Bowel Disease cohorts combined with mice experimentation, we identified multiple invertible regions where a particular orientation was correlated with disease. These include the promoter of the anti-inflammatory polysaccharide-A (PSA) of Bacteroides fragilis, which is mostly oriented OFF during inflammation but is present in the ON orientation when inflammation is resolved. We further detected increased abundances of B. fragilis-associated bacteriophages in patients with the PSA OFF orientation, and a significant reduction in the frequency of the ON orientation, in the presence of the B. fragilis-associated bacteriophage, thereby altering the bacterial induced immune modulation. Altogether, we reveal dynamic and reversible bacterial phase-variations driven both by bacteriophages and the host inflammatory state, signifying bacterial functional plasticity during inflammation and opening future research avenues.