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 (IBD) cohorts combined with mice experimentation, we identified multiple invertible regions in which a particular orientation was correlated with disease. These include the promoter of the anti-inflammatory polysaccharide-A (PSA) ofBacteroides fragilis, which is mostly oriented OFF during inflammation but switches to the ON orientation when inflammation is resolved. We further detected increased abundances ofBacteroides fragilisassociated bacteriophages in patients with the PSA OFF orientation. Isolation and analysis of aBacteroides fragilisassociated bacteriophage revealed that it induced the PSA OFF switch, thereby altering the bacterial induced immune modulation. Altogether, we reveal large-scale dynamic and reversible bacterial phase variations driven both by bacteriophages and the host inflammatory state signifying bacterial functional plasticity and suggesting potential clinical interventions.

Mutation bias and adaptation in bacteria

“…However, several studies have demonstrated that localized mutagenic positions can be favoured under selection [16,[144][145][146]. These include a recent study that detailed how B. fragilis utilizes reversible DNA inversions to control the expression of capsular polysaccharides as a means to cope with periods of inflammation [147]. However, whether these positions have been maintained by selection in microbial pathogens is less clear [140].…”

Bacteroidesexpand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity

“…A key evolved feature of these bacteria is the ability of each strain to produce numerous (eight or more) distinct capsular polysaccharides (CPS) 1,2 that are tightly regulated so that only one CPS is typically produced per bacterial cell. This bet-hedging strategy generates Bacteroides populations with great surface variability that protect from phage [3][4][5] while also mediating other processes such as immune modulation, biofilm formation, and affecting antibiotic resistance and inflammation [6][7][8][9][10][11] .…”

“…Horizontal triangles mark the inverted repeats recognized by Mpi recombinase for promoter inversion17 . Proposed roles for CPS diversity in B. fragilis subpopulations (colored coats) are listed3,6,[8][9][10]99 . The schematics illustrate the proposed roles of YX activation and ZX inhibition of noncognate YX in generating subpopulation CPS diversity12,13 .…”