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

Area of Science:

• Microbiology
• Immunology
• Genomics

Background:

• Reversible genomic DNA inversions regulate bacterial gene expression.
• The impact of these inversions on host diseases, such as inflammatory bowel disease (IBD), is not well understood.

Purpose of the Study:

• To investigate the role of bacterial genomic inversions in IBD pathogenesis.
• To identify specific invertible regions and their correlation with disease states.

Main Methods:

• Analysis of metagenomic samples from IBD patient cohorts.
• Investigating the orientation of invertible regions, including the Bacteroides fragilis polysaccharide A (PSA) promoter.
• Experimental models using mice colonized with human microbiota and B. fragilis, including monocolonization studies.

Main Results:

• Specific invertible regions, notably the B. fragilis PSA promoter, showed altered orientations correlating with IBD.
• The PSA promoter was predominantly in the "OFF" orientation in IBD patients, associated with increased bacteriophages.
• In mice, colitis induction led to decreased "ON" PSA orientation, which reversed with inflammation resolution; bacteriophage infection promoted the "OFF" orientation, reducing PSA and regulatory T cells (Tregs).

Conclusions:

• Bacteriophages and host inflammation dynamically regulate bacterial phase variation through genomic inversions.
• This bacterial functional plasticity contributes to disease processes, exemplified by altered PSA expression and Treg cell induction in IBD.