Mathematical Modelling of Bacterial DNA Inversion Dynamics Uncovers an Organized Multi-Locus Response to Phage Predation in Bacteroides fragilis

Phase variation enables bacteria to generate phenotypic diversity through reversible genomic DNA inversions that alter surface structures and other adaptive traits. In Bacteroides fragilis, multiple invertible regions regulate surface structures, including capsular polysaccharides, which shape the bacterial interactions with the host. Previous studies have shown that molecular phase- variable surface states can alter bacteriophage susceptibility in bacteria. Here, we modelled the dynamic interaction from a longitudinal gnotobiotic mouse experiment from a recent B. fragilis NCTC 9343-Barc2635 study. We aimed to analyze temporal patterns, region-level susceptibility, and combinatorial patterns across the 18 invertible regions, and quantify it into a dynamical framework. The model we generated revealed a structured phage-susceptibility landscape in which loci differed in effective phage-associated sensitivity and occupied distinct parameter regimes. Projecting fitted susceptibility weights onto observed "ON"-fraction trajectories showed that the temporal response was compressed into a small subset of dominant phase variable region (PVR) contributors. A two-dimensional contribution-space analysis further separated persistent contributors from rare high-impact loci, indicating that susceptibility evolves along constrained temporal paths rather than fluctuating randomly across promoter states. Several loci contributed to the modelled susceptibility signal over time in phase-dependent patterns. Specifically, the PVR of polysaccharide F (PSF) provided a persistent contribution, with a recurring PSF-centered, phase-dependent susceptibility pattern in combinatorial scoring of pairwise, triple, and quadruple loci sets. Our results do not identify a physical Barc2635 receptor or establish direct causal infection states. Instead, they show that phage predation is associated with a structured, low-dimensional, multi-locus organization of phase variation linking region- level susceptibility, temporal contribution, and recurring promoter-state combinations. Highlights* Development of a longitudinal mathematical framework for multi-locus bacterial phase variation under phage predation. * The mathematical modeling revealed an organized susceptibility landscape despite high- dimensional DNA inversion dynamics. * PSF was identified as a persistent contributor to phase-dependent multi-locus combinations during phage exposure. * Distinguished transient phase-variable responses from sustained contributors to longitudinal phage dynamics. * Established a general framework for interpreting bacterial genomic plasticity in host- bacterium-phage systems.