Biology subjects

Geva-Zatorsky, N.

Publications and source records attributed to Geva-Zatorsky, N..

6 recordsLinked to original sources

bioRxiv2026

Growth capacity and mortality burden shape microbial persistence under osmotic stress in Bacteroides thetaiotaomicron

Microbial persistence in the gut is central to sustaining beneficial host-microbiota interactions; however, characterizing determinants of persistence in vivo can be challenging due to the complexity of native microbial communities interacting with the host. Here, we used a defined microbial consortium to demonstrate that intrinsic in vitro growth capacity becomes increasingly predictive of in vivo relative abundance as intestinal osmolality increases. In Bacteroides thetaiotaomicron, in vivo abundance was higher than predicted from growth capacity alone, indicating that additional physiological factors contribute to persistence. We identify mortality as one such determinant: adaptation to prolonged osmotic stress markedly reduced cell loss without enhancing growth capacity. This adaptive phenotype was associated with rapid and reversible phase variation in cell surface-associated PUL78/80 rather than fixed de novo mutations, with the PUL78/80-OFF state becoming progressively enriched among surviving cells as mortality increased. Our findings demonstrate that in addition to growth capacity, reduced cell loss can provide a distinct route to microbial persistence during environmental perturbation.

microbiology↗

bioRxiv2026

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.

microbiology↗

bioRxiv2025

Bacteriophage-driven DNA inversions shape bacterial functionality and long-term co-existence in Bacteroides fragilis

Bacterial genomic DNA inversions, which govern molecular phase-variations, provide the bacteria with functional plasticity and phenotypic diversity. These targeted rearrangements enable bacteria to respond to environmental challenges, such as bacteriophage predation, evading immune detection or gut colonization. This study investigated the short- and long-term effects of the lytic phage Barc2635 on the functional plasticity of Bacteroides fragilis, a gut commensal. Germ-free mice were colonized with B. fragilis and exposed to Barc2635 to identify genomic alterations driving phenotypic changes. Phage exposure triggered dynamic and prolonged bacterial responses, including significant shifts in phase-variable regions (PVRs), particularly in promoter orientations of polysaccharide biosynthesis loci. These shifts coincided with increased entropy in PVR inversion ratios, reflecting heightened genomic variability. In contrast, B. fragilis in control mice exhibited stable genomic configurations after gut adaptation. The phase-variable Type 1 restriction-modification system, which affects broad gene expression patterns, showed variability in both groups. However, phage-exposed bacteria displayed more restrained variability, suggesting phage-derived selection pressures. Our findings reveal that B. fragilis employs DNA inversions to adapt rapidly to phage exposure and colonization, leveraging genomic variability for resilience. This study emphasizes gut bacterial genomic and phenotypic plasticity upon exposure to the mammalian host and to bacteriophages.

microbiology↗

bioRxiv2023

Functional and metagenomic level diversities of human gut symbiont-derived glycolipids

Bioactive metabolites produced by symbiotic microbiota causally impact host health and disease, nonetheless, incomplete functional annotation of genes as well as complexities and dynamic nature of microbiota make understanding species-level contribution in production and actions difficult. Alpha-galactosylceramides produced by Bacteroides fragilis (BfaGC) are one of the first modulators of colonic immune development, but biosynthetic pathways and the significance of the single species in the symbiont community still remained elusive. To address these questions at the microbiota level, we have investigated the lipidomic profiles of prominent gut symbionts and the metagenome-level landscape of responsible gene signatures in the human gut. We first elucidated the chemical diversity of sphingolipid biosynthesis pathways of major bacterial species. In addition to commonly shared ceramide backbone synthases showing two distinct intermediates, alpha-galactosyltransferase (agcT), the necessary and sufficient component for BfaGC production and host colonic type I natural killer T (NKT) cell regulation by B. fragilis, was characterized by forward-genetics based targeted metabolomic screenings. Phylogenetic analysis of agcT in human gut symbionts revealed that only a few ceramide producers have agcT and hence can produce aGCs, on the other hand, structurally conserved homologues of agcT are widely distributed among species lacking ceramides. Among them, alpha-glucosyl-diacylglycerol(aGlcDAG)-producing glycosyltransferases with conserved GT4-GT1 domains are one of the most prominent homologs in gut microbiota, represented by Enterococcus bgsB. Of interest, aGlcDAGs produced by bgsB can antagonize BfaGC-mediated activation of NKT cells, showing the opposite, lipid structure-specific actions to regulate host immune responses. Further metagenomic analysis of multiple human cohorts uncovered that the agcT gene signature is almost exclusively contributed by B. fragilis, regardless of age, geographical and health status, where the bgsB signature is contributed by >100 species, of which abundance of individual microbes is highly variable. Our results collectively showcase the diversities of gut microbiota producing biologically relevant metabolites in multiple layers-biosynthetic pathways, host immunomodulatory functions and microbiome-level landscapes in the host.

microbiology↗

bioRxiv2023

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

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.

microbiology↗

bioRxiv2021

Metagenomic analysis reveals the signature of gut microbiota associated with human chronotypes

Patterns of diurnal activity differ substantially between individuals, with early risers and late sleepers being examples of opposite chronotypes. Growing evidence suggests that the late chronotype significantly impacts the risk of developing mood disorders, obesity, diabetes, and other chronic diseases. Despite the vast potential of utilizing chronotype information for precision medicine, those factors that shape chronotypes remain poorly understood. Here, we assessed whether the various chronotypes are associated with different gut microbiome compositions. Using metagenomic sequencing analysis, we established a distinct signature associated with chronotype based on two bacterial genera, Alistipes (elevated in "larks") and Lachnospira (elevated in "owls"). We identified three metabolic pathways associated with the early chronotype, and linked distinct dietary patterns with different chronotypes. Our work demonstrates an association between the gut microbiome and chronotype and may represent the first step towards developing dietary interventions aimed at ameliorating the deleterious health correlates of the late chronotype.

genomics↗