3D5_2.fastqDivergent Roles of hcp Genes in Salmonella Typhimurium T6SS Shape Gut Microbiota Dysbiosis during InfectionT6SS

Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen causing significant gastrointestinal infections in humans and animals. The type VI secretion system (T6SS) plays a crucial role in its virulence, facilitating competition with host gut microbiota and promoting infection. While S. Typhimurium possesses a single T6SS, it encodes three hcp genes, which are crucial for its functionality and may exhibit non-redundant roles. In this study, we used 16S rRNA sequencing to analyze gut microbiota in BALB/c mice after infection with wild-type (WT) S. Typhimurium or mutant strains (Δhcp1, Δhcp2, Δhcp3). Our findings revealed that S. Typhimurium infection induced severe gut dysbiosis especially on the second day post-infection. Specifically, the infection led to a notable increase in Firmicutes and activated the energy pathways that promotes the breakdown of short chain fatty acids. Wild type S. Typhimurium infection caused a sharp increase in Escherichia-Shigella levels, indicating inflammation-related dysbiosis, while the Δhcp1, Δhcp2, and Δhcp3 groups showed milder changes, suggesting less disruption to gut microbiota. Deletion of individual hcp genes led to distinct bacterial taxa changes, underscoring the non-redundant functions of each hcp. Despite having only one T6SS, S. Typhimurium achieves precise modulation of its functions through the divergent roles of its Hcp proteins, enabling efficient colonization and persistence in the host gut.  These findings provide insights into the intricate mechanisms of bacterial adaptation and host-pathogen interactions, offering potential avenues for therapeutic interventions targeting T6SS-mediated dysbiosis.