2D5_4.fastqDivergent Roles of hcp Genes in Salmonella Typhimurium T6SS Shape Gut Microbiota Dysbiosis during InfectionT6SS

<em>Salmonella enterica </em>subsp.<em> enterica </em>serovar Typhimurium (<em>S. </em>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 <em>S.</em> Typhimurium possesses a single T6SS, it encodes three <em>hcp</em> 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) <em>S.</em> Typhimurium or mutant strains (Δ<em>hcp1</em>, Δ<em>hcp2</em>, Δ<em>hcp3</em>). Our findings revealed that <em>S</em>. 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 <em>S.</em> Typhimurium infection caused a sharp increase in <em>Escherichia-Shigella</em> levels, indicating inflammation-related dysbiosis, while the Δ<em>hcp</em>1, Δ<em>hcp</em>2, and Δ<em>hcp</em>3 groups showed milder changes, suggesting less disruption to gut microbiota. Deletion of individual <em>hcp</em> genes led to distinct bacterial taxa changes, underscoring the non-redundant functions of each <em>hcp</em>. Despite having only one T6SS, <em>S.</em> 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.

肠炎沙门氏菌肠炎亚种鼠伤寒血清型（S. Typhimurium）是一种兼性胞内病原体，可在人类和动物中引起严重的胃肠道感染。VI型分泌系统（T6SS）在其毒力中发挥关键作用，促进与宿主肠道微生物群的竞争并增强感染。尽管S. Typhimurium仅拥有一个T6SS，但它编码三个hcp基因（hcp genes），这些基因对其功能至关重要且可能具有非冗余作用。本研究采用16S rRNA测序技术，分析了BALB/c小鼠感染野生型（WT）S. Typhimurium或突变株（Δhcp1、Δhcp2、Δhcp3）后的肠道微生物群。研究结果表明，S. Typhimurium感染可诱导严重的肠道菌群失调（dysbiosis），尤其在感染后第二天更为显著。具体而言，感染导致厚壁菌门数量显著增加，并激活了促进短链脂肪酸分解的能量通路。野生型S. Typhimurium感染导致埃希氏菌-志贺氏菌属水平急剧升高，提示炎症相关的菌群失调；而Δhcp1、Δhcp2和Δhcp3突变株组的变化较轻微，表明其对肠道微生物群的干扰较小。单个hcp基因的缺失导致细菌类群发生显著差异，强调了每个hcp基因的非冗余功能。尽管仅拥有一个T6SS，S. Typhimurium通过其Hcp蛋白的不同作用实现对自身功能的精确调控，从而能够在宿主肠道中高效定植并持续存在。这些发现为理解细菌适应和宿主-病原体相互作用的复杂机制提供了见解，并为针对T6SS介导的菌群失调的治疗干预提供了潜在方向。