WTD5_1.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.

*鼠伤寒沙门氏菌*（Salmonella enterica subsp. enterica serovar Typhimurium，简称*S. Typhimurium*）是一种兼性胞内致病菌，可导致人类和动物发生严重的胃肠道感染。VI型分泌系统（type VI secretion system, T6SS）在其毒力中发挥关键作用，促进与宿主肠道菌群的竞争并增强感染能力。尽管*S. Typhimurium*仅拥有一个T6SS，但它编码3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功能。本研究采用16S rRNA测序技术（16S rRNA sequencing）分析了野生型（wild-type, WT）*S. Typhimurium*或突变株（Δhcp1、Δhcp2、Δhcp3）感染后BALB/c小鼠的肠道菌群。研究发现，*S. Typhimurium*感染会引发严重的肠道菌群失调，尤其在感染后第2天更为显著。具体而言，感染导致厚壁菌门（Firmicutes）显著增加，并激活促进短链脂肪酸（short chain fatty acids）分解的能量通路。野生型*S. Typhimurium*感染使埃希氏菌-志贺氏菌属（Escherichia-Shigella）丰度急剧上升，表明存在炎症相关的菌群失调；而Δhcp1、Δhcp2和Δhcp3组的变化较轻微，提示肠道菌群的破坏程度较低。单个hcp基因的缺失导致不同的细菌类群变化，突显了每个hcp基因的非冗余功能。尽管仅拥有一个T6SS，*S. Typhimurium*通过其Hcp蛋白的不同功能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与持续存活。这些发现为细菌适应及宿主-病原体互作（host-pathogen interactions）的复杂机制提供了见解，为针对T6SS介导的菌群失调的治疗干预策略提供了潜在方向。