2D2_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.

鼠伤寒沙门氏菌肠炎亚种肠炎血清型（Salmonella enterica subsp. enterica serovar Typhimurium，简称S. Typhimurium）是一种兼性胞内病原体，可引发人和动物严重的胃肠道感染。VI型分泌系统（type VI secretion system, T6SS）在其毒力发挥中起关键作用，既能促进该菌与宿主肠道菌群的竞争，又能助力感染进程。尽管S. Typhimurium仅拥有一套T6SS，但其编码三个hcp基因（hcp genes），这些基因对T6SS的功能至关重要，且可能具有非冗余作用。本研究采用16S rRNA测序技术（16S rRNA sequencing），分析了BALB/c小鼠感染S. Typhimurium野生型（WT）或突变株（Δhcp1、Δhcp2、Δhcp3）后的肠道菌群变化。结果显示，S. Typhimurium感染后（尤其是感染第二天）会引发严重的肠道菌群失调（gut dysbiosis）：厚壁菌门（Firmicutes）丰度显著上升，且促进短链脂肪酸分解的能量代谢通路被激活；野生型菌株感染导致埃希氏菌-志贺氏菌属（Escherichia-Shigella）水平急剧升高，提示存在炎症相关的菌群失调，而三个hcp突变株感染组的变化程度较轻，表明其对肠道菌群的破坏较小。单个hcp基因缺失可导致细菌类群发生独特变化，凸显了各hcp基因的非冗余功能。尽管仅拥有一套T6SS，S. Typhimurium可通过Hcp蛋白的差异化作用实现对自身功能的精准调控，使其能够在宿主肠道中高效定植并持续存活。这些发现为细菌适应及宿主-病原体互作的复杂机制提供了新的见解，也为靶向T6SS介导的菌群失调的治疗干预提供了潜在方向。