Salmonella Expansion in the Gut

项目摘要 鼠伤寒沙门氏菌（Stm）引起严重的炎症性腹泻， 估计每年有一亿患者。许多研究已经描述了小鼠的扩张机制 抗生素后治疗，导致肠道微生物群落破坏， 增强对肠病原体如Stm和艰难梭菌的易感性。然而，Stm殖民了 在没有抗生素治疗的情况下。因此，研究Stm在植物中的扩展机制具有重要意义。 非抗生素处理的宿主。我们的中心假设是肠道微生物群的特定成员和 相关代谢物促进小鼠远端肠中的Stm扩增。在这方面，我们发现， 在129 Sv/J（129）小鼠的远端肠道中扩增，但在C57 BL/6 nramp 1（B6 N）小鼠中不扩增。许多机制， 在这一过程中发挥了作用。我们以前已经表明，Stm膨胀在 B6 N小鼠的肠道由拟杆菌属控制，在129只小鼠中不存在， 短链脂肪酸丙酸酯的拟杆菌依赖性生产足以限制Stm在大肠杆菌中的扩增。 体外和体内。这项研究提案的长期目标是确定STM的机制， 在远端肠道中茁壮成长，并利用宿主/肠道细菌衍生的代谢产物进行扩张。在目标1中，我们 鉴定促进129例患者远端肠道中Stm扩张的肠道细菌衍生因子和免疫因子 小鼠在目标2中，我们将确定和表征非肠梗阻患者远端肠道扩张所需的Stm途径。 抗生素治疗的小鼠。拟议的工作是创新的，因为它建立了新的概念， 病原体可以利用宿主和寄生细菌衍生的代谢物。我们希望， 这项研究的结论将确定Stm和其他可能的肠道病原体利用特定肠道的新机制 环境和微生物群落茁壮成长，可能导致新的传播控制方法 以及合理设计有益于公众健康的治疗方法。

PROJECT SUMMARY Salmonella enterica serovar Typhimurium (Stm) causes a severe inflammatory diarrhea and infects an estimated 100 million patients per year. A number of studies have described mechanisms of expansion in mice post-antibiotic treatment which causes a disruption to the commensal microbial community and leads to enhanced susceptibility to enteric pathogens such as Stm and Clostridium difficile. However, Stm colonizes the gut in the absence of antibiotic treatment. Thus, it is important to study the mechanisms of Stm expansion in non-antibiotic treated hosts. Our central hypothesis is that specific members of the gut microbiota and associated metabolites facilitate Stm expansion in the distal gut of mice. In this regard, we found that Stm expands in the distal guts of 129Sv/J (129) mice but not in C57BL/6nramp1 (B6N) mice. Many mechanisms, which are largely uncharacterized, play a role in this process. We have shown previously that Stm expansion in the guts of B6N mice is controlled by Bacteroides spp., which are not present in 129 mice, and that Bacteroides-dependent production of the short chain fatty acid propionate is sufficient to limit Stm expansion in vitro and in vivo. The long-term goal of this research proposal is to identify the mechanisms by which Stm thrives in the distal gut and exploits host/commensal bacteria-derived metabolites to expand. In Aim 1, we will identify commensal bacteria-derived and immune factors that promote expansion of Stm in the distal gut of 129 mice. In Aim 2, we will identify and characterize Stm pathways required for expansion in the distal gut of non- antibiotic treated mice. The proposed work is innovative because it establishes new concepts on how a pathogen can exploit host and commensal bacteria-derived metabolites. It is our expectation that the outcome of this study will identify new mechanisms by which Stm, and likely other enteric pathogens, exploit specific gut environments and microbial communities to thrive, potentially leading to new methods of transmission control and to the rational design of therapeutics that will benefit public health.