Salmonella Expansion in the Gut

项目总结 鼠伤寒沙门氏菌(STM)引起严重的炎症性腹泻，并感染 估计每年有1亿名患者。许多研究已经描述了小鼠的扩张机制 抗生素后治疗会破坏共生微生物群落，并导致 增强对STM和艰难梭菌等肠道病原体的敏感性。然而，STM殖民了 肠道在没有抗生素治疗的情况下。因此，对STM扩增机制的研究具有重要意义。 未经抗生素处理的宿主。我们的中心假设是肠道微生物区系的特定成员和 相关代谢物促进STM在小鼠远端肠道的扩张。在这方面，我们发现STM 在129Sv/J(129)小鼠的远端肠道内扩张，但在C57BL/6nramp1(B6N)小鼠体内不扩张。很多机制， 它们在这一过程中扮演着重要角色。我们以前已经展示过，STM在 B6N小鼠的肠道受类杆菌控制，而129只小鼠中没有类杆菌 类杆菌依赖的短链脂肪酸丙酸酯的生产足以限制STM在 体外和体内。这项研究计划的长期目标是确定STM 在远端肠道中茁壮成长，并利用宿主/共生细菌衍生的代谢物进行扩张。在目标1中，我们将 鉴定促进STM在129人远端肠道扩张的共生细菌来源和免疫因子 老鼠。在目标2中，我们将识别和表征在非肠道远端扩张所需的STM通路。 抗生素处理过的小鼠。拟议的工作是创新的，因为它建立了关于如何 病原菌可以利用宿主和共生细菌衍生的代谢物。我们期望结果是 这项研究将确定STM和可能的其他肠道病原体利用特定肠道的新机制 环境和微生物群落蓬勃发展，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.