Role of different Lipid A structures of commensal bacteria in the regulation of colitogenic CD4+ T cell responses

我们证明了肠道细菌群落的组成，更准确地说，拟杆菌属与肠杆菌科的比例决定了在遗传易感宿主中诱导结肠炎或维持肠道稳态。重要的是，在其胃肠道系统内主要含有厌氧拟杆菌属群的Rag 1-/-小鼠被保护免于诱导转移性结肠炎，而用高CFU的肠杆菌科定殖的Rag 1-/-小鼠对肠道炎症高度敏感。从机理上讲，我们发现在E.大肠杆菌，并因此肠细菌对厌氧脂质A结构的调整，将结肠炎诱导E.大肠杆菌菌株进入结肠炎预防之一。在本项目中，我们将确定表达不同Lipid A结构的细菌对肠DC的活化和成熟的影响，将表征用不同大肠杆菌或Lipid A致敏的树突状细胞的T细胞活化能力以及致结肠炎性或非致结肠炎性T细胞应答。该项目应该提供一个基础，是否肠道细菌可能预防或诱导炎症性肠病，并可能提供一个新的预防或治疗策略在炎症性肠病（IBD）的基础。

We demonstrated that the composition of intestinal bacterial communities, more precisely the proportion of Bacteroidetes to Enterobacteriaceae decides on induction of colitis or maintenance of intestinal homeostasis in genetically predisposed hosts. Importantly, Rag1-/- mice that harbor predominantly the anaerobic Bacteroidetes group within their gastrointestinal system are protected from induction of transfer colitis, whereas Rag1-/- mice colonized with a high CFU of Enterobacteriaceae are highly susceptible to intestinal inflammation. Mechanistically, we show that the exchange of laurate by palmitate in the Lipid A of E. coli, and therefore the adjustment of the enterobacterial to the anaerobic Lipid A structure, converts a colitis inducing E. coli strain into a colitis preventing one. Within this project we will define the effects of bacteria expressing different Lipid A structures on activation and maturation of intestinal DC, the T cell activating capacity of dendritic cells primed with different commensal bacteria or Lipid A and colitogenic or non colitogenic T cell responses will be characterized. The project ought to provide a basis as to whether commensal bacteria might prevent or induce inflammatory intestinal diseases and might provide a basis for new preventive or therapeutical strategies in inflammatory bowel diseases (IBD).