Interactions of human mast cells with bacteria and bacterial products: relevance for inflammatory bowel disease

该提案的目的是了解粘膜肥大细胞(MC)与肠道微生物区系的细菌或细菌产物之间相互作用的机制和在健康和疾病中的功能意义。在过去，我们发现人粘膜MC对肠道微生物区系中的革兰氏阴性菌具有促进介质释放和细胞因子产生的反应。这种反应可能不依赖于Toll样受体(TLR)，因为我们的数据表明TLR配体不能诱导人类肠道(HiMC)释放介质和细胞因子。一个可能的机制是细菌溶血素，我们发现它是HiMC介体释放的有效触发因素。在第二个资助期，我们将进一步研究共生菌或细菌产物激活MC的机制。其次，我们将在人类和小鼠的炎症条件下研究MC对细菌的反应。第三，我们将评估益生菌是否调节MC-细菌的相互作用，以及肥大细胞介体是否调节肠道微生物区系的组成和功能。通过回答这些问题，我们将加深对肥大细胞-细菌相互作用的理解，以及肥大细胞在宿主对肠道微生物区系的反应和控制中的作用。此外，我们的方法应该为相关疾病的机制提供新的见解，例如炎症性肠病和其他与肠道屏障损伤相关的疾病。

The objective of the proposal is to understand the mechanisms and the functional implications of interactions between mucosal mast cells (MC) and bacteria or bacterial products of the intestinal microbiota in health and disease. In the past, we found that human mucosal MC respond with enhanced mediator release and cytokine production towards gram-negative bacteria of the intestinal microbiota. This response is likely not dependent on Toll-like receptors (TLR), because our data showed that TLR ligands fail to induce mediator and cytokine release in human intestinal (hiMC). A possible mechanism is bacterial hemolysin we identified as potent trigger of hiMC mediator release. In the 2nd funding period, we will further investigate the mechanisms involved in MC activation by commensal bacteria or bacterial products. Secondly, we will study MC responses to bacteria in inflammatory conditions in humans and in mice. Third, we will evaluate whether probiotics modulate MC-bacteria interactions and whether mast cell mediators modulate the composition and the function of the intestinal microbiota. By answering these questions, we will enhance our understanding of mast cell-bacteria interactions, and mast cell functions in the host’s response and control of the intestinal microbiota. Moreover, our approach should give new insight into the mechanisms of relevant diseases such as inflammatory bowel diseases and other diseases associated with gut barrier impairments.