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）与健康和疾病中肠道微生物群的细菌或细菌产物之间相互作用的机制和功能意义。在过去，我们发现人粘膜MC对肠道微生物群的革兰氏阴性菌的反应是增强的介质释放和细胞因子产生。这种反应可能不依赖于Toll样受体（TLR），因为我们的数据显示TLR配体不能诱导人肠道（hiMC）中的介质和细胞因子释放。一个可能的机制是细菌溶血素，我们确定为hiMC介质释放的有效触发剂。在第二个资助期，我们将进一步研究微生物或细菌产物激活MC的机制。其次，我们将研究MC在人类和小鼠炎症条件下对细菌的反应。第三，我们将评估益生菌是否调节MC-细菌相互作用，以及肥大细胞介质是否调节肠道微生物群的组成和功能。通过回答这些问题，我们将提高我们对肥大细胞-细菌相互作用的理解，以及肥大细胞在宿主响应和控制肠道微生物群中的功能。此外，我们的方法应该为相关疾病的机制提供新的见解，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.