Therapy of IBD: Identification of bacteria, bacterial components and the host intestinal immune mechanisms

肠道菌群是一个复杂的微生物群落，定植在胃肠道中。肠道菌群组成和微生物数量因当地环境条件的不同而不同。在之前的工作中，我们发现共生菌株B. vulgatus能够预防甚至更显著地治愈IBD，并且促进IBD愈合，预防甚至诱导的细菌因子似乎是脂质A，脂多糖的生物活性部分。脂质A的酰化和磷酸化模式似乎决定了抗炎或促炎作用。因此，我们将重点从两个方面进行研究，一是宿主免疫系统和微生物在IBD治疗中的先决条件，二是治疗性LPS与TLR4的相互作用。我们将分析：(i)普通杆菌的作用是一种物种还是一种菌株的特异性作用，（ii）哪种细胞类型介导普通杆菌/LPSBV对IBD的愈合，（iii）给药LPSBV是否改变肠道微生物群的组成，（iv）治疗性LPS/TLR4相互作用的机制，以及(v)介导普通杆菌/LPSBV抗炎作用的细胞内过程。该项目将加深对LPS/TLR4在IBD中的相互作用、对肠道免疫稳态的贡献以及这种相互作用在恢复免疫稳态中的潜力的理解。了解影响肠道免疫平衡或失衡的机制和因素对于开发新的治疗方法和治疗肠道炎症性疾病的新策略至关重要。

The intestinal microbiota is a complex community of microorganisms that colonizes the gastrointestinal tract. Composition of the intestinal microbiota and number of microorganisms differs in dependency of the local environmental conditions. In previous work we showed that the commensal strain B. vulgatus is able to prevent and even more strikingly to heal IBD and that the bacterial factor promoting healing, prevention and even induction of IBD seems to be Lipid A, the bioactive part of LPS. The acylation and phosphorylation pattern of Lipid A seems to decide on an anti-inflammatory or pro-inflammatory effect. Therefore we will focus on two aspects, first the prerequisites of the host immune system and the microbes in healing IBD and second the interaction of therapeutic LPS with TLR4. We will analyze whether (i) the effect of B. vulgatus is a species or a strain specific effect, (ii) which cell type mediates healing of IBD by Bacteroides vulgatus/LPSBV, (iii) whether administration of LPSBV alters the composition of intestinal microbiota, (iv) the mechanisms of therapeutic LPS/TLR4 interaction, and (v) the intracellular processes mediating the antiinflammatory effect of B. vulgatus/LPSBV. The project will result in a deepened understanding of LPS/TLR4 interaction in IBD, the contribution to intestinal immune homeostasis and the potential of this interaction in restoring immune homoeostasis. Understanding the mechanisms and players influencing balance or imbalance of intestinal immune homoeostasis is essential for the development of novel therapeutics and therefore for new strategies in treatment of intestinal inflammatory disorders.