Disruption of NF-kappaB signalling by ancient microbial molecules: novel therapies of the future?
Disruption of NF-kappaB signalling by ancient microbial molecules: novel therapies of the future?
复制标题
古代微生物分子对 NF-kappaB 信号传导的破坏：未来的新疗法？
DOI：
10.1136/gut.2009.179614
复制
发表时间：
2010
期刊：
影响因子：
24.5
通讯作者：
Polk,DBrent
中科院分区：
文献类型：
--
作者：
Yan,Fang;Polk,DBrent
INTRODUCTION The intestinal microbiota consisting of the complex and dynamic communities of microbes is a component of the human ecosystem, which profoundly influences health through effects on nutrition, immunity, intestinal epithelial homeostasis and intestinal development. However, the composition of the ‘normal healthy intestinal microbiota’is not currently clearly defined. Likewise, the characteristics of the hostemicrobial interaction that contribute to beneficial effects on human health and disruption of this interaction that leads to various disease states are poorly understood. Recent studies using metagenomic analysis of gut microbiome have identified unique bacterial genome sequences that functionally associate with host health. 1 2 Furthermore, analysis of the known bacterial genomic sequences, such as Lactobacillus strains, predicts secreted and cell surface proteins with potential regulatory effects on intestinal cells. 3 4 Therefore, functional studies of microbe-derived proteins are needed to determine whether the nature of the microbe-derived molecules is as important as the specific microbial composition of the gut. For example, two novel Lactobacillus rhamnosus GG (LGG)-derived proteins have been cloned and shown to prevent cytokineinduced intestinal injury and apoptosis. 5 Regulation of signalling pathways to induce diverse cellular responses serves as one of the mechanisms by which microbes and microbial products exert their action on the host. Intestinal microbial regulation of nuclear factor (NF)-kB signalling is one of the best-studied pathways determining intestinal homeostasis and diseases. NF-kB is a key transcriptional factor controlling the expression of genes mediating inflammatory and antiapoptotic responses (reviewed by Hayden et al6). Growing evidence suggests that ‘optimal’NF-kB activity plays a significant role in maintaining normal intestinal homeostasis. However, hyper-activation of NF-kB results in chronic intestinal inflammatory disorders (reviewed by Spehlmann and Eckmann7). It is well known that toll-like receptors (TLRs), a class of membrane receptors that sense extracellular microbes through recognition of microbial products, trigger anti-pathogen signalling cascades in intestinal epithelial cells and mucosal immune cells. In the best understood pathway, activation of one of the TLR adaptor proteins, MyD88, leads to NF-kB activation, which defends against most pathogens to maintain intestinal homeostasis and prevent injury. 8 9 One integrating target of TLRs is the activation of NF-kB. Since studies regarding TLRs have recently been extensively reviewed, 10 11 this article will not address microbial product activation of NF-kB through these pathways. This review focuses on new insights into intestinal microbe-derived molecules that inhibit NF-kB activation and its transcriptional activity for disease prevention and treatment. The biological consequences of NF-kB signalling regulated by these molecules on innate and adaptive immune responses in intestinal epithelial cells and immune cells involved in intestinal protection will be discussed (figure 1). The majority of studies referenced in this review are from publications since 2007.
