Sim Shuzhen, Hibberd Martin L
Infectious Diseases, Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.
BMC Microbiol. 2016 Jan 15;16:6. doi: 10.1186/s12866-016-0624-8.
Gut bacteria-host interactions have been implicated in the pathogenesis of numerous human diseases, but few mechanisms have been described. The genetically tractable nematode worm Caenorhabditis elegans can be infected with pathogenic bacteria, such as the human gut commensal Enterococcus faecalis, via feeding, making it a good model for studying these interactions.
An RNAi screen of 17 worm candidate genes revealed that knockdown of the transcription factor nhr-49, a master regulator of fat metabolism, shortens worm lifespan upon infection with E. faecalis (and other potentially pathogenic bacteria) compared to Escherichia coli. The functional similarity of nhr-49 to the mammalian peroxisome proliferator-activated receptors (PPARs) suggests that this is mediated through a link between fatty acid metabolism and innate immunity. In addition, knockdown of either dlg-1 or ajm-1, which encode physically interacting proteins in the C. elegans epithelial junction, also reduces worm lifespan upon E. faecalis challenge, demonstrating the importance of the intestinal epithelium as an immune barrier.
The protective roles identified for nhr-49, dlg-1, and ajm-1 suggest mechanistic interactions between the gut microbiota, host fatty acid metabolism, innate immunity, and epithelial junction integrity that are remarkably similar to those implicated in human metabolic and inflammatory diseases.
肠道细菌与宿主的相互作用与多种人类疾病的发病机制有关，但相关机制的描述较少。基因易操作的线虫秀丽隐杆线虫可通过摄食感染致病细菌，如人类肠道共生菌粪肠球菌，这使其成为研究这些相互作用的良好模型。
对17个线虫候选基因进行的RNA干扰筛选显示，与大肠杆菌相比，敲低脂肪代谢的主要调节因子转录因子nhr-49会缩短粪肠球菌（及其他潜在致病细菌）感染后的线虫寿命。nhr-49与哺乳动物过氧化物酶体增殖物激活受体（PPARs）的功能相似性表明，这是通过脂肪酸代谢与先天免疫之间的联系介导的。此外，敲低dlg-1或ajm-1（它们在秀丽隐杆线虫上皮连接中编码相互作用的蛋白质）也会降低粪肠球菌攻击后的线虫寿命，这证明了肠上皮作为免疫屏障的重要性。
nhr-49、dlg-1和ajm-1所确定的保护作用表明，肠道微生物群、宿主脂肪酸代谢、先天免疫和上皮连接完整性之间的机制相互作用与人类代谢和炎症性疾病中涉及的机制非常相似。
