Garcia-So Jeewon, Zhang Xinwen, Yang Xiaohua, Rubinstein Mara Roxana, Mao De Yu, Kitajewski Jan, Liu Kang, Han Yiping W
Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.
Department of Periodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
JCI Insight. 2019 Feb 7;4(3):e125436. doi: 10.1172/jci.insight.125436.
Fusobacterium nucleatum is an oral anaerobe prevalent in intrauterine infection associated with a wide spectrum of adverse pregnancy outcomes. We demonstrate here that F. nucleatum triggers placental inflammation through maternal, rather than paternal, TLR4-mediated signaling. Elimination of TLR4 from maternal endothelial cells alleviated placental inflammation and reduced fetal and neonatal death, while elimination of TLR4 in the hematopoietic cells had no effect. The placental inflammatory response followed a spatiotemporal pattern, with NF-κB activation observed first in the maternal endothelial cells and then in the decidual cells surrounding the endothelium, followed by induction of inflammatory cytokines and chemokines. Supplementation of pregnant mice with fish oil as a source of omega-3 fatty acids suppressed placental inflammation, reduced F. nucleatum proliferation in the placenta, and increased fetal and neonatal survival. In vitro analysis illustrates that omega-3 fatty acids inhibit bacterial-induced inflammatory responses from human umbilical cord endothelial cells. Our study therefore reveals a mechanism by which microbial infections affect pregnancy and identifies a prophylactic therapy to protect against intrauterine infections.
具核梭杆菌是一种口腔厌氧菌，在与多种不良妊娠结局相关的宫内感染中普遍存在。我们在此证明，具核梭杆菌通过母体而非父体的TLR4介导信号触发胎盘炎症。从母体内皮细胞中消除TLR4可减轻胎盘炎症并减少胎儿和新生儿死亡，而在造血细胞中消除TLR4则没有效果。胎盘炎症反应呈现出时空模式，首先在母体内皮细胞中观察到NF-κB激活，然后在内皮周围的蜕膜细胞中观察到，随后诱导炎症细胞因子和趋化因子。给怀孕小鼠补充鱼油作为ω-3脂肪酸的来源可抑制胎盘炎症，减少具核梭杆菌在胎盘中的增殖，并提高胎儿和新生儿的存活率。体外分析表明，ω-3脂肪酸可抑制细菌诱导的人脐静脉内皮细胞炎症反应。因此，我们的研究揭示了微生物感染影响妊娠的机制，并确定了一种预防宫内感染的治疗方法。
