Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Nat Microbiol. 2019 Nov;4(11):1851-1861. doi: 10.1038/s41564-019-0498-2. Epub 2019 Jul 22.
Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction and increased concentrations of 12,13-diHOME in their faeces. However, the mechanism, source and contribution of this lipid to allergic inflammation remain unknown. Here, we show that intra-abdominal treatment of mice with 12,13-diHOME increased pulmonary inflammation and decreased the number of regulatory T (T) cells in the lungs. Treatment of human dendritic cells with 12,13-diHOME altered expression of PPARγ-regulated genes and reduced anti-inflammatory cytokine secretion and the number of T cells in vitro. Shotgun metagenomic sequencing of neonatal faeces indicated that bacterial epoxide hydrolase (EH) genes are more abundant in the gut microbiome of neonates who develop atopy and/or asthma during childhood. Three of these bacterial EH genes (3EH) specifically produce 12,13-diHOME, and treatment of mice with bacterial strains expressing 3EH caused a decrease in the number of lung T cells in an allergen challenge model. In two small birth cohorts, an increase in the copy number of 3EH or the concentration of 12,13-diHOME in the faeces of neonates was found to be associated with an increased probability of developing atopy, eczema or asthma during childhood. Our data indicate that elevated 12,13-diHOME concentrations impede immune tolerance and may be produced by bacterial EHs in the neonatal gut, offering a mechanistic link between perturbation of the gut microbiome during early life and atopy and asthma during childhood.
患有儿童期特应症和哮喘风险的新生儿表现出肠道微生物组的紊乱、代谢功能障碍和粪便中 12,13-二氢羟基二十碳四烯酸（12,13-diHOME）浓度增加。然而，这种脂质的机制、来源和对过敏炎症的贡献仍不清楚。在这里，我们表明，用 12,13-diHOME 对小鼠进行腹腔内治疗会增加肺部炎症并减少肺部调节性 T (T) 细胞的数量。用 12,13-diHOME 处理人树突状细胞会改变 PPARγ 调节基因的表达，并减少体外抗炎细胞因子的分泌和 T 细胞的数量。对新生儿粪便的鸟枪法宏基因组测序表明，在儿童时期发生特应症和/或哮喘的新生儿肠道微生物组中，细菌环氧化物水解酶 (EH) 基因更为丰富。这些细菌 EH 基因中有三个（3EH）特异性产生 12,13-diHOME，用表达 3EH 的细菌菌株治疗小鼠会导致变应原挑战模型中肺部 T 细胞数量减少。在两个小型出生队列中，发现新生儿粪便中 3EH 的拷贝数增加或 12,13-diHOME 的浓度增加与儿童时期特应症、湿疹或哮喘发生的概率增加相关。我们的数据表明，升高的 12,13-diHOME 浓度会阻碍免疫耐受，并且可能是由新生儿肠道中的细菌 EHs 产生的，为生命早期肠道微生物组的紊乱与儿童期特应症和哮喘之间提供了一种机制联系。
