Suppl Table 1 AF information.xlsx

The interplay between genetic and environmental factors during pregnancy can predispose to inflammatory diseases postnatally, including eosinophilic esophagitis, a chronic allergic disease triggered by food. Herein, we examined the effects of amniotic fluid (AF) on esophageal epithelial differentiation and responsiveness to pro-allergic stimuli. Multiplex analysis of AF revealed the expression of 66 cytokines, whereas 5 cytokines including IL-4 and TSLP were not detected. Several pro-inflammatory cytokines including TNFa and IL-12 were highly expressed in the AF from women who underwent preterm birth, while EGF was the highest in term birth samples. Exposure of esophageal epithelial cells to AF resulted in transient phosphorylation of ERK1/2 and the transcription of early response genes, highlighting the direct impact of AF on esophageal epithelial cells. In a 3-dimensional spheroid model, AF modified the esophageal epithelial differentiation program and enhanced the transcription of IL-13-target genes, including <i>CCL26</i> and <i>CAPN14, </i>which encodes for a major genetic susceptibility locus for eosinophilic esophagitis. Notably,<i> CAPN14</i> exhibited upregulation in spheroids exposed to preterm but not term AF following differentiation. Collectively, our findings call attention to the role of AF as a potential mediator of the intrauterine environment that influences subsequent esophageal disorders.

妊娠期间遗传与环境因素的相互作用，可增加个体产后罹患炎症性疾病的风险，其中包括嗜酸性食管炎（eosinophilic esophagitis）——一种由食物诱发的慢性过敏性疾病。本研究探讨了羊水（amniotic fluid, AF）对食管上皮分化及对促变应性刺激的应答反应的影响。对羊水的多重分析显示，其可检测到66种细胞因子的表达，而未检测到包括白细胞介素4（IL-4）和胸腺基质淋巴细胞生成素（TSLP）在内的5种细胞因子。早产孕妇的羊水中，肿瘤坏死因子α（TNF-α）、白细胞介素12（IL-12）等多种促炎细胞因子呈高表达；而足月产羊水样本中，表皮生长因子（EGF）的表达水平最高。将食管上皮细胞暴露于羊水后，可引发细胞外调节蛋白激酶1/2（ERK1/2）的瞬时磷酸化以及早期应答基因的转录，证实羊水可直接作用于食管上皮细胞。在三维球体培养模型中，羊水可调控食管上皮的分化程序，并增强白细胞介素13（IL-13）靶基因的转录水平，其中包括<i>CCL26</i>与<i>CAPN14</i>——后者编码嗜酸性食管炎的主要遗传易感位点。值得注意的是，分化完成后，暴露于早产羊水的球体中<i>CAPN14</i>（钙蛋白酶14，CAPN14）表达上调，而暴露于足月产羊水的球体则未出现该现象。综上，本研究结果提示，羊水可作为宫内环境的潜在介质，对个体后续食管疾病的发生发展产生影响。