Braskett Melinda, Goleva Elena, Bronova Irina, Bronoff Anna Sofia, Lyubchenko Katherine, Nagendra Gautam, Warren Mika, Shillingford Nick, Cynamon Harry, Alam Lamia, Bhardwaj Vrinda, Hall Clifton F, Durazo-Arvizu Ramon, Ong Peck Y, Berdyshev Evgeny, Leung Donald Y M
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine at USC, Los Angeles, California, USA.
Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
Allergy. 2025 Jul 17. doi: 10.1111/all.16660.
Lipids play an essential role in epithelial barrier integrity. Despite increasing evidence of epithelial barrier dysfunction in eosinophilic esophagitis (EoE), the lipid composition of the esophageal epithelium is not characterized and any disruptions in EoE are unknown.
Esophageal brushings and biopsies were collected from patients (ages 1-19 years) who underwent clinically indicated esophagogastroduodenoscopy. Participants were classified based on the number of eosinophils per high-power field (eos/HPF) in esophageal biopsies into: an EoE group (> 15 eos/HPF) and a control group (0-1 eos/HPF). Brushing samples were analyzed by targeted lipidomics using liquid chromatography tandem-mass spectrometry. The expression of inflammatory mediators and lipid biosynthesis enzymes was quantified by RT-PCR in esophageal biopsies and in a primary human esophageal epithelial cell line treated with IL-4/IL-13.
EoE group had a significant increase in non-hydroxy fatty acid sphingosine ceramides (NS-CER) (p < 0.01), and a decrease in non-hydroxy fatty acid phytoceramides (NP-CER) with 18-carbon sphingoid bases, resulting in selectively increased NS-CER/NP-CER ratios as compared to controls in esophageal brushes (Mean ± SD: 5.0 ± 1.9 vs. 1.6 ± 1.2 p < 0.01). EoE biopsies had significantly decreased expression of DEGS1 (p < 0.01) and DEGS2 (p < 0.05) mRNA, enzymes responsible for the biosynthesis of NS-CER and NP-CER. A significant inverse correlation between NS-CER/NP-CER and DEGS2/DEGS1 mRNA ratios (p < 0.01) was observed. Conversely, a positive correlation between the NS-CER/NP-CER ratio and CCL26, IL-5, and IL-13 mRNA expression (p < 0.05) was noted. IL-4/IL-13 significantly dysregulated the expression of DEGS1 and DEGS2 mRNA in a primary esophageal epithelial cell line.
Distinctive abnormalities in esophageal epithelium sphingolipid composition and production were revealed in EoE. Mechanistic ex vivo data demonstrate dysregulation of lipid biosynthesis enzymes by IL-4/IL-13. The characteristic lipid profile in EoE has significant implications for epithelial barrier dysfunction and may serve as a biomarker of disease activity.
脂质在上皮屏障完整性中起重要作用。尽管嗜酸性食管炎（EoE）中上皮屏障功能障碍的证据越来越多，但食管上皮的脂质组成尚未明确，EoE中的任何破坏情况也未知。
从接受临床指征的食管胃十二指肠镜检查的患者（1 - 19岁）中收集食管刷检物和活检组织。根据食管活检组织中每个高倍视野的嗜酸性粒细胞数量（嗜酸性粒细胞/HPF）将参与者分为：EoE组（>15个嗜酸性粒细胞/HPF）和对照组（0 - 1个嗜酸性粒细胞/HPF）。使用液相色谱串联质谱法通过靶向脂质组学分析刷检样本。通过RT-PCR在食管活检组织和用IL-4/IL-13处理的原代人食管上皮细胞系中定量炎症介质和脂质生物合成酶的表达。
EoE组中非羟基脂肪酸鞘氨醇神经酰胺（NS-CER）显著增加（p < 0.01），具有18碳鞘氨醇碱基的非羟基脂肪酸植物神经酰胺（NP-CER）减少，导致食管刷检物中NS-CER/NP-CER比值与对照组相比选择性增加（平均值±标准差：5.0±1.9对1.6±1.2，p < 0.01）。EoE活检组织中负责NS-CER和NP-CER生物合成的DEGS1（p < 0.01）和DEGS2（p < 0.05）mRNA表达显著降低。观察到NS-CER/NP-CER与DEGS2/DEGS1 mRNA比值之间存在显著负相关（p < 0.01）。相反，NS-CER/NP-CER比值与CCL26、IL-5和IL-13 mRNA表达之间存在正相关（p < 0.05）。IL-4/IL-13显著失调原代食管上皮细胞系中DEGS1和DEGS2 mRNA的表达。
EoE中揭示了食管上皮鞘脂组成和产生的独特异常。体外机制数据表明IL-4/IL-13对脂质生物合成酶的失调作用。EoE中的特征性脂质谱对上皮屏障功能障碍具有重要意义，可能作为疾病活动的生物标志物。
