Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC, United States.
Front Immunol. 2023 Jan 24;14:1067602. doi: 10.3389/fimmu.2023.1067602. eCollection 2023.
Children born by cesarean section (CS) are at a greater risk of inflammatory bowel disease (IBD). However, the mechanisms underlying the association are not yet well understood. Herein, we investigated the impact of CS delivery on colonic inflammation and mechanisms underlying these effects in offspring.
CS mice model and dextran sulfate sodium (DSS)-induced colitis model were constructed and used to analyze the impact of CS on the development of colitis. Colonic tight junction markers and epithelium differentiation markers were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Levels of zonulin in serum were detected by enzyme-linked immunosorbent assay (ELISA). Immune cells in colon were analyzed by flow cytometry. Metabolic profiling between human vaginal delivery (VD) and CS AF were analyzed by using mass spectrometry. Transcriptome changes between VD AF- and CS AF-treated human intestine epithelial cells were analyzed by RNA-sequencing. A multi-omics approach that integrated transcriptomics with metabolomics to identify the pathways underlying colonic inflammation associated with delivery modes. Then, the identified pathways were confirmed by immunoblotting and ELISA.
Mice pups delivered by CS exhibited a defective intestinal homeostasis manifested by decreased expression of tight junction markers of and in the colons, increased levels of zonulin in serum and dysregulated expression of intestinal epithelium differentiation markers of , , and CS pups were more susceptible to DSS-induced colitis compared to VD pups. The proportion of macrophage, dendritic cells (DCs), and natural killer cells (NKs) in the colons were altered in an age-dependent manner compared with pups born naturally. The metabolites in AF differed between CS and VD cases, and the CS AF-induced differentially expressed genes (DEGs) were significantly enriched in pathways underlying IBD. Signal transducer and activator of transcription 3 (STAT3) signaling was downregulated in NCM460 intestinal epithelial cells by CS AF compared to VD AF and in colon of CS pups compared to VD pups. Deficiency in metabolites like vitamin D2 glucosiduronate in CS AF may attribute to the risk of inflammatory intestine through STAT3 signaling.
Our study provides a novel insight into the underlying mechanisms of CS-associated intestinal inflammation and potential prevention strategies.
通过剖宫产（CS）出生的儿童患炎症性肠病（IBD）的风险更高。然而，其相关机制尚不清楚。在此，我们研究了 CS 分娩对结肠炎发展的影响及其潜在机制。通过定量实时聚合酶链反应（qRT-PCR）分析 CS 对 colonic 炎症的影响。通过酶联免疫吸附试验（ELISA）检测血清中 zonulin 的水平。通过流式细胞术分析结肠中的免疫细胞。通过质谱分析比较人阴道分娩（VD）和 CS 羊水（AF）之间的代谢物谱。通过 RNA-seq 分析 VD-AF 和 CS-AF 处理的人肠上皮细胞之间的转录组变化。通过整合转录组学和代谢组学的多组学方法，鉴定与分娩方式相关的 colonic 炎症的潜在途径。然后，通过免疫印迹和 ELISA 验证鉴定出的途径。
CS 分娩的小鼠幼仔表现出肠道内稳态缺陷，其 colons 中的紧密连接标记物 和 的表达降低，血清中 zonulin 的水平升高，肠道上皮分化标记物 的表达失调。与 VD 幼仔相比，CS 幼仔更容易发生 DSS 诱导的结肠炎。与自然分娩的幼仔相比，结肠中巨噬细胞、树突状细胞（DCs）和自然杀伤细胞（NKs）的比例随年龄变化而改变。CS 和 VD 病例之间的 AF 中的代谢物不同，CS-AF 诱导的差异表达基因（DEGs）在 IBD 相关途径中显著富集。CS-AF 相对于 VD-AF 下调 NCM460 肠上皮细胞中的信号转导和转录激活因子 3（STAT3）信号，CS 幼仔的结肠中也出现这种情况。CS-AF 中维生素 D2 葡糖苷酸等代谢物的缺乏可能通过 STAT3 信号导致炎症性肠道的风险。
本研究为 CS 相关肠道炎症的潜在机制提供了新的见解，并为潜在的预防策略提供了依据。
