新生儿呼吸窘迫综合征中的肠-肺轴: 来自药物警戒与孟德尔随机化的整合证据

doi:10.5246/jcps.2026.07.046

中国药学(英文版) ›› 2026, Vol. 35 ›› Issue (7): 643-657.DOI: 10.5246/jcps.2026.07.046

新生儿呼吸窘迫综合征中的肠-肺轴: 来自药物警戒与孟德尔随机化的整合证据

朱祎潇¹^,²^,^#, 林丽¹^,²^,^#, 杨礼靖¹, 滕程倩³, 张丽蓉¹^,², 陈安迪³, 魏晓霞²^,³^,⁴^,^*(), 陈晓辉³^,^*()

^1. 福建医科大学药学院，福建福州 350001
^2. 福建医科大学省立临床医学院，福建省立医院、福州大学附属省立医院药学部，福建医科大学药学院，福建福州 350001
^3. 福建医科大学省立临床医学院，福建省立医院、福州大学附属省立医院麻醉科，福建福州 350001
^4. 福州大学医学院，福建福州 350001

收稿日期:2026-04-24 修回日期:2026-05-10 接受日期:2026-05-23 出版日期:2026-08-06 发布日期:2026-08-06
通讯作者: 魏晓霞, 陈晓辉

Gut-lung axis in neonatal respiratory distress syndrome: integrated evidence from pharmacovigilance and Mendelian randomization

Yixiao Zhu¹^,², Li Lin¹^,², Lijing Yang¹, Chengqian Teng³, Lirong Zhang¹^,², Andi Chen³, Xiaoxia Wei²^,³^,⁴^,^*(), Xiaohui Chen³^,^*()

^1. School of Pharmacy, Fujian Medical University, Fuzhou 350001, Fujian, China
^2. Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Pharmacy, Fujian Medical University, Fuzhou 350001, Fujian, China
^3. Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, Fujian, China
^4. School of Medicine, Fuzhou University, Fuzhou 350001, Fujian, China

Received:2026-04-24 Revised:2026-05-10 Accepted:2026-05-23 Online:2026-08-06 Published:2026-08-06
Contact: Xiaoxia Wei, Xiaohui Chen
About author:
^# The authors contributed equally to this work.
Supported by:
the Wu Jieping Medical Foundation (Grant No. 320.6750.2025-06-272)

摘要/Abstract

摘要：

新生儿呼吸窘迫综合征(neonatal respiratory distress syndrome, NRDS)是导致新生儿发病和死亡的重要原因之一，通常与早产、肺表面活性物质缺乏及炎症反应密切相关。越来越多的研究表明，肠道菌群及炎症细胞因子可能通过“肠-肺轴”参与NRDS的发生发展，但其潜在因果关系尚未阐明。本研究整合美国食品药品监督管理局不良事件报告系统(FAERS)的药物警戒数据，并结合双向孟德尔随机化(Mendelian randomization, MR)及中介MR分析，系统探讨药物暴露、肠道菌群与炎症细胞因子在NRDS中的作用。基于2004–2024年的FAERS数据，共筛选出162种与NRDS风险显著相关的药物，主要包括抗生素、全身用激素及免疫调节剂。MR分析结果显示，CAG-177 sp003514385和Chromatiales丰度增加可提升血浆潜伏相关肽转化生长因子β1(latency-associated peptide transforming growth factor beta 1, LAP-TGF-β1)及CUB结构域包含蛋白1(CUB domain–containing protein 1, CDCP1)水平，而二者均对NRDS具有保护作用。相反，Syntrophomonadia丰度升高与NRDS风险增加相关，但较高水平的CDCP1可在一定程度上部分缓解这一不利影响。敏感性分析进一步验证了上述结果的稳健性。总体而言，本研究为药物暴露、肠道菌群失衡、炎症细胞因子信号通路与NRDS风险之间的关联提供了新的证据，并提示LAP-TGF-β1和CDCP1有望成为NRDS的潜在生物标志物和治疗靶点，凸显了基于肠道微生态和细胞因子调控策略在NRDS预防与治疗中的应用前景。

关键词: 新生儿呼吸窘迫综合征, 肠道菌群, 炎症细胞因子, 孟德尔随机化研究, 肠-肺轴, 微生物群靶向治疗

Abstract:

Neonatal respiratory distress syndrome (NRDS) is a major cause of neonatal morbidity and mortality and is closely linked to prematurity, surfactant deficiency, and inflammatory processes. Emerging evidence suggests that the gut microbiota and inflammatory cytokines may modulate NRDS through the gut-lung axis; however, the underlying causal relationships remain incompletely understood. In the present study, we integrated pharmacovigilance data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) with bidirectional and mediation Mendelian randomization (MR) analyses to investigate the roles of drug exposure, gut microbiota, and inflammatory cytokines in NRDS. FAERS data spanning 2004 to 2024 identified 162 drugs significantly associated with NRDS risk, including antibiotics, systemic hormones, and immunomodulatory agents. MR analyses revealed that increased abundances of CAG-177 sp003514385 and Chromatiales were associated with elevated plasma levels of latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) and CUB domain-containing protein 1 (CDCP1), both of which exhibited protective effects against NRDS. In contrast, increased abundance of Syntrophomonadia was associated with a higher risk of NRDS, although elevated CDCP1 levels partially mitigated this effect. Sensitivity analyses supported the robustness of these findings. Overall, this study provided novel evidence linking drug exposure, gut microbiota dysbiosis, inflammatory cytokine signaling, and NRDS risk, and identified LAP-TGF-β1 and CDCP1 as potential biomarkers and therapeutic targets, highlighting the promise of microbiota- and cytokine-targeted strategies for the prevention and management of NRDS.

Key words: Neonatal respiratory distress syndrome, Gut microbiota, Inflammatory cytokines, Mendelian randomization, Gut-lung axis, Microbiota-targeted therapy

Supporting: /attached/file/20260809/20260809005100_145.pdf

朱祎潇, 林丽, 杨礼靖, 滕程倩, 张丽蓉, 陈安迪, 魏晓霞, 陈晓辉. 新生儿呼吸窘迫综合征中的肠-肺轴: 来自药物警戒与孟德尔随机化的整合证据[J]. 中国药学(英文版), 2026, 35(7): 643-657.

Yixiao Zhu, Li Lin, Lijing Yang, Chengqian Teng, Lirong Zhang, Andi Chen, Xiaoxia Wei, Xiaohui Chen. Gut-lung axis in neonatal respiratory distress syndrome: integrated evidence from pharmacovigilance and Mendelian randomization[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(7): 643-657.

图/表 8

Table 1.

Figure 1. A tree diagram of signal-generating drugs associated with NRDS.

Figure 2. The causal association of gut microbiota on NRDS.

Figure 3. The causal association of NRDS on gut microbiota.

Figure 4. The causal association of inflammatory cytokines on NRDS.

Figure 5. The correlation circular heatmap of gut microbiome-inflammatory cytokines.

Table 2. Summary table of mediating inflammatory cytokines.

Table 3. Summary of effect (beta).

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新生儿呼吸窘迫综合征中的肠-肺轴: 来自药物警戒与孟德尔随机化的整合证据

Gut-lung axis in neonatal respiratory distress syndrome: integrated evidence from pharmacovigilance and Mendelian randomization

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