肠道微生物群衍生的短链脂肪酸通过ACSL4/LPCAT3途径减轻妊娠期糖尿病患者的胎盘铁下垂和胰岛素抵抗
Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway.
摘要(中文译文)
妊娠期糖尿病（GDM）与肠道菌群失调及胎盘功能障碍相关。本研究旨在探讨肠道菌群来源的短链脂肪酸（SCFAs）是否通过抑制铁死亡（一种新型的铁依赖性细胞死亡形式）来改善GDM中的胎盘损伤和胰岛素抵抗。采用链脲佐菌素诱导GDM大鼠模型，并通过广谱抗生素混合物清除肠道菌群。评估生理参数、肠道菌群组成及SCFA水平。分析胎盘及代谢组织中的铁死亡标志物（Fe、MDA、ROS）、关键调控酶（GPX4、ACSL4、LPCAT3）、多不饱和脂肪酸（PUFA）谱及炎症情况。采用人滋养层细胞（HTR-8/SVneo）胰岛素抵抗模型验证SCFAs的因果作用。GDM及抗生素诱导的菌群失调导致产SCFA细菌显著耗竭，结肠SCFA水平降低。与此同时，胎盘出现严重铁死亡，表现为铁蓄积、脂质过氧化、GPX4下调以及ACSL4和LPCAT3上调。PUFA底物被显著消耗，全身炎症水平升高。胰岛素抵抗诱导滋养层细胞铁死亡及功能障碍，而SCFA处理可有效逆转上述改变。SCFAs恢复GPX4表达，抑制ACSL4/LPCAT3，保留PUFAs，并减轻炎症。肠道菌群来源的SCFAs通过抑制胎盘滋养层细胞中ACSL4/LPCAT3介导的铁死亡通路，在GDM中发挥关键保护作用，从而改善胰岛素敏感性并减轻细胞损伤。本研究结果凸显肠-胎盘轴作为GDM潜在治疗靶点的价值，值得在人体研究中进一步验证。
Abstract
Gestational diabetes mellitus (GDM) is associated with gut microbiota dysbiosis and placental dysfunction. This study aimed to investigate whether gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate placental injury and insulin resistance in GDM by suppressing ferroptosis, a novel form of iron-dependent cell death. A GDM rat model was induced by streptozotocin, and gut microbiota was depleted via a broad-spectrum antibiotic cocktail. Physiological parameters, gut microbiota composition, and SCFA levels were assessed. Placental and metabolic tissues were analyzed for ferroptosis markers (Fe, MDA, ROS), key regulatory enzymes (GPX4, ACSL4, LPCAT3), polyunsaturated fatty acid (PUFA) profiles, and inflammation. An insulin resistance model in human trophoblast cells (HTR-8/SVneo) was used to validate the causal role of SCFAs. GDM and antibiotic-induced dysbiosis led to a significant depletion of SCFA-producing bacteria and reduced colonic SCFA levels. This was concomitant with severe placental ferroptosis, characterized by iron accumulation, lipid peroxidation, and downregulation of GPX4 alongside upregulation of ACSL4 and LPCAT3. PUFA substrates were significantly consumed, and systemic inflammation was elevated. , insulin resistance induced trophoblast ferroptosis and dysfunction, which was effectively rescued by SCFA treatment. SCFAs restored GPX4 expression, suppressed ACSL4/LPCAT3, preserved PUFAs, and attenuated inflammation. Gut microbiota-derived SCFAs play a critical protective role in GDM by inhibiting the ACSL4/LPCAT3-mediated ferroptotic pathway in placental trophoblasts, thereby improving insulin sensitivity and mitigating cellular injury. Our findings highlight the gut-placenta axis as a potential therapeutic target for GDM, warranting further validation in human studies.
如何引用
AMA
Yang Han, Lingyi Kong, Tao Wang, Niankun Chen, Dongyu Wang, Zilian Wang, et al. Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway.. Frontiers in microbiology. 2026; doi:10.3389/fmicb.2026.1715392.
APA
Yang Han, Lingyi Kong, Tao Wang, Niankun Chen, Dongyu Wang, Zilian Wang, et al (2026). Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway.. Frontiers in microbiology. https://doi.org/10.3389/fmicb.2026.1715392
GB/T 7714
Yang Han, Lingyi Kong, Tao Wang, Niankun Chen, Dongyu Wang, Zilian Wang, et al. Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway.[J]. Frontiers in microbiology, 2026 doi:10.3389/fmicb.2026.1715392.
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