Su Xiaotao, Li Tiemei, Wang Yuge, Wei Lei, Jian Banghao, Kang Xinmei, Hu Mengyan, Li Chunyi, Wang Shisi, Lu Danli, Shen Shishi, Huang Huipeng, Liu Yuxin, Deng Xiaohui, Zhang Bingjun, Cai Wei, Lu Zhengqi
Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Center of Clinical Immunology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Stroke Vasc Neurol. 2025 Jun 30;10(3):359-370. doi: 10.1136/svn-2024-003494.
Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive.
Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1.
We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production.
Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.
肠杆菌易位是急性缺血性卒中（AIS）患者致命感染的主要原因。越来越多的证据表明，间充质干细胞（MSC）能有效改善卒中预后。MSC是否能抑制卒中后肠杆菌易位仍不清楚。
本研究纳入了AIS患者和健康个体。短暂性大脑中动脉闭塞的小鼠在再灌注后立即接受骨髓源性MSC（BM-MSC）治疗。用卒中生态失调指数和循环内毒素评估肠杆菌易位。用阿尔辛蓝染色评估黏液厚度。通过HSD11B2、HSD11B1和SRD5A1的表达分析肝脏糖皮质激素（GC）代谢。
我们发现，卒中后肠道黏液层变薄，导致明显的肠杆菌易位。肠道黏液的变薄归因于杯状细胞因脑缺血后全身GC升高而减少黏蛋白产生。移植的BM-MSC恢复了黏液厚度，从而维持肠道微生物群稳态并防止肠杆菌入侵。机制上，移植的BM-MSC驻留在肝脏并增强肝细胞中的过氧化物酶体增殖物激活受体γ信号传导。因此，HSD11B2和SRD5A1的表达增加，而HSD11B1的表达下调，这促进了GC分解代谢，随后恢复了黏蛋白产生。
我们的研究结果表明，MSC移植可改善卒中后肠道屏障完整性，并通过增强肝脏GC代谢来抑制肠杆菌易位，从而代表AIS中肝-肠-脑轴的一种保护性调节因子。
