Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Br J Pharmacol. 2021 Sep;178(18):3708-3729. doi: 10.1111/bph.15512. Epub 2021 Jun 16.
Hypertension is an important cardiovascular risk factor that is prevalent in the systemic lupus erythematosus patient population. Here, we have investigated whether intestinal microbiota is involved in hypertension in a genetic mouse model of systemic lupus erythematosus.
Twenty-six-week-old female NZW/LacJ (control) and NZBWF1 (F1 hybrid of New Zealand Black and New Zealand White strains; systemic lupus erythematosus) mice were treated for 6 weeks with a broad-spectrum antibiotic mixture or with vancomycin. Faecal microbiota transplantation was performed from donor systemic lupus erythematosus group to recipient to germ-depleted or germ-free mice.
Antibiotic treatment inhibited the development of hypertension and renal injury, improved endothelial dysfunction and vascular oxidative stress, and decreased aortic Th17 infiltration in NZBWF1 mice. High BP and vascular complications found in systemic lupus erythematosus mice, but not autoimmunity, kidney inflammation and endotoxemia, were reproduced by the transfer of gut microbiota from systemic lupus erythematosus donors to germ-free or germ-depleted mice. Increased proportions of Bacteroides were linked with high BP in these mice. The reduced endothelium-dependent vasodilator responses to acetylcholine and the high BP induced by microbiota from hypertensive systemic lupus erythematosus mice were inhibited after IL-17 neutralization.
Changes in T-cell populations, endothelial function, vascular inflammation and hypertension driven by a genetic systemic lupus erythematosus background can be modified by antibiotic-induced changes in gut microbiota. The vascular changes induced by hypertensive systemic lupus erythematosus microbiota were mediated by Th17 infiltration in the vasculature.
高血压是系统性红斑狼疮患者中普遍存在的重要心血管危险因素。在这里，我们研究了肠道微生物群是否参与了系统性红斑狼疮遗传小鼠模型中的高血压。
26 周龄雌性 NZW/LacJ（对照）和 NZBWF1（新西兰黑和新西兰白杂交的 F1 杂种；系统性红斑狼疮）小鼠用广谱抗生素混合物或万古霉素治疗 6 周。从系统性红斑狼疮供体组向受体去定植或无菌小鼠进行粪便微生物群移植。
抗生素治疗抑制了 NZBWF1 小鼠高血压和肾脏损伤的发展，改善了内皮功能障碍和血管氧化应激，并减少了主动脉 Th17 浸润。系统性红斑狼疮小鼠中发现的高血压和血管并发症，但不是自身免疫、肾脏炎症和内毒素血症，通过从系统性红斑狼疮供体转移肠道微生物群到去定植或去定植小鼠中得到了重现。这些小鼠中，Bacteroides 的比例增加与高血压有关。用抗 IL-17 中和后，这些小鼠对乙酰胆碱的内皮依赖性血管舒张反应减弱和由高血压系统性红斑狼疮小鼠的微生物群引起的高血压得到抑制。
在遗传背景下由 T 细胞群、内皮功能、血管炎症和高血压驱动的变化，可以通过抗生素诱导的肠道微生物群变化来改变。由高血压系统性红斑狼疮微生物群引起的血管变化是由血管内 Th17 浸润介导的。
