Wang Yi, Jiang Yu, Li Mingxing, Xiao Yaqin, Zhao Qianyun, Zeng Jiuping, Wei Shulin, Chen Shuhan, Zhao Yueshui, Du Fukuan, Chen Yu, Deng Shuai, Shen Jing, Li Xiaobing, Li Wanping, Wang Fang, Sun Yuhong, Gu Li, Xiao Zhangang, Wang Shengpeng, Wu Xu
Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; Sichuan Fifth People's Hospital, Chengdu, Sichuan 610015, China.
Department of Gerontology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646100, China.
Phytomedicine. 2025 Jan;136:156318. doi: 10.1016/j.phymed.2024.156318. Epub 2024 Dec 5.
Rosavin (RSV) is a naturally occurring compound isolated from Rhodiola species. While RSV has been reported with pharmacological activities of anti-oxidation, anti-inflammation, anti-stress and immunomodulation, its effect on colitis and the underlying mechanisms remain unclear.
This study aims to investigate whether and how RSV alleviated colitis in mice.
The protective effect of RSV (50, 100, 200 mg/kg, p.o.) was investigated in dextran sulfate sodium (DSS) mediated mouse models of acute and chronic colitis. Alterations in fecal microbiota were evaluated by 16S rRNA sequencing. Pseudo germ-free mice achieved by antibiotics treatment were applied to assess the RSV-mediated functional role of gut microbiota in colitis. RNA sequencing was performed to determine RSV-induced colonic response. Primary T cell culture was conducted to examine the effect of RSV on Th17 and Treg differentiation. Whole blood assay, dual luciferase reporter assay, and molecular docking methods were applied to investigate the mechanisms and targets of RSV in Th17 regulation.
Oral RSV significantly relieved DSS-mediated acute and chronic colitis in mice, which recovered body weight loss, reduced disease activity index, alleviated colon injury, inhibited inflammation, suppressed the apoptosis of intestinal epithelia, and maintained intestinal barrier function. Moreover, RSV specifically regulated intestinal microbiota by recovering DSS-mediated microbial changes and elevating beneficial microbes such as Lactobacillus and Akkermansia. Antibiotics treatment experiment showed that the protective role of RSV was at least partially dependent on gut microbiota; however, in vitro incubation showed that RSV did not directly promote the growth of Lactobacillus and Akkermansia strains. Further analysis showed that RSV-mediated genetic alterations in colon were enriched in pathways related to lymphocyte regulation. Additionally, RSV regulated the balance of Th17/Treg in colitis mice. Importantly, RSV inhibited the differentiation of Th17 cell in vitro, suppressed the production of IL-17 by Th17 cells, and downregulated Rorc encoding RORγt and its downstream Il17. RSV significantly inhibited the RORγt transcription activity and bound to its ligand binding domain.
RSV alleviates murine colitis through regulating intestinal immunity. Notably, RSV is identified as a novel regulator of Th17 cells that inhibits RORγt-mediated Th17 differentiation. These findings potentiate the Rhodiola-derived natural chemicals as novel anti-colitis agents.
红景天苷（RSV）是从红景天属植物中分离出的一种天然化合物。虽然已有报道称RSV具有抗氧化、抗炎、抗应激和免疫调节等药理活性，但其对结肠炎的影响及潜在机制仍不清楚。
本研究旨在探讨RSV是否以及如何减轻小鼠结肠炎。
在葡聚糖硫酸钠（DSS）介导的急性和慢性结肠炎小鼠模型中研究RSV（50、100、200mg/kg，口服）的保护作用。通过16S rRNA测序评估粪便微生物群的变化。应用抗生素处理获得的伪无菌小鼠来评估RSV介导的肠道微生物群在结肠炎中的功能作用。进行RNA测序以确定RSV诱导的结肠反应。进行原代T细胞培养以检测RSV对Th17和Treg分化的影响。应用全血检测、双荧光素酶报告基因检测和分子对接方法来研究RSV在Th17调节中的机制和靶点。
口服RSV可显著减轻DSS介导的小鼠急性和慢性结肠炎，恢复体重减轻，降低疾病活动指数，减轻结肠损伤，抑制炎症，抑制肠上皮细胞凋亡，并维持肠道屏障功能。此外，RSV通过恢复DSS介导的微生物变化并增加有益微生物如乳酸杆菌和阿克曼氏菌，特异性调节肠道微生物群。抗生素处理实验表明，RSV的保护作用至少部分依赖于肠道微生物群；然而，体外培养表明RSV不会直接促进乳酸杆菌和阿克曼氏菌菌株的生长。进一步分析表明，RSV介导的结肠基因改变在与淋巴细胞调节相关的途径中富集。此外，RSV调节结肠炎小鼠中Th17/Treg的平衡。重要的是，RSV在体外抑制Th17细胞的分化，抑制Th17细胞产生IL-17，并下调编码RORγt的Rorc及其下游的Il17。RSV显著抑制RORγt的转录活性并与其配体结合域结合。
RSV通过调节肠道免疫减轻小鼠结肠炎。值得注意的是，RSV被鉴定为一种新型的Th17细胞调节剂，可抑制RORγt介导的Th17分化。这些发现增强了红景天衍生的天然化学物质作为新型抗结肠炎药物的潜力。
