Anti-inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota
Anti-inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota
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大黄酸通过抑制PI3K/Akt/mTOR信号通路及调节肠道菌群发挥抗溃疡性结肠炎作用
DOI：
10.1002/ptr.7429
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发表时间：
2022-03-01
影响因子：
7.2
通讯作者：
Gao, Fei
中科院分区：
文献类型：
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作者：
Dong, Lingling;Du, Hongling;Gao, Fei
本研究旨在探讨大黄酸对小鼠溃疡性结肠炎（UC）的治疗作用及其可能机制。采用LPS诱导的UC细胞模型和DSS诱导的UC小鼠模型，分别在体内外观察大黄酸的抗UC作用。通过网络药理学分析来确定大黄酸治疗UC的潜在信号通路，并通过蛋白质印迹法进一步证实结果。进行16 sRNA测序以研究大黄酸对UC小鼠肠道微生物群的调节作用。如结果所示，大黄酸可以显著抑制促炎细胞因子（例如，TNF-α、IL-6和IL-1 β），并减轻DSS诱导的小鼠UC相关症状（例如，结肠缩短、体重减轻、腹泻和便血）。通过网络药理学分析，预测PI 3 K/Akt/mTOR信号通路是大黄酸治疗UC的潜在相互作用蛋白。Western blotting检测发现，大黄酸通过降低PI 3 K、Akt、mTOR和p70 S6 K1磷酸化蛋白水平，显著抑制PI 3 K/Akt/mTOR信号通路。通过16 sRNA基因测序分析，大黄酸给药可以部分逆转DSS诱导的小鼠肠道菌群失调，并减少致病菌（例如，肠杆菌科（Enterobacteriaceae）和Turicibacter）。它与上述促炎细胞因子的产生正相关，而益生菌（例如，非特异性-S24 -7和Rikenellaceae）与促炎细胞因子的产生呈负相关。总之，莱茵河具有抗UC疗效，这通过抑制PI 3 K/Akt/mTOR信号通路和调节肠道微生物群来减轻UC症状和减少肠道炎症来证明。
This study aimed to analyze the therapeutic effect of Rhein on ulcerative colitis (UC) in mice and its possible mechanism. LPS-induced UC cell model and DSS-induced UC mouse model were used to analyze the antiinflammatory effect of Rhein on UC in vitro and in vivo, respectively. Network pharmacology analysis was conducted to identify potential signaling pathways involved in Rhein treating UC, and the results were further confirmed through western blotting assay. 16sRNA sequencing was performed to study the regulatory effect of Rhein on gut microbiota in UC mice. As indicated by the results, Rhein could significantly inhibit the production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6 and IL-1 beta) in vivo and in vitro, and alleviate DSS-induced UC-associated symptoms in mice (e.g., colon shortening, weight loss, diarrhea and hematochezia). The PI3K/Akt/mTOR signaling pathway was predicted as the potential interacting protein of Rhein in the treatment of UC through network pharmacology analysis. It was found through western blotting assay that the Rhein treatment could significantly inhibit the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylated protein levels of PI3K, Akt, mTOR and p70S6K1. By 16sRNA gene sequencing analysis, Rhein administration could partially reverse the gut dysbacteriosis of mice induced by DSS and decrease pathogenic bacteria (e.g., Enterobacteriaceae and Turicibacter). It was positively correlated with the production of pro-inflammatory cytokines above, whereas the increase in probiotics (e.g., Unspecified-S24-7 and Rikenellaceae) was negatively correlated with the production of pro-inflammatory cytokines. In conclusion, Rhine had anti-UC efficacy, which was demonstrated by mitigating the UC symptoms and reducing intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway and modulating gut microbiota.