Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.
Front Immunol. 2021 May 7;12:628358. doi: 10.3389/fimmu.2021.628358. eCollection 2021.
Irinotecan (CPT-11)-induced gastrointestinal toxicity strongly limits its anticancer efficacy. Fisch., especially flavonoids, has strong anti-inflammatory and immunomodulatory activities. Herein, we investigate the protective effect of the total flavonoids of (TFGU) on CPT-11-induced colitis mice from the perspective of gut microbiota and fecal metabolism. The body weight and colon length of mice were measured. Our results showed that oral administration of TFGU significantly attenuated the loss of body weight and the shortening of colon length induced by CPT-11. The elevated disease activity index and histological score of colon as well as the up-regulated mRNA and protein levels of TNF-α, IL-1β, and IL-6 in the colonic tissue of CPT-11-treated mice were significantly decreased by TFGU. Meanwhile, TFGU restored the perturbed gut microbial structure and function in CPT-11-treated mice to near normal level. TFGU also effectively reversed the CPT-11-induced fecal metabolic disorders in mice, mainly call backing the hypoxanthine and uric acid in purine metabolism. Spearman's correlation analysis further revealed that abundance negatively correlated with fecal uric acid concentration, suggesting the pivotal role of gut microbiota in CPT-11-induced colitis. Since uric acid is a ligand of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, TFGU was further validated to inhibit the activation of NLRP3 inflammasome by CPT-11. Our findings suggest TFGU can correct the overall gut microbial dysbiosis and fecal metabolic disorders in the CPT-11-induced colitis mice, underscoring the potential of using dietary as a chemotherapeutic adjuvant.
伊立替康（CPT-11）诱导的胃肠道毒性强烈限制了其抗癌疗效。鱼类，特别是类黄酮，具有很强的抗炎和免疫调节作用。在此，我们从肠道微生物群和粪便代谢的角度研究了 （TFGU）总黄酮对 CPT-11 诱导的结肠炎小鼠的保护作用。测量了小鼠的体重和结肠长度。我们的结果表明，TFGU 的口服给药显著减轻了 CPT-11 诱导的体重减轻和结肠缩短。CPT-11 处理小鼠结肠组织中 TNF-α、IL-1β 和 IL-6 的 mRNA 和蛋白水平上调，疾病活动指数和组织学评分升高，这一现象也被 TFGU 显著降低。同时，TFGU 将 CPT-11 处理小鼠中失调的肠道微生物结构和功能恢复到接近正常水平。TFGU 还有效逆转了 CPT-11 诱导的小鼠粪便代谢紊乱，主要是通过嘌呤代谢中的次黄嘌呤和尿酸来恢复。Spearman 相关性分析进一步表明， 丰度与粪便尿酸浓度呈负相关，提示肠道微生物群在 CPT-11 诱导的结肠炎中起关键作用。由于尿酸是 NOD 样受体家族吡喃结构域包含 3 （NLRP3）炎性小体的配体，因此进一步验证了 TFGU 可抑制 CPT-11 诱导的 NLRP3 炎性小体的激活。我们的研究结果表明，TFGU 可以纠正 CPT-11 诱导的结肠炎小鼠中整体肠道微生物失调和粪便代谢紊乱，强调了使用膳食 作为化疗佐剂的潜力。
