College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
J Ethnopharmacol. 2019 Jun 28;238:111887. doi: 10.1016/j.jep.2019.111887. Epub 2019 Apr 17.
Traditional Chinese medicine (TCM) holds that deficiency of spleen-Qi is the major pathogenesis of chemotherapy-induced diarrhea (CID). Herb pair of Atractylodes macrocephala Koidz. (AM) and Panax ginseng C. A. Mey. (PG) has good effects of supplementing Qi and strengthening spleen.
To investigate therapeutic effects and mechanism of Atractylodes macrocephala essential oil (AMO) and Panax ginseng total saponins (PGS) alone and in combination (AP) on 5-fluorouracil (5-FU) chemotherapy induced diarrhea in mice.
The mice were administered with AMO, PGS and AP respectively for 11 days, and intraperitoneally injected with 5-FU for 6 days since the 3rd day of the experiment. During the experiment, the body weights and diarrhea scores of mice were recorded daily. Thymus and spleen indexes were calculated after sacrifice of the mice. Pathological changes in ileum and colonic tissues were examined by hematoxylin-eosin (HE) staining. And the content levels of intestinal inflammatory cytokines were measured by enzyme-linked immmunosorbent assays (ELISA). 16S rDNA Amplicon Sequencing was used to analyze and interpret the gut microbiota of fecal samples.
AP significantly inhibited body weights loss, diarrhea, reductions of thymus and spleen indexes, and pathological changes of ileums and colons induced by 5-FU. Neither AMO nor PGS alone significantly improved above-mentioned abnormalities. Besides, AP could significantly suppressed the 5-FU-mediated increases of the intestinal inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-1β and IL-17), while AMO or PGS only inhibited some of them after 5-FU chemotherapy. Gut microbiota analysis indicated that 5-FU induced overall structural changes of gut microbiota were reversed after AP treatment. Additionally, AP significantly modulated the abundances of different phyla similar to normal values, and restored the ratios of Firmicutes/Bacteroidetes (F/B). At genus level, AP treatment dramatically decreased potential pathogens like Bacteroides, Ruminococcus, Anaerotruncus and Desulfovibrio. AP also antagonized the abnormal effects of AMO and PGS alone on certain genera like Blautia, Parabacteroides and Lactobacillus. Neither AMO nor PGS alone inhibited changes of gut microbial structure caused by 5-FU.
AP, combination of AMO and PGS, not AMO or PGS alone, significantly ameliorated diarrhea, inhibited intestinal pathology, and modulated gut microbial structure in 5-FU induced mice. AP also antagonized abnormal effects of AMO or PGS on certain genera. The results illustrated that gut microbiota was involved in the combined effects of AP on 5-FU induced diarrhea.
ETHNOPHARMACOLOGICAL 相关性：中医（TCM）认为脾气虚是化疗引起的腹泻（CID）的主要发病机制。白术（AM）和人参（PG）的药对具有补气健脾的良好作用。
研究白术挥发油（AMO）和人参总皂苷（PGS）单独及联合（AP）对氟尿嘧啶（5-FU）化疗诱导的小鼠腹泻的治疗作用及机制。
小鼠分别给予 AMO、PGS 和 AP，连续 11 天，自实验第 3 天起每天腹腔注射 5-FU 6 天。实验过程中，每天记录小鼠体重和腹泻评分。小鼠处死时计算胸腺和脾脏指数。采用苏木精-伊红（HE）染色观察回肠和结肠组织的病理变化。采用酶联免疫吸附试验（ELISA）检测肠道炎症细胞因子含量。16S rDNA 扩增子测序用于分析和解释粪便样本中的肠道微生物群。
AP 能显著抑制 5-FU 诱导的体重减轻、腹泻、胸腺和脾脏指数降低以及回肠和结肠组织病理改变。AMO 或 PGS 单独使用均不能显著改善上述异常。此外，AP 能显著抑制 5-FU 引起的肠道炎症细胞因子（TNF-α、IFN-γ、IL-6、IL-1β和 IL-17）的增加，而 AMO 或 PGS 单独使用仅在化疗后抑制其中一些细胞因子。肠道微生物组分析表明，AP 治疗可逆转 5-FU 引起的肠道微生物组整体结构变化。此外，AP 可显著调节不同门的丰度，使其接近正常值，并恢复厚壁菌门/拟杆菌门（F/B）的比值。在属水平上，AP 处理可显著降低拟杆菌、瘤胃球菌、厌氧真杆菌和脱硫弧菌等潜在致病菌。AP 还拮抗了 AMO 和 PGS 单独使用对某些属（如布劳特氏菌、副拟杆菌和乳酸杆菌）的异常作用。AMO 或 PGS 单独使用均不能抑制 5-FU 引起的肠道微生物结构变化。
AP，即 AMO 和 PGS 的组合，而不是 AMO 或 PGS 单独使用，能显著改善腹泻，抑制肠道病理变化，并调节 5-FU 诱导的小鼠肠道微生物结构。AP 还拮抗了 AMO 或 PGS 对某些属的异常作用。结果表明，肠道微生物群参与了 AP 对 5-FU 诱导的腹泻的联合作用。
