黄连经吴茱萸炮制后通过增加肠道能量代谢物α-酮戊二酸和罗伊氏乳杆菌改善溃疡性结肠炎的疗效。
Coptidis Rhizoma processed with Evodia Rutaecarpa improves the effect on ulcerative colitis by increasing intestinal energy metabolites alpha-ketoglutarate and Lactobacillus reuteri.
机构信息
Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology, Southern Medical University, Guangzhou 510515, China.
Department of Gastroenterology, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou 510010, China.
出版信息
Phytomedicine. 2023 Dec;121:155115. doi: 10.1016/j.phymed.2023.155115. Epub 2023 Sep 27.
BACKGROUND
Evodia Rutaecarpa-processed Coptidis Rhizoma (ECR) is a traditional Chinese medicine for the treatment of ulcerative colitis (UC) in China. However, the mechanisms underlying the ECR processing are not elucidated.
PURPOSE
Coptidis Rhizoma (CR) regulates the gut microbiota in the treatment of gastrointestinal diseases. This study explored the mechanism of action of ECR before and after processing in UC in view of the regulation of gut microecology.
STUDY DESIGN
A preclinical experimental investigation was performed using a mouse model of UC to examine the regulatory effect of ECR and its mechanisms through gut microbiota analysis and metabolomic assays.
METHODS
Mice received 4% dextran sulfate sodium to establish a UC model and treated with ECR and CR. Colonic histopathology and inflammatory changes were observed. Gut microbiota was analyzed using 16 s rRNA sequencing. Transplants of Lactobacillus reuteri were used to explore the correlation between ECR processing and the gut microbiota. The expression of mucin-2, Lgr5, and PCNA in colonic epithelial cells was measured using immunofluorescence. Wnt3a and β-catenin levels were detected by western blotting. The metabolites in the colon tissue were analyzed using a targeted energy metabolomic assay. The effect of energy metabolite α-ketoglutarate (α-KG) on L. reuteri growth and UC were verified in mice.
RESULTS
ECR improved the effects on UC in mice compared to CR, including alleviating colonic injury and inflammation, and modulating gut microbiota by increasing L. reuteri level. L. reuteri dose-dependently alleviated colonic injury, increased mucin-2 level, and promoted colonic epithelial regeneration by increasing Lgr5 and PCNA expression. This was consistent with the results before and after ECR processing. L. reuteri promoted epithelial regeneration by upregulating Wnt/β-catenin pathway. Moreover, ECR increased metabolites levels (especially α-KG) to promote energy metabolism in the colon tissue compared to CR. α-KG treatment increased L. reuteri level and alleviated mucosal damage in UC mice. It promoted L. reuteri growth by increasing the energy metabolic status by enhancing α-KG dehydrogenase activity.
CONCLUSION
ECR processing improves the therapeutic effects of UC via the α-KG-L. reuteri-epithelial regeneration axis.
背景
吴茱萸炮制黄连（ECR）是中国治疗溃疡性结肠炎（UC）的一种传统中药。然而，其炮制机制尚不清楚。
目的
黄连（CR）在治疗胃肠道疾病时调节肠道微生物群。本研究从肠道微生态调节的角度，探讨了炮制前后 ECR 在 UC 中的作用机制。
研究设计
采用 UC 小鼠模型进行临床前实验研究，通过肠道微生物组分析和代谢组学检测，研究 ECR 的调节作用及其机制。
方法
小鼠接受 4%葡聚糖硫酸钠建立 UC 模型，并给予 ECR 和 CR 治疗。观察结肠组织病理学和炎症变化。采用 16s rRNA 测序分析肠道微生物群。通过移植乳酸杆菌（Lactobacillus reuteri）来探讨 ECR 炮制与肠道微生物群的相关性。采用免疫荧光法检测结肠上皮细胞中黏蛋白-2、Lgr5 和 PCNA 的表达。采用 Western blot 检测 Wnt3a 和 β-catenin 水平。采用靶向能量代谢组学检测结肠组织中的代谢物。在小鼠中验证能量代谢物α-酮戊二酸（α-KG）对 L. reuteri 生长和 UC 的影响。
结果
与 CR 相比，ECR 改善了 UC 小鼠的疗效，包括减轻结肠损伤和炎症，以及通过增加 L. reuteri 水平调节肠道微生物群。L. reuteri 呈剂量依赖性地减轻结肠损伤，增加黏蛋白-2 水平，并通过增加 Lgr5 和 PCNA 表达促进结肠上皮细胞再生。这与 ECR 炮制前后的结果一致。L. reuteri 通过上调 Wnt/β-catenin 通路促进上皮细胞再生。此外，与 CR 相比，ECR 增加了代谢物水平（尤其是 α-KG），以促进结肠组织的能量代谢。α-KG 处理增加了 UC 小鼠的 L. reuteri 水平和黏膜损伤的缓解。它通过增强α-KG 脱氢酶活性来增加能量代谢状态，从而促进 L. reuteri 的生长。
结论
ECR 炮制通过 α-KG-L. reuteri-上皮再生轴改善 UC 的治疗效果。
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