Ye Chenxiao, Wu Changhong, Li Yan, Chen Chao, Li Xinrong, Zhang Jin, Xu Zhili, Chen Haitao, Guo Yong
The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
J Ethnopharmacol. 2024 Oct 28;333:118411. doi: 10.1016/j.jep.2024.118411. Epub 2024 May 31.
Previous studies have revealed that a high-fat diet (HFD) promotes the progression of colorectal cancer (CRC) in close association with disturbances in the intestinal flora and metabolic disorders. Xianglian pill (XLP) is a well-established traditional prescription with unique advantages in controlling intestinal flora imbalance and inflammation. However, its therapeutic effects on HFD-related CRC remain largely unknown.
The primary objective of this research was to investigate the anticancer mechanism of XLP in countering HFD-related CRC.
The protective effect of XLP was evaluated using azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC model of mice exposed to a HFD. The degree of colorectal carcinogenesis, including body weight, colon length, and histopathology, was measured in mice treated with XLP and untreated mice. The effect of XLP on gut microbiota and its metabolites was detected using 16S rDNA and liquid chromatography/mass spectrometry analysis. Furthermore, a "pseudo-sterile" mouse model was constructed using antibiotics (Abx) to verify whether the gut microbiota and metabolites play a role in the pathogenesis of CRC.
XLP inhibited colorectal tumorigenesis in a dose-dependent fashion. Our findings also highlighted that XLP protected the integrity of the intestinal barrier by reducing the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as the infiltration of pro-inflammatory macrophages. Mechanistically, XLP inhibited the TLR4/MyD88 pathway. Notably, the XLP treatment increased the proportion of probiotics (particularly Akkermansia) and significantly reduced fecal deoxycholic acid (DCA), a microbiota-derived metabolite of bile acids (BA) closely related to Muribaculaceae. Furthermore, after Abx treatment, XLP showed no clear antitumor effects on CRC. Simultaneously, DCA-supplemented feedings promoted colorectal tumorigenesis and provoked obvious colonic inflammation, M1 macrophage infiltration, and colonic injury. In vitro, the results of RAW-264.7 macrophages and normal intestinal epithelial cells treated with DCA corroborated our in vivo findings, demonstrating consistent patterns in inflammatory responses and intestinal barrier protein expression.
Our findings suggest that XLP inhibits colorectal cancer associated with HFD via inactivating TLR4/MyD88 by remodeling gut microbiota composition and BA metabolism.
先前的研究表明，高脂饮食（HFD）与肠道菌群紊乱和代谢紊乱密切相关，会促进结直肠癌（CRC）的进展。香连丸（XLP）是一种成熟的传统方剂，在控制肠道菌群失衡和炎症方面具有独特优势。然而，其对HFD相关CRC的治疗效果仍 largely未知。
本研究的主要目的是探讨XLP对抗HFD相关CRC的抗癌机制。
使用氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）诱导暴露于HFD的小鼠建立CRC模型，评估XLP的保护作用。测量用XLP处理的小鼠和未处理小鼠的结直肠癌发生程度，包括体重、结肠长度和组织病理学。使用16S rDNA和液相色谱/质谱分析检测XLP对肠道微生物群及其代谢产物的影响。此外，使用抗生素（Abx）构建“假无菌”小鼠模型，以验证肠道微生物群和代谢产物是否在CRC发病机制中起作用。
XLP以剂量依赖方式抑制结直肠癌发生。我们的研究结果还突出表明，XLP通过降低促炎细胞因子如IL-6和TNF-α的表达以及促炎巨噬细胞的浸润来保护肠道屏障的完整性。从机制上讲，XLP抑制TLR4/MyD88途径。值得注意的是，XLP治疗增加了益生菌（特别是阿克曼氏菌）的比例，并显著降低了粪便脱氧胆酸（DCA），DCA是一种与毛螺菌科密切相关的胆汁酸（BA）的微生物衍生代谢产物。此外，在Abx处理后，XLP对CRC没有明显的抗肿瘤作用。同时，补充DCA的饲料促进了结直肠癌发生，并引发明显的结肠炎症、M1巨噬细胞浸润和结肠损伤。在体外，用DCA处理RAW-264.7巨噬细胞和正常肠上皮细胞的结果证实了我们的体内研究结果，表明炎症反应和肠道屏障蛋白表达存在一致模式。
我们的研究结果表明，XLP通过重塑肠道微生物群组成和BA代谢使TLR4/MyD88失活，从而抑制与HFD相关的结直肠癌。
