Qingjie Fuzheng Granule prevents colitis-associated colorectal cancer by inhibiting abnormal activation of NOD2/NF-κB signaling pathway mediated by gut microbiota disorder

doi:https://doi.org/10.1016/j.chmed.2025.04.001

Archive > Volume 17 Issue 3 > 2025,17(3):500-512. DOI:https://doi.org/10.1016/j.chmed.2025.04.001 Prev Next

清解扶正颗粒通过减轻肠道菌群紊乱并抑制NOD2/NF-κB通路异常激活阻断结肠炎相关性结直肠癌形成

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Qingjie Fuzheng Granule prevents colitis-associated colorectal cancer by inhibiting abnormal activation of NOD2/NF-κB signaling pathway mediated by gut microbiota disorder

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摘要:

目的：本研究通过结合16S rRNA测序和转录组测序的结果，采用多组学数据关联分析，探讨清解扶正颗粒（QFG）阻断结肠炎相关性结直肠癌（CAC）形成的药效机制。方法：项目采用氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导BALB/c小鼠构建CAC模型，治疗组口服QFG干预。通过疾病活动指数、组织病理学及T细胞亚群比例评估QFG对CAC形成的阻断作用；利用RNA-seq和16S rRNA测序技术解析疾病基因改变及肠道菌群变化；整合多组学数据筛选关键药效通路，并探究与CAC相关的微生物标志谱。结果：研究结果显示，长期QFG干预可有效抑制AOM/DSS诱导的CAC形成，降低血清炎症因子水平，提升CD3+ T细胞比例，改善CD4+/CD8+ T细胞比值，且无肝肾毒性。同时发现，QFG可逆转结肠“炎-癌”转化所致厚壁菌门/拟杆菌门（Firmicutes/Bacteroidetes）比例失衡，改善肠道菌群紊乱。结合转录组测序结果，发现抑制核苷酸结合寡聚化结构域2（NOD2）/核因子κB（NF-κB）信号通路是QFG阻断CAC形成的关键作用机制途径。此外，QFG显著降低芽孢杆菌纲（Bacilli）、芽孢杆菌目（Bacillales）、葡萄球菌科（Staphylococcaceae）、葡萄球菌属（Staphylococcus）、乳杆菌目（Lactobacillales）、气球菌属（Aerococcus）、异普雷沃菌属（Alloprevotella）及阿克曼菌属（Akkermansia）丰度，同时上调梭菌目（Clostridiales）、毛螺菌科（Lachnospiraceae）、毛螺菌科_NK4A136_group（Lachnospiraceae_NK4A136_group）、瘤胃菌科（Ruminococcaceae）及鼠杆菌科（Muribaculaceae），这些菌群与CAC小鼠相关症状或NOD2/NF-κB通路呈显著相关性。结论：本研究构建了CAC发生发展、免疫应答、微生物标志谱及关键通路之间的关联网络，阐明QFG多途径阻断CAC的作用机制，为药物临床作为预防性治疗策略的应用转化提供科学依据。

Abstract:

Objective: This study investigates the efficacy and mechanisms of Qingjie Fuzheng Granules (QFG) in inhibiting colitis-associated colorectal cancer (CAC) development via RNA sequencing (RNA-seq) and 16S ribosomal RNA (rRNA) correlation analysis. Methods: CAC was induced in BALB/c mice using azoxymethane (AOM) and dextran sulfate sodium (DSS), and QFG was administered orally to the treatment group. The effects of QFG on CAC were evaluated using disease index, histology, and serum T-cell ratios. RNA-seq and 16S rRNA analysis assessed the transcriptome and microbiome change. Key pharmacodynamic pathways were identified by integrating these data and confirmed via Western blotting and immunofluorescence. The link between microbiota and CACrelated markers was explored using linear discriminant analysis effect size and Spearman correlation analysis. Results: Long-term treatment with QFG prevented AOM/DSS-induced CAC formation, reduced levels of interleukin (IL)-1b, tumor necrosis factor-alpha (TNF-a), IL-6, and interferon c (IFN-c), and increased CD3+ and CD4+/CD8+ T cells ratio, without causing hepatic or renal toxicity. A 16S rRNA analysis revealed that QFG rebalanced the Firmicutes/Bacteroidetes ratio and mitigated AOM/DSS-induced microbiota disturbances. Transcriptomics and Western blotting analysis identified the nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/nuclear factor kappa-B (NF-jB) pathway as key for QFG’s treatment against CAC. Furthermore, QFG decreased the abundance of Bacilli, Bacillales, Staphylococcaceae, Staphylococcus, Lactobacillales, Aerococcus, Alloprevotella, and Akkermansia, while increasing Clostridiales, Lachnospiraceae, Lachnospiraceae_NK4A136_group, Ruminococcaceae, and Muribaculaceae, which were highly correlated with CAC-related markers or NOD2/NF-jB pathway. Conclusion: By mapping the relationships between CAC, immune responses, microbiota, and key pathways, this study clarifies the mechanism of QFG in inhibiting CAC, highlighting its potential for clinical use as preventive therapy.

关键词:

结肠炎相关性结直肠癌;肠道菌群;NOD2/NF-κB通路;清解扶正颗粒;T细胞

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This work was supported by the National Natural Science Foundation of China (No. 82204925), the Financial Project of Fujian Province (No. X2024004) and the Natural Science Foundation of Fujian Province, China (No. 2024J01782, 2022J01368).

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清解扶正颗粒通过减轻肠道菌群紊乱并抑制NOD2/NF-κB通路异常激活阻断结肠炎相关性结直肠癌形成

Original articles

Qingjie Fuzheng Granule prevents colitis-associated colorectal cancer by inhibiting abnormal activation of NOD2/NF-κB signaling pathway mediated by gut microbiota disorder

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