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

清解扶正顆粒通過減輕腸道菌群紊亂并抑制NOD2/NF-κB通路異常激活阻斷結(jié)腸炎相關(guān)性結(jié)直腸癌形成

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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：本研究通過結(jié)合16S rRNA測序和轉(zhuǎn)錄組測序的結(jié)果，采用多組學(xué)數(shù)據(jù)關(guān)聯(lián)分析，探討清解扶正顆粒（QFG）阻斷結(jié)腸炎相關(guān)性結(jié)直腸癌（CAC）形成的藥效機(jī)制。 方法：項(xiàng)目采用氧化偶氮甲烷（AOM）/葡聚糖硫酸鈉（DSS）誘導(dǎo)BALB/c小鼠構(gòu)建CAC模型，治療組口服QFG干預(yù)。通過疾病活動指數(shù)、組織病理學(xué)及T細(xì)胞亞群比例評估QFG對CAC形成的阻斷作用；利用RNA-seq和16S rRNA測序技術(shù)解析疾病基因改變及腸道菌群變化；整合多組學(xué)數(shù)據(jù)篩選關(guān)鍵藥效通路，并探究與CAC相關(guān)的微生物標(biāo)志譜。 結(jié)果：研究結(jié)果顯示，長期QFG干預(yù)可有效抑制AOM/DSS誘導(dǎo)的CAC形成，降低血清炎癥因子水平，提升CD3+ T細(xì)胞比例，改善CD4+/CD8+ T細(xì)胞比值，且無肝腎毒性。同時發(fā)現(xiàn)，QFG可逆轉(zhuǎn)結(jié)腸“炎-癌”轉(zhuǎn)化所致厚壁菌門/擬桿菌門（Firmicutes/Bacteroidetes）比例失衡，改善腸道菌群紊亂。結(jié)合轉(zhuǎn)錄組測序結(jié)果，發(fā)現(xiàn)抑制核苷酸結(jié)合寡聚化結(jié)構(gòu)域2（NOD2）/核因子κB（NF-κB）信號通路是QFG阻斷CAC形成的關(guān)鍵作用機(jī)制途徑。此外，QFG顯著降低芽孢桿菌綱（Bacilli）、芽孢桿菌目（Bacillales）、葡萄球菌科（Staphylococcaceae）、葡萄球菌屬（Staphylococcus）、乳桿菌目（Lactobacillales）、氣球菌屬（Aerococcus）、異普雷沃菌屬（Alloprevotella）及阿克曼菌屬（Akkermansia）豐度，同時上調(diào)梭菌目（Clostridiales）、毛螺菌科（Lachnospiraceae）、毛螺菌科_NK4A136_group（Lachnospiraceae_NK4A136_group）、瘤胃菌科（Ruminococcaceae）及鼠桿菌科（Muribaculaceae），這些菌群與CAC小鼠相關(guān)癥狀或NOD2/NF-κB通路呈顯著相關(guān)性。 結(jié)論：本研究構(gòu)建了CAC發(fā)生發(fā)展、免疫應(yīng)答、微生物標(biāo)志譜及關(guān)鍵通路之間的關(guān)聯(lián)網(wǎng)絡(luò)，闡明QFG多途徑阻斷CAC的作用機(jī)制，為藥物臨床作為預(yù)防性治療策略的應(yīng)用轉(zhuǎn)化提供科學(xué)依據(jù)。

    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.

    關(guān)鍵詞:
    結(jié)腸炎相關(guān)性結(jié)直腸癌;腸道菌群;NOD2/NF-κB通路;清解扶正顆粒;T細(xì)胞

    Keywords:


    Project Supported:
    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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