Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

IF 4.8 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2024-07-03 DOI:10.1016/j.intimp.2024.112610

Yonglong Chang, Qinling Ou, Xuhui Zhou, Kechao Nie, Piao Zheng, Jinhui Liu, Linzi Chen, Haixia Yan, Duanyang Guo, Sifang Zhang

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Abstract

Background: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain.

Aims: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC.

Methods: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1β and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB.

Results: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth.

Conclusion: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

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建皮解毒汤通过色氨酸代谢-AhR途径抑制TAMs的M2极化，从而抑制结直肠癌的生长。

背景：传统中药健皮解毒汤（JPJDF）用于结直肠癌（CRC）治疗已有四十多年的历史。目的：本研究旨在进一步探讨健皮解毒汤对 CRC 的治疗机制：方法：使用偶氮甲烷（AOM）和右旋糖酐硫酸钠（DSS）建立CAC小鼠模型。肠道组织和内容物进行了 16S rRNA 基因测序和非靶向代谢组学分析。使用酶联免疫吸附法测定血清中 IL-1β 和 TNF-α 的水平。免疫组化技术用于评估 Ki67、ZO-1、Occludin、CD68 和 CD206 的表达。此外，还进行了Western印迹以评估AhR和NF-κB的蛋白表达：结果：JPJDF抑制了AOM/DSS处理小鼠的结直肠肿瘤发生，同时还抑制了肿瘤细胞的增殖并上调了紧密连接蛋白的表达。16S rRNA基因测序分析结果显示，JPJDF通过增加有益菌的丰度改变了肠道微生物群的组成。此外，JPJDF还能减少色氨酸代谢物，有效缓解炎症，显著恢复CAC小鼠的肠道屏障功能。分子生物学实验证实，JPJDF可抑制AhR和M2型肿瘤相关巨噬细胞的表达水平，从而促进抗肿瘤免疫，抑制CAC的生长：结论：JPJDF可通过调节肠道微生物群来调节色氨酸代谢-AhR通路，减轻肠道炎症反应，改善肠道屏障功能，增强抗肿瘤免疫力，有效抑制CAC生长。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.