Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
Cancer Institute, School of Medicine, Jianghan University, Wuhan, China.
J Transl Med. 2023 Mar 16;21(1):198. doi: 10.1186/s12967-023-04042-5.
Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ's application, there still lack of strategies to increase the chemotherapy sensitivity.
Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman's correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response.
Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α T cell) recruitment.
The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.
替莫唑胺（TMZ）是治疗神经胶质瘤的首选化疗药物。作为第二代烷化剂，TMZ具有更好的口服生物利用度。然而，其疗效有限（低于 50%），耐药发生率高，严重限制了 TMZ 的应用，目前仍然缺乏提高化疗敏感性的策略。
利用 Luci-GL261 神经胶质瘤原位异种移植模型结合生物发光成像来评估 TMZ 的抗肿瘤效果，并区分 TMZ 敏感（S）/非敏感（NS）个体。整合微生物组学和代谢组学分析，以阐明肠道细菌在 TMZ 敏感性中的作用。采用 Spearman 相关分析检测粪便细菌水平与药效学指标的相关性。采用抗生素联合 TMZ 治疗，以确定肠道微生物群在 TMZ 反应中的作用。采用流式细胞术分析、ELISA 和组织病理学分析，探讨免疫调节在肠道微生物群介导的 TMZ 反应中的潜在作用。
首先，在神经胶质瘤发展和 TMZ 治疗过程中，肠道细菌组成发生了显著变化。同时，体内抗癌评估表明，TMZ 给药后的化疗疗效存在显著差异。此外，16s rRNA 基因测序和非靶向代谢组学分析显示，TMZ 敏感和非敏感小鼠的肠道微生物群和免疫浸润状态存在明显差异，而差异肠道细菌和相关代谢物的丰度与 TMZ 药效学指标显著相关。进一步验证表明，抗生素处理可消除肠道菌群，从而加速神经胶质瘤的发展，降低 TMZ 的疗效，并抑制免疫细胞（巨噬细胞和 CD8α T 细胞）的募集。
本研究证实了肠道微生物群通过免疫调节参与神经胶质瘤的发展和个体化 TMZ 疗效，因此肠道细菌可以作为临床 TMZ 应用的预测生物标志物和治疗靶点。
