Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
Sci Rep. 2024 Jun 6;14(1):13063. doi: 10.1038/s41598-024-63993-x.
Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.
结直肠癌（CRC）是一个普遍存在的全球健康问题，5-氟尿嘧啶（5-FU）是一种常用的化疗药物。然而，5-FU 的疗效常受到药物耐受性的限制。丁酸钠（NaB）是肠道菌群的衍生物，已在体外和体内通过促进细胞凋亡作用显示出抗癌特性，并在与传统化疗药物联合使用时显示出改善疗效的潜力。本研究旨在评估 NaB 与 5-FU 联合应用于 CRC 的影响和潜在机制。我们采用了一系列综合检测方法，包括 CCK-8、EdU 染色、Hoechst 33258 染色、流式细胞术、ROS 测定、MMP 测定、免疫荧光和线粒体自噬测定，以检测 NaB 对 CRC 细胞体外生物学功能的影响。Western blot 和免疫组化用于验证上述实验结果。建立异种移植肿瘤模型评估 NaB 的体内抗 CRC 活性。随后，通过 16S rRNA 基因测序分析肠道菌群。本研究发现，丁酸钠（NaB）在体外对肿瘤细胞增殖具有抑制作用，并促进肿瘤细胞凋亡，同时通过增强线粒体自噬途径抑制肿瘤进展。此外，与单一用药相比，NaB 与 5-氟尿嘧啶（5-FU）联合治疗具有更好的治疗效果。此外，这种联合治疗导致肠道微生物群中特定的拟杆菌、LigiLactobacillus、产丁酸细菌和产乙酸细菌的富集。肠道微生物群的改善有助于提高治疗效果并减少 5-FU 的不良反应。综上所述，这些发现表明，通过肠道菌群发酵合成的组蛋白乙酰化抑制剂 NaB 有潜力显著增强 5-FU 在 CRC 治疗中的疗效，并改善 CRC 患者的预后。
