The gut microbiota plays a pivotal role in the immunomodulatory and protumorigenic microenvironment of colorectal cancer (CRC). However, the effect of ginsenoside Rk3 (Rk3) on CRC and gut microbiota remains unclear. Therefore, the purpose of this study is to explore the potential effect of Rk3 on CRC from the perspective of gut microbiota and immune regulation. Our results reveal that treatment with Rk3 significantly suppresses the formation of colon tumors, repairs intestinal barrier damage, and regulates the gut microbiota imbalance caused by CRC, including enrichment of probiotics such as Akkermansia muciniphila and Barnesiella intestinihominis, and clearance of pathogenic Desulfovibrio. Subsequent metabolomics data demonstrate that Rk3 can modulate the metabolism of amino acids and bile acids, particularly by upregulating glutamine, which has the potential to regulate the immune response. Furthermore, we elucidate the regulatory effects of Rk3 on chemokines and inflammatory factors associated with group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) signaling pathways, and inhibits the hyperactivation of the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway. These results indicate that Rk3 modulates gut microbiota, regulates ILC3s immune response, and inhibits the JAK-STAT3 signaling pathway to suppress the development of colon tumors. More importantly, the results of fecal microbiota transplantation suggest that the inhibitory effect of Rk3 on colon tumors and its regulation of ILC3 immune responses are mediated by the gut microbiota. In summary, these findings emphasize that Rk3 can be utilized as a regulator of the gut microbiota for the prevention and treatment of CRC.

肠道微生物群在结直肠癌（CRC）的免疫调节和促肿瘤微环境中发挥着关键作用。然而，人参皂苷 Rk3 (Rk3) 对 CRC 和肠道微生物群的影响仍不清楚。因此，本研究的目的是从肠道菌群和免疫调节的角度探讨Rk3对CRC的潜在影响。我们的研究结果表明，Rk3 治疗可显着抑制结肠肿瘤的形成，修复肠道屏障损伤，并调节 CRC 引起的肠道微生物群失衡，包括富集益生菌，如Akkermansia muciniphila和Barnesiella intestinihominis ，以及清除致病性Desulfovibrio 。随后的代谢组学数据表明，Rk3 可以调节氨基酸和胆汁酸的代谢，特别是通过上调谷氨酰胺，从而具有调节免疫反应的潜力。此外，我们阐明了 Rk3 对与第 3 组先天淋巴细胞 (ILC3) 和 T 辅助细胞 17 (Th17) 信号通路相关的趋化因子和炎症因子的调节作用，并抑制 Janus 激酶信号转导器和转录激活剂 3 的过度激活(JAK-STAT3) 信号通路。这些结果表明，Rk3 调节肠道微生物群，调节 ILC3 免疫反应，并抑制 JAK-STAT3 信号通路，从而抑制结肠肿瘤的发展。更重要的是，粪便微生物群移植的结果表明，Rk3对结肠肿瘤的抑制作用及其对ILC3免疫反应的调节是由肠道微生物群介导的。总之，这些发现强调 Rk3 可用作肠道微生物群的调节剂，用于预防和治疗 CRC。