Bai Xue, Duan Zhiguang, Deng Jianjun, Zhang Zhuo, Fu Rongzhan, Zhu Chenhui, Fan Daidi
Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an, 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China.
Plastic and Cosmetic Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, China.
J Adv Res. 2025 Jun;72:37-52. doi: 10.1016/j.jare.2024.06.028. Epub 2024 Jul 3.
Dysbiosis of the gut microbiota is emerging as a pivotal factor in the pathogenesis of colorectal cancer (CRC). Ginsenoside Rh4 (Rh4) is an active compound isolated from ginseng with beneficial effects in modulating intestinal inflammation and gut microbiota dysbiosis, but how Rh4 regulates the gut microbiota to alleviate CRC remains underexplored.
We investigated the impact of Rh4 on CRC and the mechanism of its action in inhibiting CRC via modulation of gut microbiota.
We used the AOM/DSS model and employed transcriptomics, genomics and metabolomics techniques to explore the inhibitory impact of Rh4 on CRC. Furthermore, we employed experiments involving antibiotic treatment and fecal microbiota transplantation (FMT) to investigate the role of the gut microbiota. Finally, we elucidated the pivotal role of key functional bacteria and metabolites regulated by Rh4 in CRC.
Our research findings indicated that Rh4 repaired intestinal barrier damage caused by CRC, alleviated intestinal inflammation, and inhibited the development of CRC. Additionally, Rh4 inhibited CRC in a gut microbiota-dependent manner. Rh4 increased the diversity of gut microbiota, enriched the probiotic Akkermansia muciniphila (A. muciniphila), and alleviated gut microbiota dysbiosis caused by CRC. Subsequently, Rh4 regulated A. muciniphila-mediated bile acid metabolism. A. muciniphila promoted the production of UDCA by enhancing the activity of 7α-hydroxysteroid dehydrogenase (7α-HSDH). UDCA further activated FXR, modulated the TLR4-NF-κB signaling pathway, thus inhibiting the development of CRC.
Our results confirm that Rh4 inhibits CRC in a gut microbiota-dependent manner by modulating gut microbiota-mediated bile acid metabolism and promoting the production of UDCA, which further activates the FXR receptor and regulates the TLR4-NF-κB signaling pathway. Our results confirm that Rh4 has the potential to be used as a modulator of gut microbiota for preventing and treatment of CRC.
肠道微生物群失调正逐渐成为结直肠癌（CRC）发病机制中的关键因素。人参皂苷Rh4（Rh4）是从人参中分离出的一种活性化合物，在调节肠道炎症和肠道微生物群失调方面具有有益作用，但Rh4如何调节肠道微生物群以减轻CRC仍未得到充分研究。
我们研究了Rh4对CRC的影响及其通过调节肠道微生物群抑制CRC的作用机制。
我们使用AOM/DSS模型，并采用转录组学、基因组学和代谢组学技术来探究Rh4对CRC的抑制作用。此外，我们进行了抗生素治疗和粪便微生物群移植（FMT）实验，以研究肠道微生物群的作用。最后，我们阐明了Rh4调节的关键功能细菌和代谢产物在CRC中的关键作用。
我们的研究结果表明，Rh4修复了CRC引起的肠道屏障损伤，减轻了肠道炎症，并抑制了CRC的发展。此外，Rh4以肠道微生物群依赖的方式抑制CRC。Rh4增加了肠道微生物群的多样性，富集了益生菌嗜黏蛋白阿克曼氏菌（A. muciniphila），并减轻了CRC引起的肠道微生物群失调。随后，Rh4调节A. muciniphila介导的胆汁酸代谢。A. muciniphila通过增强7α-羟基类固醇脱氢酶（7α-HSDH）的活性促进了熊去氧胆酸（UDCA）的产生。UDCA进一步激活法尼醇X受体（FXR），调节Toll样受体4-核因子κB（TLR4-NF-κB）信号通路，从而抑制CRC的发展。
我们的结果证实，Rh4通过调节肠道微生物群介导的胆汁酸代谢并促进UDCA的产生，以肠道微生物群依赖的方式抑制CRC，UDCA进一步激活FXR受体并调节TLR4-NF-κB信号通路。我们的结果证实，Rh4有潜力作为肠道微生物群调节剂用于预防和治疗CRC。
