Wang Jialei, Tan Qingying, Ni Min, Chen Feng, Yang Junlong, Wang Guoliang, Zhao Xiaoyong, Zhang Xiaoli, Zhang Sen
Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangxi Medical University, Nanning, China.
Digestion. 2025 May 28:1-18. doi: 10.1159/000545843.
High-fat diets (HFDs) are known to affect the gut microbiome structure and potentially promote the development and metastasis of colorectal cancer (CRC). This study aims to elucidate the molecular mechanisms through which gut microbiome dysbiosis, mediated by the propionate/GPR41 signaling pathway, promotes lymphangiogenesis and lymph node (LN) metastasis in CRC, providing new insights for CRC treatment.
Microbial diversity and composition in rectal cancer were compared between CRC patients and healthy controls using 16S rRNA sequencing. Key genes related to short-chain fatty acid metabolism, HFD, and gut microbiota were identified. In vitro assays assessed CRC cell proliferation, migration, invasion, and lymphangiogenesis. A CRC mouse model on an HFD was used to measure fecal propionate levels and analyze GPR41 expression in tumors. In vivo fluorescence imaging was employed to track cancer cell migration and lymph node metastasis.
HFD-induced microbial dysbiosis led to a significant reduction in SCFA-producing bacteria and an increase in proinflammatory species. This dysbiosis contributed to the suppression of propionate's protective effects. Propionate inhibited CRC cell proliferation, migration, and invasion under HFD conditions by activating the GPR41 pathway. Silencing GPR41 reversed these inhibitory effects, highlighting the key role of GPR41 in mediating propionate's antitumor effects. In vivo experiments further confirmed that propionate suppressed HFD-enhanced CRC lymphatic metastasis through the GPR41 signaling pathway, linking microbial dysbiosis with the modulation of cancer progression.
This study reveals that HFD promotes CRC lymphangiogenesis and LN metastasis through gut microbiota dysbiosis and suppression of the propionate-activated GPR41 signaling pathway. These findings highlight the therapeutic potential of targeting the propionate/GPR41 axis, offering a promising strategy for developing novel anticancer therapies.
已知高脂饮食（HFDs）会影响肠道微生物群结构，并可能促进结直肠癌（CRC）的发展和转移。本研究旨在阐明由丙酸盐/GPR41信号通路介导的肠道微生物群失调促进CRC淋巴管生成和淋巴结（LN）转移的分子机制，为CRC治疗提供新的见解。
使用16S rRNA测序比较CRC患者和健康对照者直肠癌中的微生物多样性和组成。鉴定了与短链脂肪酸代谢、HFD和肠道微生物群相关的关键基因。体外实验评估了CRC细胞的增殖、迁移、侵袭和淋巴管生成。使用HFD喂养的CRC小鼠模型测量粪便丙酸盐水平并分析肿瘤中GPR41的表达。采用体内荧光成像追踪癌细胞迁移和淋巴结转移。
HFD诱导的微生物失调导致产短链脂肪酸细菌显著减少，促炎菌增加。这种失调导致丙酸盐保护作用受到抑制。在HFD条件下，丙酸盐通过激活GPR41途径抑制CRC细胞的增殖、迁移和侵袭。沉默GPR41可逆转这些抑制作用，突出了GPR41在介导丙酸盐抗肿瘤作用中的关键作用。体内实验进一步证实，丙酸盐通过GPR41信号通路抑制HFD增强的CRC淋巴转移，将微生物失调与癌症进展的调节联系起来。
本研究表明，HFD通过肠道微生物群失调和抑制丙酸盐激活的GPR41信号通路促进CRC淋巴管生成和LN转移。这些发现突出了靶向丙酸盐/GPR41轴的治疗潜力，为开发新型抗癌疗法提供了一种有前景的策略。
