Yu Jing, Feng Lili, Luo Zhanhao, Yang Jingyi, Zhang Qiang, Liu Chen, Liang Dayi, Xie Yanchun, Li Hongmin, Gong Junli, He Zhen, Lan Ping
Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
J Adv Res. 2024 Nov 19. doi: 10.1016/j.jare.2024.11.024.
The intricate interplay of interleukin-10 (IL-10) and gut microbiota influences tumor development and progression, yet the impacts on colorectal cancer (CRC) metastasis remain incompletely understood.
The impact of Il10 deficiency on CRC metastasis was first evaluated in CRC metastasis tumor samples and mouse model. Antibiotic sterilization and fecal microbiota transplantation (FMT) experiment were used to assess the role of gut microbiota in IL-10 mediated CRC metastasis, and full-length 16S rDNA sequencing analysis further identified the potential target bacteria influencing CRC metastasis. The inhibitory effect of Parabacteroides distasonis (P. distasonis) on CRC metastasis was evaluated by oral administration in mice. Key metabolites involved in P. distasonis inhibition of CRC metastasis was identified by widely-targeted metabolome analysis and validated both in vivo and in vitro. The underlying mechanisms of P-hydroxyphenyl acetic acid (4-HPAA) inhibiting CRC metastasis was investigated via RNA-sequencing and validated in cellular experiments.
We revealed that serum IL-10 levels were markedly elevated in metastatic CRC patients compared to non-metastatic cases. In parallel, Il10-deficiency (Il10) in mice resulted in decreased CRC metastasis in a gut microbiota-dependent manner. Mechanistically, Il10 mice reshaped gut microbiota composition, notably enriching P. distasonis. The enriched P. distasonis produced 4-HPAA, which activated the aryl hydrocarbon receptor (AHR) and subsequently inhibited the expression of VEGFA, a typical oncogene, thereby sequentially suppressing CRC metastasis. Importantly, engineered bacteria capable of producing 4-HPAA effectively hindered CRC metastasis. Furthermore, AHR depletion significantly disrupted the 4-HPAA-induced reduction in CRC cell migration and the inhibition of metastasis in both in vitro and in vivo lung metastasis mouse models.
These findings demonstrate the significance of IL-10 deficiency in suppressing CRC metastasis through the 4-HPPA-AHR-VEGFA axis mediated by gut P. distasonis, suggesting that P. distasonis or 4-HPAA supplementation could offer a promising therapeutic strategy for CRC metastasis prevention.
白细胞介素-10（IL-10）与肠道微生物群之间复杂的相互作用影响肿瘤的发生和发展，然而其对结直肠癌（CRC）转移的影响仍不完全清楚。
首先在CRC转移瘤样本和小鼠模型中评估Il10缺陷对CRC转移的影响。采用抗生素除菌和粪便微生物群移植（FMT）实验来评估肠道微生物群在IL-10介导的CRC转移中的作用，全长16S rDNA测序分析进一步鉴定影响CRC转移的潜在靶细菌。通过给小鼠口服来评估狄氏副拟杆菌（P. distasonis）对CRC转移的抑制作用。通过广泛靶向代谢组分析鉴定P. distasonis抑制CRC转移所涉及的关键代谢物，并在体内和体外进行验证。通过RNA测序研究对羟基苯乙酸（4-HPAA）抑制CRC转移的潜在机制，并在细胞实验中进行验证。
我们发现，与非转移病例相比，转移性CRC患者血清IL-10水平显著升高。同时，小鼠中的Il10缺陷（Il10）以肠道微生物群依赖的方式导致CRC转移减少。从机制上讲，Il10小鼠重塑了肠道微生物群组成，显著富集了P. distasonis。富集的P. distasonis产生4-HPAA，其激活芳烃受体（AHR），随后抑制典型癌基因VEGFA的表达，从而依次抑制CRC转移。重要的是，能够产生4-HPAA的工程菌有效阻碍了CRC转移。此外，AHR缺失显著破坏了4-HPAA诱导的CRC细胞迁移减少以及在体外和体内肺转移小鼠模型中对转移的抑制作用。
这些发现证明了IL-10缺陷通过肠道P. distasonis介导的4-HPPA-AHR-VEGFA轴抑制CRC转移的重要性，表明补充P. distasonis或4-HPAA可能为预防CRC转移提供一种有前景的治疗策略。
