Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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白细胞介素 10 缺乏症通过富集肠道副拟杆菌 distasonis 抑制结直肠癌转移

 介绍

白细胞介素 10 （IL-10） 和肠道菌群错综复杂的相互作用影响肿瘤的发展和进展，但对结直肠癌 （CRC） 转移的影响仍不完全清楚。

 方法

首先在 CRC 转移肿瘤标本和小鼠模型中评估 Il10 缺陷对 CRC 转移的影响。采用抗生素灭菌和粪便微生物群移植 （FMT） 实验评估肠道菌群在 IL-10 介导的 CRC 转移中的作用，全长 16S rDNA 测序分析进一步确定了影响 CRC 转移的潜在靶菌。通过小鼠口服给药评价 Parabacteroides distasonis （P. distasonis） 对 CRC 转移的抑制作用。通过广泛靶向代谢组分析确定了参与 P. distasonis 抑制 CRC 转移的关键代谢物，并在体内和体外进行了验证。通过 RNA 测序研究了 P-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了验证。

 结果

我们发现，与非转移性病例相比，转移性 CRC 患者的血清 IL-10 水平显着升高。同时，小鼠中的 Il10 缺陷 （Il10^−/） 以肠道微生物群依赖性方式导致 CRC 转移减少。从机制上讲，Il10 ^−/− 小鼠重塑了肠道微生物群组成，特别是丰富了 P. distasonis。富集的 P. distasonis 产生 4-HPAA，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 的工程细菌有效阻碍了 CRC 转移。此外，在体外和体内肺转移小鼠模型中，AHR 耗竭显着破坏了 4-HPAA 诱导的 CRC 细胞迁移减少和转移抑制。

 结论

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 P. distasonis 或 4-HPAA 补充剂可能为预防 CRC 转移提供有前途的治疗策略。