Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.

IF 4.9 2区医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2024-08-01 Epub Date: 2024-02-05 DOI:10.1007/s13402-024-00920-2

Wanru Zhang, Xiali Qin, Kexin Zhang, Jiahui Ma, Mengfan Li, Ge Jin, Xiang Liu, Sinan Wang, Bangmao Wang, Jing Wu, Tianyu Liu, Weilong Zhong, Hailong Cao

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Abstract

Purpose: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression.

Methods: Apc^min/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC.

Results: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/β-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/β-catenin pathway activation.

Conclusion: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

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微生物代谢物三甲胺-N-氧化物通过抑制类雌激素 X 受体信号传导诱发肠癌。

目的：微生物菌群失调被认为是结直肠癌（CRC）的特征之一。三甲胺-N-氧化物（TMAO）作为一种依赖于肠道微生物群的代谢物，最近被认为与 CRC 的发生有关。然而，TMAO 与肠癌发生有关的证据在很大程度上仍未得到探讨。在此，我们旨在研究 TMAO 在 CRC 进展中的关键作用：方法：用 TMAO 或无菌 PBS 处理 Apcmin/+ 小鼠 14 周。方法：用 TMAO 或无菌 PBS 处理 Apcmin/+ 小鼠 14 周，分离肠组织以评估 TMAO 对肠腺瘤恶性转化的影响。通过 16S rRNA 测序分析检测小鼠粪便中的肠道微生物群。使用 HCT-116 细胞进一步证明了 TMAO 对 CRC 进展的影响：结果：服用 TMAO 会增加肿瘤细胞和干细胞增殖，减少细胞凋亡，并伴有 DNA 损伤和肠道屏障受损。肠道微生物群分析表明，TMAO诱导肠道微生物群落结构发生变化，表现为微生物群多样性和有益菌减少。从机理上讲，TMAO与类雌激素X受体（FXR）结合，从而抑制了FXR-成纤维细胞生长因子15（FGF15）轴，激活了Wnt/β-catenin信号通路，而FXR激动剂GW4064则可以抑制TMAO诱导的Wnt/β-catenin通路激活：结论：微生物代谢物TMAO可通过抑制FXR-FGF15通路促进肠癌的发生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.