山东大学初波等研究人员合作发现，肠道微生物代谢物通过抑制铁死亡促进结直肠癌的发展。相关论文于2024年1月2日在线发表在《自然—细胞生物学》杂志上。

研究人员发现从厌氧消化链球菌（Peptostreptococcus anaerobius）中提取的一种色氨酸代谢物——反式-3-吲哚丙烯酸（IDA）会促进结直肠癌的发生。从机理上讲，IDA是芳基烃受体（AHR）的内源性配体，可通过转录上调ALDH1A3（醛脱氢酶1家族成员A3）的表达，ALDH1A3利用视黄醛作为底物生成NADH，而NADH是铁死亡抑制蛋白1（FSP1）介导的还原型辅酶Q10合成所必需的。AHR或ALDH1A3的缺失在很大程度上抑制了IDA在体外和体内促进肿瘤的发展。

有趣的是，P. anaerobius在结直肠癌（CRC）患者中明显富集。在异种移植模型和Apc^Min/+小鼠中，IDA治疗或植入P. anaerobius都会促进CRC的进展。综上所述，这些研究结果表明，靶向IDA-AHR-ALDH1A3轴有望用于与铁死亡反应相关的CRC治疗。

据了解，肠道微生物群在人类健康中发挥着举足轻重的作用。新的证据表明，肠道微生物通过产生致癌代谢物参与了肿瘤发生的进程。然而，其潜在的分子机制在很大程度上还不为人知。

附：英文原文

Title: Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition

Author: Cui, Weiwei, Guo, Meng, Liu, Dong, Xiao, Peng, Yang, Chuancheng, Huang, Haidi, Liang, Chunhui, Yang, Yinghong, Fu, Xiaolong, Zhang, Yudan, Liu, Jiaxing, Shi, Shuang, Cong, Jingjing, Han, Zili, Xu, Yunfei, Du, Lutao, Yin, Chengqian, Zhang, Yongchun, Sun, Jinpeng, Gu, Wei, Chai, Renjie, Zhu, Shu, Chu, Bo

Issue&Volume: 2024-01-02

Abstract: The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA–AHR–ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.

DOI: 10.1038/s41556-023-01314-6

Source: https://www.nature.com/articles/s41556-023-01314-6