2. Academic Validation
  3. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition

Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition

  • Nat Cell Biol. 2024 Jan;26(1):124-137. doi: 10.1038/s41556-023-01314-6.
Weiwei Cui # 1,  Meng Guo # 2,  Dong Liu # 1,  Peng Xiao 1,  Chuancheng Yang 1,  Haidi Huang 3,  Chunhui Liang 1,  Yinghong Yang 1,  Xiaolong Fu 4,  Yudan Zhang 1,  Jiaxing Liu 1,  Shuang Shi 5,  Jingjing Cong 2,  Zili Han 2,  Yunfei Xu 6,  Lutao Du 6,  Chengqian Yin 7,  Yongchun Zhang 3,  Jinpeng Sun 1,  Wei Gu 8,  Renjie Chai 9 10 11 12,  Shu Zhu 13 14,  Bo Chu 15
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 4 State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.
  • 5 Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China.
  • 6 Qilu hospital of Shandong University, Jinan, China.
  • 7 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
  • 8 Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, New York, NY, USA. [email protected].
  • 9 State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China. [email protected].
  • 10 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. [email protected].
  • 11 School of Life Science, Beijing Institute of Technology, Beijing, China. [email protected].
  • 12 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. [email protected].
  • 13 Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 14 Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 15 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • # Contributed equally.
PMID: 38168770 DOI: 10.1038/s41556-023-01314-6
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.

Figures
Products