2. Academic Validation
  3. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer

Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer

  • Nat Microbiol. 2023 Apr 17. doi: 10.1038/s41564-023-01363-5.
Ji-Xuan Han # 1,  Zhi-Hang Tao # 1,  Ji-Lin Wang # 1,  Lu Zhang 1,  Chen-Yang Yu 1,  Zi-Ran Kang 1,  Yuanhong Xie 1,  Jialu Li 1,  Shiyuan Lu 1,  Yun Cui 1,  Jia Xu 2,  Enhao Zhao 2,  Ming Wang 2,  Jinxian Chen 2,  Zheng Wang 2,  Qiang Liu 3,  Hui-Min Chen 1,  Wenyu Su 1,  Tian-Hui Zou 1,  Cheng-Bei Zhou 1,  Jie Hong 1,  Haoyan Chen 1,  Hua Xiong 4,  Ying-Xuan Chen 5,  Jing-Yuan Fang 6
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. xionghua@renji.com.
  • 5 Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
  • 6 Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
  • # Contributed equally.
PMID: 37069401 DOI: 10.1038/s41564-023-01363-5
Abstract

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal Cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

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