2. Academic Validation
  3. Gut microbial-derived N-acetylmuramic acid alleviates colorectal cancer via the AKT1 pathway

Gut microbial-derived N-acetylmuramic acid alleviates colorectal cancer via the AKT1 pathway

  • Gut. 2025 Feb 27:gutjnl-2024-332891. doi: 10.1136/gutjnl-2024-332891.
Mengyao Hu # 1,  Yi Xu # 1,  Yuqing Wang # 1,  Zhenhe Huang # 1,  Lei Wang 1,  Fanan Zeng 2,  Bowen Qiu 2,  Zefeng Liu 2,  Peibo Yuan 1,  Yu Wan 1,  Shuang Ge 1,  Dian Zhong 1,  Siyu Xiao 3,  Rongrong Luo 1,  Jiaqi He 1,  Meiling Sun 4,  Xiaoduan Zhuang 4,  Nannan Guo 1,  Chunhui Cui 5,  Jie Gao 6 7,  Hongwei Zhou 8 9 10,  Xiaolong He 8 11 12
Affiliations

Affiliations

  • 1 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 5 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China hxl2027315@smu.edu.cn biodegradation@gmail.com gaojie1022@gzhmu.edu.cn drcuich@163.com.
  • 6 Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China hxl2027315@smu.edu.cn biodegradation@gmail.com gaojie1022@gzhmu.edu.cn drcuich@163.com.
  • 7 The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 8 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China hxl2027315@smu.edu.cn biodegradation@gmail.com gaojie1022@gzhmu.edu.cn drcuich@163.com.
  • 9 Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
  • 10 State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong, China.
  • 11 Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, Guangdong, China.
  • 12 Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • # Contributed equally.
PMID: 40015949 DOI: 10.1136/gutjnl-2024-332891
Abstract

Background: Gut microbial metabolites are recognised as critical effector molecules that influence the development of colorectal Cancer (CRC). Peptidoglycan fragments (PGFs) produced by microbiota play a crucial role in maintaining intestinal homeostasis, but their role in CRC remains unclear.

Objective: Here, we aimed to explore the potential contribution of PGFs in intestinal tumourigenesis.

Design: The relative abundance of peptidoglycan synthase and hydrolase genes was assessed by metagenomic analysis. Specific PGFs in the faeces and serum of CRC patients were quantified using targeted mass spectrometry. The effects of PGF on intestinal tumourigenesis were systematically evaluated using various murine models of CRC and organoids derived from CRC patients. Downstream molecular targets were screened and evaluated using proteome microarray, transcriptome Sequencing and rescue assays.

Results: Metagenomic analysis across seven independent cohorts (n=1121) revealed a comprehensive reduction in peptidoglycan synthase gene relative abundance in CRC patients. Targeted mass spectrometry identified significant depletion of a specific PGF, N-acetylmuramic acid (NAM) in CRC patients, which decreased as tumours progressed (p<0.001). NAM significantly inhibits intestinal tumourigenesis in various models, including APC Min/+, AOM/DSS-treated and MC38 tumour-bearing mice. Additionally, NAM inhibits the growth of patient-derived CRC organoids in a concentration-dependent manner. Mechanistically, NAM inhibits the activation of Akt1 by directly binding to it and blocking its phosphorylation, which is a partial mediator of NAM's Anticancer effects.

Conclusion: The PGF NAM protects against intestinal tumourigenesis by targeting the Akt1 signalling pathway. NAM may serve as a novel potential preventive and therapeutic biomarker against CRC.

Keywords

COLONIC MICROFLORA; COLORECTAL CANCER.

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