Basic Study
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World J Gastroenterol. Apr 14, 2024; 30(14): 2018-2037
Published online Apr 14, 2024. doi: 10.3748/wjg.v30.i14.2018
Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer
Qi-Long Wu, Xiao-Ting Fang, Xin-Xin Wan, Qing-Yong Ding, Yan-Jun Zhang, Ling Ji, Yong-Liang Lou, Xiang Li
Qi-Long Wu, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
Xiao-Ting Fang, Department of Health Inspection and Quarantine, School of Laboratory Medicine and Life Sciences, Wenzhou 325035, Zhejiang Province, China
Xin-Xin Wan, Qing-Yong Ding, Yan-Jun Zhang, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang Provincial Key Laboratory of Medical Genetics, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
Ling Ji, Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Yong-Liang Lou, School of Laboratory Medicine and Life Sciences, Institute of One Health, Wenzhou Medical University, Zhejiang Provincial Key Laboratory of Medical Genetics, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
Xiang Li, Department of Health Inspection and Quarantine, School of Laboratory Medicine and Life Sciences, Institute of One Health, Wenzhou Medical University, Zhejiang Provincial Key Laboratory of Medical Genetics, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
Co-corresponding authors: Yong-Liang Lou and Xiang Li.
Author contributions: Lou YL and Li X are responsible for funding acquisition; Wu QL, Fang XT, and Li X contributed to study conceptualization; Ji L, Lou YL and Li X supervised the study; Li X wrote, reviewed and edited the manuscript and performed project management; Wu QL, Fang XT, Wan XX, Ding QY, and Zhang YJ participated in the data curation and investigation; Wu QL and Fang XT contributed to the methodology of this study; Wu QL is responsible for original draft preparation; Ji L is responsible for resources; Ji L and Lou YL were involved in project administration, Li X and Lou YL contributed equally to this work as co-corresponding authors; All authors were involved in the critical review of the results and have contributed to, read, and approved the final manuscript.
Supported by the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A) and the Health Project of the Science and Technology Department of Wenzhou, No. Y20220029.
Institutional review board statement: This work was approved by the First Affiliated Hospital of Wenzhou Medical University.
Institutional animal care and use committee statement: All animal studies were conducted in compliance with the animal experiment guidelines of Wenzhou Medical University. The protocols were approved by the Animal Experimental Ethics Committee, No. wydw2022-0217).
Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.
Data sharing statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: National Center for Biotechnology Information (NCBI) BioProject, https://www.ncbi.nlm.nih.gov/bioproject/, PRJNA799208: National Center for Biotechnology Information (NCBI) SRA, https://www.ncbi.nlm.nih.gov/sra/, PRJNA1015171 and National Genomics Data Center (NGDC) China National Center for Bioinformation (CNCB)/Beijing Institute of Genomics (BIG), Chinese Academy of Sciences (CAS) Open Archive for Miscellaneous Data (OMIX), https://ngdc.cncb.ac.cn/omix/, PRJCA019758.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiang Li, PhD, Associate Professor, Deputy Director, Postdoc, Department of Health Inspection and Quarantine, School of Laboratory Medicine and Life Sciences, Institute of One Health, Wenzhou Medical University, Zhejiang Provincial Key Laboratory of Medical Genetics, Ministry of Education, No. 1 Qiuzhen Road, Wenzhou 325035, Zhejiang Province, China. yhx2008@163.com
Received: October 31, 2023
Peer-review started: October 31, 2023
First decision: December 15, 2023
Revised: January 11, 2024
Accepted: February 29, 2024
Article in press: February 29, 2024
Published online: April 14, 2024
Processing time: 164 Days and 10.5 Hours
ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. Fusobacterium nucleatum (F. nucleatum) has been implicated in the initiation, progression, and prognostic outcomes of CRC. Butyrate, a short-chain fatty acid (SCFA) derived from the bacterial fermentation of soluble dietary fiber, exhibits inhibitory effects on several types of cancers.

Research motivation

Recent research has demonstrated that the SCFA butyrate can suppress the proliferation, enrichment, and adherence of F. nucleatum in CRC tissues. This suppression is achieved by the downregulation of adhesion-associated outer membrane proteins, including RadD, FomA, and FadA. Consequently, this leads to a decrease in the colonization and invasion of F. nucleatum and mitigates its contribution to chemoresistance. Therefore, this study aims to investigate whether F. nucleatum can influence the synthesis of the intestinal metabolite butyric acid, thereby facilitating the development of CRC.

Research objectives

Exploring whether F. nucleatum affects the production of intestinal metabolite butyrate to promote CRC development.

Research methods

Fecal samples were collected from mice in the treatment group following oral administration of F. nucleatum for the analysis of SCFAs and 16S rDNA. Concurrently, CRC cells underwent co-treatment with F. nucleatum and sodium butyrate (NaB) in vitro to assess alterations in the cell cycle, mitochondrial functionality, and the expression of pertinent proteins.

Research results

The abundance of F. nucleatum is markedly elevated in fecal specimens and CRC tissues from patients with CRC. F. nucleatum suppresses the synthesis of the SCFA butyric acid. NaB impairs mitochondrial functionality and impedes the cell cycle in CRC cells. Both NaB and F. nucleatum modulate the growth of CRC cells via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. The presence of AMPK is essential for NaB’s effectiveness in inhibiting CRC cell proliferation.

Research conclusions

Our findings showed that the abundance of F. nucleatum is significantly high in fecal samples and CRC tissues from CRC patients. F. nucleatum impedes the synthesis of the SCFA butyric acid. NaB compromises mitochondrial functionality and obstructs the cell cycle in CRC cells. The growth of CRC cells is modulated by both NaB and F. nucleatum via the AMPK signaling pathway. The presence of AMPK is critical for the ability of NaB to curb CRC cell proliferation.

Research perspectives

The outcomes of this research could enhance our comprehension of CRC pathogenesis, potentially leading to the formulation of more efficacious therapeutic strategies.