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
Abstract
BACKGROUND

Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.

AIM

To investigate the mechanism by which F. nucleatum affects CRC occurrence and development.

METHODS

Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum. Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.

RESULTS

Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum, the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.

CONCLUSION

F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.

Keywords: Colorectal cancer; Fusobacterium nucleatum; Butyric acid; Gut microbiota; Adenosine monophosphate-activated protein kinase signal pathway

Core Tip: In this study, we unravel the mechanism of Fusobacterium nucleatum (F. nucleatum) in the progression of colorectal cancer (CRC), focusing on the interplay between intestinal flora and metabolism. Our results reveal that F. nucleatum suppresses the production of the short-chain fatty acid butyric acid. We discovered that sodium butyrate impairs mitochondrial function and impedes the cell cycle in CRC cells. Furthermore, the study highlights that both sodium butyrate and F. nucleatum orchestrate CRC cell proliferation via the adenosine monophosphate-activated protein kinase signaling pathway. These insights may enhance our understanding of CRC pathogenesis and aid in the development of more effective treatment strategies.