Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2022; 28(18): 1981-1995
Published online May 14, 2022. doi: 10.3748/wjg.v28.i18.1981
Fusobacterium nucleatum promotes colon cancer progression by changing the mucosal microbiota and colon transcriptome in a mouse model
Na Wu, Yu-Qing Feng, Na Lyu, Di Wang, Wei-Dong Yu, Yong-Fei Hu
Na Wu, Di Wang, Wei-Dong Yu, Department of Central Laboratory & Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China
Yu-Qing Feng, Yong-Fei Hu, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
Na Lyu, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Author contributions: Wu N and Feng YQ contributed equally to this work and performed the majority of experiments. Wu N, Yu WD, and Hu YF designed and coordinated the study; Wu N, Feng YQ, Lyu N, and Wang D performed the experiments; Wu N and Feng YQ analyzed and interpreted the data; Wu N, Feng YQ and Hu YF wrote the manuscript; all authors approved the final version of the article.
Supported by National Natural Science Foundation of China, No. 32070116; and Open Project Program of CAS Key Laboratory of Pathogenic Microbiology and Immunology, No. CASPMI202102.
Institutional animal care and use committee statement: The study was reviewed and approved by the Institutional Animal Care Committee of the Peking University People’s Hospital. All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals.
Conflict-of-interest statement: The authors declare no competing interests.
Data sharing statement: The raw 16S amplicon sequencing and transcriptome data in this study have been deposited in the NCBI Sequence Read Archive (SRA) under BioProject number PRJNA767246.
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 NonCommercial (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: Yong-Fei Hu, PhD, Professor, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing 100193, China. huyongfei@cau.edu.cn
Received: January 30, 2022
Peer-review started: January 30, 2022
First decision: February 24, 2022
Revised: February 28, 2022
Accepted: March 26, 2022
Article in press: March 26, 2022
Published online: May 14, 2022
Processing time: 101 Days and 23.5 Hours
Abstract
BACKGROUND

Fusobacterium nucleatum (F. nucleatum) has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer (CRC), which has attracted broad attention. However, the mechanism by which it is involved in CRC development is not fully understood.

AIM

To explore its potential causative role in CRC development, we evaluated the colon pathology, mucosa barrier, colon microbiota and host transcriptome profile after F. nucleatum infection in an azoxymethane/dextran sulfate sodium salt (AOM/DSS) mouse model.

METHODS

Three groups of mice were compared to reveal the differences, i.e., the control, AOM/DSS-induced CRC and AOM/DSS-FUSO infection groups.

RESULTS

Both the AOM/DSS and AOM/DSS-FUSO groups exhibited a significantly reduced body weight and increased tumor numbers than the control group, and AOM/DSS mice with F. nucleatum infection showed the highest tumor formation ratio among the three groups. Moreover, the colon pathology was the most serious in the AOM/DSS-FUSO group. We found that the structure of the colon microbiota changed considerably after F. nucleatum infection; striking differences in mucosal microbial population patterns were observed between the AOM/DSS-FUSO and AOM/DSS groups, and inflammation-inducing bacteria were enriched in the mucosal microbiota in the AOM/DSS-FUSO group. By comparing intestinal transcriptomics data from AOM vs AOM/DSS-FUSO mice, we showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota. The most microbiota-sensitive genes were oncogenes in the intestine, and the cyclic adenosine monophosphate signaling pathway, neuroactive ligand–receptor interaction, PPAR signaling pathway, retinol metabolism, mineral absorption and drug metabolism were highly enriched in the AOM/DSS-FUSO group. Additionally, we showed that microbial dysbiosis driven by F. nucleatum infection enriched eight taxa belonging to Proteobacteria, which correlates with increased expression of oncogenic genes.

CONCLUSION

Our study demonstrated that F. nucleatum infection altered the colon mucosal microbiota by enriching pathogens related to the development of CRC, providing new insights into the role of F. nucleatum in the oncogenic microbial environment of the colon.

Keywords: Fusobacterium nucleatum; Mucosal microbiota; Transcriptome; Colorectal cancer; Inflammation-inducing bacteria

Core Tip: Fusobacterium nucleatum (F. nucleatum) has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer (CRC). However, the mechanism by which it is involved in CRC development is not fully understood. Here, striking differences in mucosal microbial population patterns were observed and inflammation-inducing bacteria were enriched in the mucosal microbiota in the azoxymethane/dextran sulfate sodium salt-FUSO group. We showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota. Additionally, we showed that microbial dysbiosis driven by F. nucleatum infection enriched eight taxa belonging to Proteobacteria, which correlates with increased expression of oncogenic genes.