Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2024; 16(4): 1319-1333
Published online Apr 15, 2024. doi: 10.4251/wjgo.v16.i4.1319
Causal roles of gut microbiota in cholangiocarcinoma etiology suggested by genetic study
Zhi-Tao Chen, Chen-Chen Ding, Kai-Lei Chen, Yang-Jun Gu, Chi-Cheng Lu, Qi-Yong Li
Zhi-Tao Chen, Yang-Jun Gu, Qi-Yong Li, Division of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou 310000, Zhejiang Province, China
Chen-Chen Ding, Pediatric Psychology, The Affiliated Mental Health Centre & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
Kai-Lei Chen, School of Medicine, Zhejiang Shuren University, Hangzhou 310000, Zhejiang Province, China
Chi-Cheng Lu, School of Medicine, Zhejiang Chinese Medical University Zhejiang Shuren College, Hangzhou 310000, Zhejiang Province, China
Author contributions: Li QY interpreted the study design; Chen ZT and Ding CC downloaded data, performed statistical analysis, and drafted the manuscript; Chen KL, Gu YJ, and Lu CC performed data analysis and revised manuscript; Chen ZT, Ding CC, and Li QY helped revised our manuscript; all authors agreed to submit to the current journal, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Institutional review board statement: The research does not involve any animal experiments and clinical data or human subjects, which does not require any special ethical clearance as per the guidelines of our institution.
Informed consent statement: Informed consent statement is not required since our manuscript solely utilizes publicly available data for analysis.
Conflict-of-interest statement: The authors declare that they have no competing interests.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: The datasets used and analyzed in the present study are available from the corresponding authors on reasonable request. The datasets generated and/or analyzed during the current study are available in GWAS Catalog (https://www.ebi.ac.uk/gwas/) and MiBioGen (https://mibiogen.gcc.rug.nl) database.
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: Qi-Yong Li, PhD, Deputy Director, Researcher, Surgeon, Division of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, No. 848 Dongxin Road, Hangzhou 310000, Zhejiang Province, China. liqiyong@zju.edu.cn
Received: October 23, 2023
Peer-review started: October 23, 2023
First decision: December 12, 2023
Revised: December 20, 2023
Accepted: January 15, 2024
Article in press: January 15, 2024
Published online: April 15, 2024
Processing time: 170 Days and 12.2 Hours
Abstract
BACKGROUND

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with poor prognosis. Previous studies have implicated the gut microbiota in CCA, but evidence for causal mechanisms is lacking.

AIM

To investigate the causal relationship between gut microbiota and CCA risk.

METHODS

We performed a two-sample mendelian randomization study to evaluate potential causal associations between gut microbiota and CCA risk using genome-wide association study summary statistics for 196 gut microbial taxa and CCA. Genetic variants were used as instrumental variables. Multiple sensitivity analyses assessed result robustness.

RESULTS

Fifteen gut microbial taxa showed significant causal associations with CCA risk. Higher genetically predicted abundance of genus Eubacteriumnodatum group, genus Ruminococcustorques group, genus Coprococcus, genus Dorea, and phylum Actinobacteria were associated with reduced risk of gallbladder cancer and extrahepatic CCA. Increased intrahepatic CCA risk was associated with higher abundance of family Veillonellaceae, genus Alistipes, order Enterobacteriales, and phylum Firmicutes. Protective effects against CCA were suggested for genus Collinsella, genus Eisenbergiella, genus Anaerostipes, genus Paraprevotella, genus Parasutterella, and phylum Verrucomicrobia. Sensitivity analyses indicated these findings were reliable without pleiotropy.

CONCLUSION

This pioneering study provides novel evidence that specific gut microbiota may play causal roles in CCA risk. Further experimental validation of these candidate microbes is warranted to consolidate causality and mechanisms.

Keywords: Cholangiocarcinoma; Mendelian randomization; Gut microbiota; Instrumental variables; Sensitivity analyses

Core Tip: Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with poor prognosis. Emerging evidence suggests the gut microbiota may play a causal role in CCA pathogenesis, but robust genetic evidence is still lacking. Using genome-wide association study summary statistics, our study provides novel evidence that 15 gut microbial taxa may confer either protective or detrimental causal effects on CCA risk.