Identifying and ranking causal microbial biomarkers for colorectal cancer at different cancer subsites and stages: a Mendelian randomization study

Hongfeng Li; Dashuang Sheng; Chuandi Jin; Guoping Zhao; Lei Zhang

doi:10.3389/fonc.2023.1224705

Identifying and ranking causal microbial biomarkers for colorectal cancer at different cancer subsites and stages: a Mendelian randomization study

Front Oncol. 2023 Jul 19:13:1224705. doi: 10.3389/fonc.2023.1224705. eCollection 2023.

Authors

Hongfeng Li^{1

2}, Dashuang Sheng^{1

2}, Chuandi Jin^{1

2}, Guoping Zhao^{1

2

3

4}, Lei Zhang^{1

2

3

5}

Affiliations

¹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Microbiome-X, National Institute of Health Data Science of China, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.
⁴ CAS Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁵ Shandong Children's Microbiome Center, Children's Hospital Affiliated to Shandong University, Jinan, China.

Abstract

Introduction: The gut microbiome is directly involved in colorectal carcinogenesis, but much of the epidemiological evidence for the effect of the gut microbiome on colorectal cancer (CRC) risk comes from observational studies, and it is unclear whether identified microbial alterations are the cause or consequence of CRC development.

Methods: Univariate Mendelian randomization (MR) analysis and multivariate MR analysis based on Bayesian model averaging were performed to comprehensively explore the microbial risk factors associated with CRC. The Network Module Structure Shift method was used to identify microbial biomarkers associated with CRC. Mediation analysis was used to explore the dietary habits-microbiota-CRC pathway.

Results: The results of the four methods showed that 9 bacteria had a robust causal relationship with the development of CRC. Among them, Streptococcus thermophilus reduced the risk of CRC; Eubacterium ventriosum and Streptococcus were beneficial bacteria of malignant tumors of colon (CC); Erysipelotrichaceae was a protective factor for malignant tumors of rectal (CR); Bacteroides ovatus was a risk factor for benign tumors. Finally, the mediation analysis revealed 10 pathways by which dietary regulation bacteria affected the risk of CRC, including alcohol consumption increased the risk of CC by reducing the abundance of Eubacterium ventriosum (mediated proportion: 43.044%), and the mediated proportion of other pathways was 7.026%-34.22%.

Discussion: These findings will contribute to the understanding of the different carcinogenic mechanisms of intestinal flora in the colon and rectum and the risk of tumor transformation, thereby aiding CRC prevention, early screening, and the development of future strategies to reduce CRC risk.

Keywords: Mendelian randomization analysis; causal microbial biomarkers; colorectal cancer; dietary habit; gut microbiota.

Grants and funding

The study was supported by National Natural Science Foundation of China (no.82172320), TaiShan Industrial Experts Program (no. tscy20190612), TaiShan Scholars Program of Shandong Province (no. tshw20120206), Shandong University Outstanding Young Scholars Program (to LZ).