Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer

• Published in: Gut microbes Vol. 16; no. 1; p. 2341647
• Main Authors: Li, Dan, Zhong, Chenhan, Yang, Mengyuan, He, Li, Chang, Hang, Zhu, Ning, Celniker, Susan E, Threadgill, David W, Snijders, Antoine M, Mao, Jian-Hua, Yuan, Ying
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2024; Taylor & Francis Group
• Subjects: Animals; Azoxymethane; Bacteria - classification; Bacteria - genetics; Bacteria - isolation & purification; Bacteria - metabolism; BASIC BIOLOGICAL SCIENCES; Collaborative Cross Mice - genetics; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - genetics; Colorectal Neoplasms - microbiology; Colorectal tumor susceptibility; conditional knockout mouse; Disease Models, Animal; Dual Oxidases - genetics; Dual Oxidases - metabolism; DUOX2; Female; Gastrointestinal Microbiome; Genetic Predisposition to Disease; genome-wide association study; gut microbiome; Humans; Male; Mice; Polymorphism, Single Nucleotide; Research Paper; gut microbiome; Colorectal tumor susceptibility; DUOX2; azoxymethane; conditional knockout mouse; genome-wide association study
• ISSN: 1949-0976; 1949-0984; 1949-0984
• DOI: 10.1080/19490976.2024.2341647

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.