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Gut microbial structural variation associates with immune checkpoint inhibitor response
Rong Liu (Central South University, Xiangya Hospital Central South University), You Feng Zou (Central South University), Weiquan Wang (Central South University, Xiangya Hospital Central South University), Junhong Chen (Central South University, Xiangya Hospital Central South University), Lei Zhang (Central South University, Xiangya Hospital Central South University), Jia Feng (Central South University, Xiangya Hospital Central South University), Ji‐Ye Yin (Central South University, Xiangya Hospital Central South University), Xiao‐Yuan Mao (Central South University, Xiangya Hospital Central South University), Qing Li (Central South University, Xiangya Hospital Central South University), Zhiying Luo (Central South University, Second Xiangya Hospital of Central South University), Wei Zhang (Central South University, Xiangya Hospital Central South University), Daoming Wang (University Medical Center Groningen, University of Groningen)
Abstract: The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts' prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.