Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome
2022
Jin, Wen-Bing | Li, Ting-Ting | Huo, Da | Qu, Sophia | Li, Xin V. | Arifuzzaman, Mohammad | Lima, Svetlana F. | Shi, Hui-Qing | Wang, Aolin | Putzel, Gregory G. | Longman, Randy S. | Artis, David | Guo, Chun-Jun
Hundreds of microbiota genes are associated with host biology/disease. Unraveling the causal contribution of a microbiota gene to host biology remains difficult because many are encoded by nonmodel gut commensals and not genetically targetable. A general approach to identify their gene transfer methodology and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. We developed a pipeline that identifies the gene transfer methods for multiple nonmodel microbes spanning five phyla, and we demonstrated the utility of their genetic tools by modulating microbiome-derived short-chain fatty acids and bile acids in vitro and in the host. In a proof-of-principle study, by deleting a commensal gene for bile acid synthesis in a complex microbiome, we discovered an intriguing role of this gene in regulating colon inflammation. This technology will enable genetically engineering the nonmodel gut microbiome and facilitate mechanistic dissection of microbiota-host interactions.
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