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Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome.
- Source :
-
Cell [Cell] 2022 Feb 03; Vol. 185 (3), pp. 547-562.e22. Date of Electronic Publication: 2022 Jan 19. - Publication Year :
- 2022
-
Abstract
- 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.<br />Competing Interests: Declaration of interests D.A. has contributed to scientific advisory boards at Genentech, Pfizer, Takeda, FARE, and the KRF. The other authors declare no competing interests. A provisional patent application has been filed by the Weill Cornell Center for Technology Licensing based on this work.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Bile Acids and Salts metabolism
CRISPR-Cas Systems genetics
Clostridium genetics
Colitis chemically induced
Colitis microbiology
Colitis pathology
Dextran Sulfate
Drug Resistance, Microbial genetics
Female
Gene Expression Regulation, Bacterial
Gene Transfer Techniques
Germ-Free Life
Inflammation pathology
Intestines pathology
Male
Metabolome genetics
Metagenomics
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis, Insertional genetics
Mutation genetics
RNA, Ribosomal, 16S genetics
Transcription, Genetic
Mice
Gastrointestinal Microbiome genetics
Genes, Bacterial
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 185
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 35051369
- Full Text :
- https://doi.org/10.1016/j.cell.2021.12.035