Genetic manipulation of the human gut bacterium Eggerthella lenta reveals a widespread family of transcriptional regulators

Xueyang Dong, Ben G. H. Guthrie, Margaret Alexander, Cecilia Noecker, Lorenzo Ramirez, Nathaniel R. Glasser, Peter J. Turnbaugh and Emily P. Balskus ()
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Xueyang Dong: Harvard University
Ben G. H. Guthrie: University of California San Francisco
Margaret Alexander: University of California San Francisco
Cecilia Noecker: University of California San Francisco
Lorenzo Ramirez: University of California San Francisco
Nathaniel R. Glasser: Harvard University
Peter J. Turnbaugh: University of California San Francisco
Emily P. Balskus: Harvard University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Eggerthella lenta is a prevalent human gut Actinobacterium implicated in drug, dietary phytochemical, and bile acid metabolism and associated with multiple human diseases. No genetic tools are currently available for the direct manipulation of E. lenta. Here, we construct shuttle vectors and develop methods to transform E. lenta and other Coriobacteriia. With these tools, we characterize endogenous E. lenta constitutive and inducible promoters using a reporter system and construct inducible expression systems, enabling tunable gene regulation. We also achieve genome editing by harnessing an endogenous type I-C CRISPR-Cas system. Using these tools to perform genetic knockout and complementation, we dissect the functions of regulatory proteins and enzymes involved in catechol metabolism, revealing a previously unappreciated family of membrane-spanning LuxR-type transcriptional regulators. Finally, we employ our genetic toolbox to study the effects of E. lenta genes on mammalian host biology. By greatly expanding our ability to study and engineer gut Coriobacteriia, these tools will reveal mechanistic details of host-microbe interactions and provide a roadmap for genetic manipulation of other understudied human gut bacteria.

Date: 2022
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DOI: 10.1038/s41467-022-33576-3

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