Barcoded overexpression screens in gut Bacteroidales identify genes with roles in carbon utilization and stress resistance

Yolanda Y. Huang (), Morgan N. Price, Allison Hung, Omree Gal-Oz, Surya Tripathi, Christopher W. Smith, Davian Ho, Héloïse Carion, Adam M. Deutschbauer and Adam P. Arkin ()
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Yolanda Y. Huang: Lawrence Berkeley National Laboratory
Morgan N. Price: Lawrence Berkeley National Laboratory
Allison Hung: University of California-Berkeley
Omree Gal-Oz: Lawrence Berkeley National Laboratory
Surya Tripathi: University of California-Berkeley
Christopher W. Smith: State University of New York
Davian Ho: University of California-Berkeley
Héloïse Carion: University of California-Berkeley
Adam M. Deutschbauer: Lawrence Berkeley National Laboratory
Adam P. Arkin: Lawrence Berkeley National Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract A mechanistic understanding of host-microbe interactions in the gut microbiome is hindered by poorly annotated bacterial genomes. While functional genomics can generate large gene-to-phenotype datasets to accelerate functional discovery, their applications to study gut anaerobes have been limited. For instance, most gain-of-function screens of gut-derived genes have been performed in Escherichia coli and assayed in a small number of conditions. To address these challenges, we develop Barcoded Overexpression BActerial shotgun library sequencing (Boba-seq). We demonstrate the power of this approach by assaying genes from diverse gut Bacteroidales overexpressed in Bacteroides thetaiotaomicron. From hundreds of experiments, we identify new functions and phenotypes for 29 genes important for carbohydrate metabolism or tolerance to antibiotics or bile salts. Highlights include the discovery of a d-glucosamine kinase, a raffinose transporter, and several routes that increase tolerance to ceftriaxone and bile salts through lipid biosynthesis. This approach can be readily applied to develop screens in other strains and additional phenotypic assays.

Date: 2024
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DOI: 10.1038/s41467-024-50124-3

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