ABSTRACT
The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived Klebsiella spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral Klebsiella strain to different mucosal sites – the oral and gut mucosae – at the steady state and during inflammation. We find that K. aerogenes, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named “locus of colonization in the inflamed gut (LIG)” that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among K. aerogenes strains, and these genes are also present in several other Klebsiella species. The Tn screening revealed that the LIG locus is required for the adaptation of K. aerogenes in its ectopic niche. In particular, we determined K. aerogenes employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.
Acknowledgments
The authors wish to thank the University of Michigan Center for Gastrointestinal Research (NIH 5P30DK034933), and the Host Microbiome Initiative, the Germ-Free Mouse Facility, the Advanced Genomics Core for technical assistance, and the In-Vivo Animal for histological evaluation, all at the University of Michigan. This work was supported by the National Institutes of Health grants DK119219 (to N.K.), JSPS KAKENHI JP23H00404 (to N.K.), K99AI159620 (to G. C.-F.), National Natural Science Foundation of China grant 82070546 (to Y.G.), Crohn’s & Colitis Foundation Research Fellowship Award and Career Development Award (to. Y.G., Y.K., and K.S.), the Office of the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Peer-Reviewed Cancer Research Program under Award No. W81XWH2010547 (to S.K.).
Disclosure statement
The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest
Author contributions
Y.G. and N.K. conceived and designed the experiments. Y.G. performed experiments with help from S.K., G.C.-F., Y.K., D.W., K.S., G.N., and C.J.A. N.I. performed bioinformatic analysis of Tn-seq data. Y.G. and N.K. wrote the manuscript with contributions from all authors.
Data availability statement
The data that support the findings of this study are available from the corresponding author, NK, upon reasonable request. The Klebsiella aerogenes SK431 genomic sequence, Tn-Seq data used in this study are available from the BioProject website (https://www.ncbi.nlm.nih.gov/bioproject/), accession numbers PRJNA763502.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2333463