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Catestatin selects for colonization of antimicrobial-resistant gut bacterial communities

Abstract

The gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. One of the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as chromogranin A (CgA) peptide catestatin (CST: hCgA352-372). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and CST knockout (CST-KO) mice (where only the 63 nucleotides encoding CST have been deleted) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohn’s disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.

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Fig. 1: CST treatment affects the murine fecal microbiota.
Fig. 2: Taxa able to endure CST treatment benefit from its presence in the environment.
Fig. 3: CST treatment promotes the abundance of the antimicrobial resistance gene, eptA.
Fig. 4: Omptin enzyme is responsible for the degradation of CST in E coli.

Data availability

All data generated or analyzed during this study are included in this manuscript and its supplementary information files. The 16S rRNA gene amplicon sequence data were deposited under BioProject number PRJNA741992.

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Acknowledgements

PG-D thanks the National Council of Science and Technology in Mexico (CONACyt) for the Ph.D. grant assigned to CVU 690069. We thank Dr. Matthias Heinemann of Department of Molecular Systems Biology, University of Groningen, the Netherlands, for providing us ΔeptA and ΔompT E. coli BW25113 mutant strain; Dr. Greet Vandermeulen of Department of chronic diseases and metabolism, Faculty of Medicine, KU Leuven, Belgium for the help with SCFAs analysis.

Funding

SKM is supported by a Merit Review Grant (I01 BX003934) from the Department of Veterans Affairs, USA. SEA is supported by a Rosalind Franklin Fellowship, co-funded by the European Union and the University of Groningen, The Netherlands.

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PG-D, MS, SKM, and SEA conceived and designed the study. PG-D, MS, BD, and SKM performed the experiments, and PG-D, MS, BD, and SEA analyzed the data. PG-D, MS, SEA wrote the original manuscript that was reviewed by AD, BD, KV, SKM, and SEA. Funding for these studies were acquired by SEA and SKM. All authors read and approved the final manuscript.

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Correspondence to Sushil K. Mahata or Sahar El Aidy.

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González-Dávila, P., Schwalbe, M., Danewalia, A. et al. Catestatin selects for colonization of antimicrobial-resistant gut bacterial communities. ISME J (2022). https://doi.org/10.1038/s41396-022-01240-9

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  • DOI: https://doi.org/10.1038/s41396-022-01240-9

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