Catestatin selects for the 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. Among 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 catestatin (CST). 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 mice with a knockout in the CST coding region of the chromogranin-A gene (CST-KO) 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. Remarkably, 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.

Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts

“…Speci cally, butyrate was signi cantly lower in the donor CST-KO mice compared to their WT counterparts as reported previously (Fig. 1F) (González-Dávila et al, 2021). Levels of acetate and butyrate increased signi cantly in CST-KO FMT−WT compared to CST-KO (Fig.…”

Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts

“…Recently, we and others have shown that CST-KO mice display altered gut microbiota composition compared to their wild-type counterparts (González-Dávila et al, 2021; Muntjewerff, Lutter, et al, 2021). In particular, CST treatment reduced the abundance of Staphylococcus and Turicibacter in CST-KO and WT mice, while Alistipes , Akkermansia , and Roseburia were significantly increased in the CST-KO group (González-Dávila et al, 2021).…”

“…The copyright holder for this preprint this version posted February 24, 2022. ; https://doi.org/10.1101/2022.02.24.481402 doi: bioRxiv preprint in CST-KO and WT mice, while Alistipes, Akkermansia, and Roseburia were significantly increased in the CST-KO group (González-Dávila et al, 2021).…”

“…Recently, we and others have shown that CST-KO mice display altered gut microbiota composition compared to their wild-type counterparts (González-Dávila et al, 2021;. In particular, CST treatment reduced the abundance of Staphylococcus and Turicibacter (which was not certified by peer review) is the author/funder.…”

“…Additionally, levels of the short chain fatty acids (SCFAs), butyrate and acetate, were significantly increased in CST-KO mice treated with CST (González-Dávila et al, 2021). Analogously, supplementation of CST-KO mice with CST restored paracellular intestinal epithelial permeability, reversed inflammation, and fibrosis, all of which are characteristic of CST-KO mice (Muntjewerff, Tang, et al, 2021).…”