AUTHOR=Giraud Etienne , Baucheron Sylvie , Foubert Isabelle , Doublet Benoît , Nishino Kunihiko , Cloeckaert Axel 

TITLE=Major primary bile salts repress Salmonella enterica serovar Typhimurium invasiveness partly via the efflux regulatory locus ramRA

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1338261

DOI=10.3389/fmicb.2024.1338261

ISSN=1664-302X

ABSTRACT=<p>Bile represses <italic>Salmonella enterica</italic> serovar Typhimurium (<italic>S</italic>. Typhimurium) intestinal cell invasion, but it remains unclear which bile components and mechanisms are implicated. Previous studies reported that bile inhibits the RamR binding to the <italic>ramA</italic> promoter, resulting in <italic>ramA</italic> increased transcription, and that <italic>ramA</italic> overexpression is associated to decreased expression of type III secretion system 1 (TTSS-1) invasion genes and to impaired intestinal cell invasiveness in <italic>S</italic>. Typhimurium. In this study, we assessed the possible involvement of the <italic>ramRA</italic> multidrug efflux regulatory locus and individual bile salts in the bile-mediated repression of <italic>S</italic>. Typhimurium invasion, using Caco-2 intestinal epithelial cells and <italic>S</italic>. Typhimurium strain ATCC 14028s. Our results indicate that (i) major primary bile salts, chenodeoxycholate and its conjugated-derivative salts, cholate, and deoxycholate, activate <italic>ramA</italic> transcription in a RamR-dependent manner, and (ii) it results in repression of <italic>hilA</italic>, encoding the master activator of TTSS-1 genes, and as a consequence in the repression of cellular invasiveness. On the other hand, crude ox bile extract and cholate were also shown to repress the transcription of <italic>hilA</italic> independently of RamR, and to inhibit cell invasion independently of <italic>ramRA</italic>. Altogether, these data suggest that bile-mediated repression of <italic>S</italic>. Typhimurium invasion occurs through pleiotropic effects involving partly <italic>ramRA</italic>, as well as other unknown regulatory pathways. Bile components other than the bile salts used in this study might also participate in this phenomenon.</p>