The Quorum Sensing Peptide EntF* Promotes Colorectal Cancer Metastasis in Mice: A New Factor in the Microbiome-Host Interaction

Abstract

BackgroundColorectal cancer, one of the most common malignancies worldwide, is associated with a high mortality rate, mainly caused by metastasis. Comparative metagenome-wide analyses between healthy individuals and cancer patients suggest a role for the human intestinal microbiota. Nevertheless, which microbial molecules are involved in this communication is largely unknown, with current studies mainly focusing on short chain fatty acids and amino acid metabolites as potential mediators. However, quorum sensing peptides are not yet considered in this microbiome-host interaction: their in vivo presence nor any in vivo host-effect have been reported.ResultsFor the first time, we showed that a quorum sensing peptide metabolite, EntF* produced by intestinal microbiota (E. faecium), is present in the blood circulation of mice. Moreover, it significantly promotes colorectal cancer metastasis in vivo, with metastatic lesions found in both liver and lung tissues, using an orthotopic mice model evaluating bioluminescence as well as macroscopic and microscopic presence of metastatic tumour nodules. In vitro tests on E-cadherin expression levels thereby indicated that the first, second, sixth and tenth amino acid of EntF* were critical for the epithelial-mesenchymal transition (EMT) effect, responsible for tumour metastasis.ConclusionThis paper adds a new group of molecules, the quorum sensing peptides, as an additional causative factor explaining the microbiome-host interaction. The presence of a selected quorum sensing peptide (metabolite) in the mouse was proven for the first time and its in vivo effect on colorectal metastasis was demonstrated. We anticipate our in vivo results to be a starting point for broader microbiome-health investigations, not only limited to colorectal cancer metastasis, but also for developing novel bio-therapeutics in other disease areas, giving due attention to the QSP produced by the microbiome.

A Bioanalytical Screening Method for Enterococcus faecalis RNPP-type Quorum Sensing Peptides in Murine Feces

“…Regarding other quorum sensing peptides, one report mentions the presence of a thiolacton peptide without compelling evidence via mass spectrometry [54]. Recently, Debunne et al provided proof on the in vivo presence of a specific quorum sensing peptide metabolite, in other words, EntF*, linked to E. faecium [55] and Streptococci quorum sensing peptides have been found in the human oral cavity [56]. Another report strongly indicated the presence of the quorum sensing peptide PapRIV, produced by Bacillus cereus strains, in mouse plasma [57].…”

A fit-for-purpose LC-MS/MS method for the analysis of selected Streptococcal quorum sensing peptides in human saliva

“…More recently, Debunne et al demonstrated the in vivo presence of a quorum sensing peptide metabolite in blood, i.e. EntF* [13].…”