Enterobacteria-mediated the overproduction of intestinal exosomes S1P to drive Th17-mediated colon tumor growth

Abstract

Abstract The tumorigenic function of exosomes has become widely recognized. However, the potential role of intestinal mucosa-derived exosome-like nanoparticles (IDENs) in the regulation of the intestinal immune system of a colon tumor–bearing host has not been studied. We hypothesize that, along with epithelial cells, intestinal bacteria and immune cells, IDENs in the intestinal mucosa play a crucial role in gut immune regulation. We find that enterobacteria-secreted particles (ET-BSPs)induce the overproduction of exosome-like nanoparticles from gut mucosal cells. These nanoparticles promote colon cancer by influencing the recruitment and proliferation of Th17 cells in the intestine. A key component of these bacterially induced nanoparticles is their ability to induce the production of lipid sphingosine-1-phosphate in mucosal cells. Moreover, the release of sphingosine-1-phosphate causes elevated levels of chemokine (C-C motif) ligand 20 (CCL20) and prostaglandin E2 (PGE2) in the exosome-like nanoparticles. CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. We demonstrate the biological effect of sphingosine-1-phosphate production by exosome-like nanoparticles on tumor growth in APCMin/+ and MC38 tumor-bearing mouse models. These findings provide deeper insights into how host-microbe relationships are mediated by particles secreted from both bacterial and host cells