Abstract
Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify a novel pathogen-host interaction that promotes gut inflammation and the development of colon cancer. We find that enteropathogenic bacteria-secreted particles (ET-BSPs) stimulate intestinal epithelium to produce IDENs (intestinal mucosa-derived exosome-like nanoparticles) containing elevated levels of sphingosine-1-phosphate, CCL20 and prostaglandin E2 (PGE2). CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. By influencing the recruitment and proliferation of Th17 cells in the intestine, IDENs promote colon cancer. We demonstrate the biological effect of sphingosine-1-phosphate contained in IDENs on tumor growth in spontaneous and transplanted colon cancer mouse models. These findings provide deeper insights into how host-microbe relationships are mediated by particles secreted from both bacterial and host cells.
Highlights
Gut-associated inflammation plays a crucial role in the progression of colon cancer
The results presented in this study suggest that a hierarchy of intestinal mucosa-derived exosome-like nanoparticles (IDENs) factors, each of which encompasses a distinct set of mechanisms, plays a role in the intestinal homeostasis of Th17 cells
In colon tumour-bearing hosts, IDENs are more potent in their recruitment and proliferation of Th17 cells because of S1Pmediated overproduction of IDENCCL20 þ prostaglandin E2 (PGE2) þ
Summary
Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify a novel pathogen–host interaction that promotes gut inflammation and the development of colon cancer. We demonstrate the biological effect of sphingosine-1-phosphate contained in IDENs on tumour growth in spontaneous and transplanted colon cancer mouse models. These findings provide deeper insights into how host–microbe relationships are mediated by particles secreted from both bacterial and host cells. Dysregulation of the interactions between the gut epithelium and intestinal bacteria leads to the loss of host immune tolerance and promotes the development of colon cancer[1]. As a proof of concept, we used three well-established Th17-regulated colon cancer mouse models to determine whether IDENs under different pathophysiological conditions play a role in the induction of intestinal Th17 cells by communicating with enterobacteria (ET)-secreted particles (ET-BSPs). Dysregulation of the composition of IDENs (for example, the overproduction of S1P) promotes colon tumour growth
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