Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation

Abstract

SUMMARY Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis.

Paneth cell–derived growth factors support tumorigenesis in the small intestine

“…Intestinal adenoma formation was studied in Apc Min mice using established protocols ( Miyata et al, 2018 ). Briefly, mice were euthanized at 20 wk of age, and the colon and small intestine were collected and opened longitudinally.…”

“…Human and mouse tissue preparation, processing and immunofluorescence staining followed standard protocols ( Miyata et al, 2018 ). Briefly, tissues were fixed in 4% PFA overnight at 4°C.…”

Clostridium ramosum regulates enterochromaffin cell development and serotonin release

“…TLRs are known to stimulate cell proliferation by inducing the production of amphiregulin and prostaglandin E 2 , both of which are ligands for epidermal growth factor receptor 47 . Furthermore, by sensing luminal bacteria, intestinal myeloid cells alter epithelial-cell differentiation preferentially in the colon, where the density of macrophages is higher than in the small intestine 48 .…”

Enteric Tuft Cells in Host-Parasite Interactions

“…DCLK1 was also found to regulate mRNA expression of cyclooxygenase 2 (COX-2), an enzyme involved in ETC production of prostaglandins, which can in turn contribute to epithelial repair [21,22,97]. Interestingly, prostaglandins were found to suppress differentiation towards the tuft cell fate in colonic organoids, the effect being reversed when colonic organoids were treated with aspirin, a COX-1 and -2 inhibitor [98], suggesting that ETCs could potentially self-limit their numbers/functions by releasing prostaglandins.…”