Butyrate, IL-4, and EP4 Receptors: A Triad of Colorectal Homeostasis, Protecting Against Onset of Cancer and IBD?

Abstract

In this article, onset mechanisms of colorectal cancer and intestinal bowel diseases (IBD) are postulated to involve the aberrant expression/hyper-activation of E-type prostanoid 4 (EP4) receptors. Although prostaglandin E₂ and EP4 receptors are important factors for maintaining colorectal homeostasis, their mediated signaling is also considered to be involved in the etiology of severe intestinal diseases. To prevent uncontrollable activations of EP4 receptors, two safety factors are proposed: butyrate as an external safety factor and interleukin (IL)-4 as an internal safety factor. Thus, for maintaining vulnerable colorectal homeostasis, the levels of EP4 receptors, butyrate, and IL-4 are proposed as an important triad for protecting against development/onset risks of, at least, EP4 receptor-mediated cancer and IBD.

Keywords: EP4 receptors; IBD; butyrate; colorectal cancer; colorectal homeostasis; interleukin‐4; prostaglandin E2.

FIGURE 1

The homeostasis‐maintaining mechanisms of colorectal epithelial cells: Butyrate and/or IL‐4 regulates expression levels of EP4 receptors. (a) Normal physiological butyrate gradient along the axis of the crypt is produced from sufficient dietary fibers by microbiota. The homeostasis of colorectal epithelial cells in the crypt is maintained by the first proliferation stage and second differentiation stage. The cells migrate toward the lumen side, and finally they are removed by apoptosis. The turnover period of sequential events is 3–5 days. (b) The expression levels of EP4 receptors and β‐catenin‐mediated signaling are regulated by the butyrate concentration, which will switch epithelial cells from the proliferation to differentiation stage. (c) The EP4 receptor‐expressing levels on Th1 cells and Th17 cells are modulated by IL‐4 produced by Th2 cells. IL‐4 also supports the roles of Treg cells, which would inhibit Th1 cell‐ and Th17 cell‐evoked inflammation around the colorectal mucosa and serum to maintain homeostasis.

FIGURE 2

Possible pathophysiological mechanisms of colorectal cancer and IBD. (a) When lacking sufficient dietary fibers in food, concentrations of butyrate would decrease, and so the first proliferation stage would persist. (b) If EP4 receptor‐mediated β‐catenin signaling is not down‐regulated, the epithelial cells would aberrantly proliferate, leading to the development of colorectal cancer. (c) If there is an absence of Th2 cells and/or privation of IL‐4 around the area of the excessively proliferating epithelial cells, this would aggravate IBD by aberrant inflammation via EP4 receptor‐activated/expanded Th1 cells and Th17 cells because of the PGE₂ from aberrantly proliferating epithelial cells.

FIGURE 3

The mechanisms of butyrate‐concentration‐regulated EP4 receptor expression levels. (a) When the concentration of butyrate is high in the environment, butyrate that is taken up activates CBP/p300, which induces histone H3 hyper‐acetylation and remodeling of chromatin structures, and then stimulates HIF‐1α‐mediated down‐regulation of EP4 receptor‐expression via pulling out the c‐Myc and Sp‐1 complex by displacing c‐Myc from the EP4 promoter region. (b) When the concentration of butyrate is low in the environment, PARP14‐, c‐Myc, and Sp‐1 complex‐induced EP4 receptor expression is retained, which would lead to sustained proliferation activity by de novo synthesis of PGE₂ through a positive feedback loop.

FIGURE 4

The mechanisms of IL‐4‐regulated EP4 receptor expression levels. (a) IL‐4 activates STAT6, which is replaced by PPAR14, and this increases HIF‐1α expression followed by down‐regulation of EP4 receptor expression. (b) Reduction of IL‐4 would retain PARP14 in the EP4 receptor‐promoter region, and so the HDAC1, HDAC2, as well as c‐Myc and Sp‐1 complex would continuously induce EP4 receptor expression, leading to sustained inflammation by de novo synthesis of PGE₂ through a positive feedback loop. JAK: Janus kinase.

FIGURE 5

The schemes of normal colorectal homeostasis (a) and aberrant proliferation to colorectal cancer (b). (a) Butyrate produced from sufficient dietary fibers by microbiota regulates expression levels of EP4 receptors both in epithelial cells and Th cell‐subsets, consequently maintaining homeostasis via balanced activities between normal proliferation in an autocrine manner and normal inflammation in a paracrine manner. (b) When lacking sufficient dietary fibers in food, the butyrate concentration would decrease, leading to the development of colorectal cancer due to a positive feedback loop through the EP4 receptors as epithelial cell‐mediated aberrant proliferation.

FIGURE 6

The schemes of aberrant inflammation to IBD (a) and from IBD to colorectal cancer, and vice versa (b). (a) The reduction of IL‐4 results in the over‐expression and hyper‐activation of EP4 receptors followed by excessive production of PGE₂ in epithelial cells as well as Th1 cells and Th17 cells, leading to the onset of IBD via aberrant inflammation. (b) The reduction of IL‐4 would also depress the activities of Treg cells, which would lead to reduced butyrate levels, possibly inducing the development of colorectal cancer followed by and/or concomitantly with IBD via hyper‐activation of EP4 receptors and over‐production of environmental PGE₂.