Inflammation accelerating intestinal fibrosis: from mechanism to clinic

Abstract

Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice.

Keywords: Cytokine; ECM; Fibrosis; Inflammation; Intestinal microflora; Intestine.

Fig. 1

Pathophysiological alterations of cardiovascular and intestinal tract in humans during stress. The pressure signals sensed by the paraventricular nucleus of the hypothalamus go via the sympathetic nervous to thicken the endothelium and intima, increase collagen in the media, and thicken the left ventricle. The expression of occludin, connexin, and ZO-1 was found to be increased, as well as the of CD68⁺ and CD163⁺ Mφs in the intestine

Fig. 2

Pathophysiological diagram of intestinal fibrosis. Inflammation is triggered by distinctive inflammatory and associated non-immune cells, as well as microbiota that enhance epithelial and endothelial EMT and EndoMT and catalyze myoblast activation through pathways such as cytokines, growth factors, and oxidative stress. This process ultimately results in the formation of fibrosis

Fig. 3

Diagram illustrating putative IL-6 and TGF-β signaling processes involved in intestinal fibrogenesis and interaction with other signaling outlets. The processes behind the TGF-β and IL-6 signaling pathway in fibrosis depicted schematically

Fig. 4

Diagram illustrating the of IL-36 cell signaling pathway in fibrosis process. IL-36 interacts to the IL-36R, which is heterodimerized with IL-1R3 (IL-1RAcP). The IL-36R/IL-36/IL-1R3 complex recruit MyD88 and interleukin-1 receptor-associated kinases (IRAKs), activating the mitogen-activated protein kinase(MAPK) and nuclear factor-κB (NF-κB) pathways. Dendritic cells and fibroblasts are activated and eventually fibrosis occurs. Direct induction shown as a solid black line, indirect induction as dotted black lines