MicroRNAs in Inflammatory Bowel Disease and Its Complications

Abstract

Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.

Keywords: Crohn’s disease; colitis-associated cancer; extraintestinal manifestations; non-coding RNA; ulcerative colitis.

Figure 1

Intestinal and extraintestinal complications of IBD. * Mainly associated with Crohn’s disease; ** mainly associated with ulcerative colitis. Created with Biorender.com.

Figure 2

miRNAs involved in CAC-associated canonical signaling pathways. In the development of CAC, major signaling pathways involve the upregulation and downregulation of several miRNAs. miRNA upregulation leads to the increased expression of proinflammatory cytokines, morphological changes, and increased epithelial barrier permeability. Feedback contributes to CAC progression by further exacerbating these changes. After activation of the proinflammatory state, these associated changes go back and stimulate miRNAs to create positive feedback mechanisms. The loss of major downregulated miRNAs leads to increased proinflammatory pathway activation, leading to the compounding effects of inflammation on accelerating tumor development. Black arrow: activation. Brown arrow: positive feedback. Created with Biorender.com.

Figure 3

IBD affects the heart through multiple mechanisms. Gut dysbiosis can contribute to cardiovascular complications through affecting indirect neurogenic signaling, directly sending exosomes to modulate cardiac regulators, and impairing vasorelaxation through circulating inflammatory markers. Created with Biorender.

Figure 4

Venn diagrams showing significantly dysregulated miRNAs in ileal/colonic tissue (A), peripheral blood (B), fecal matter (C), and saliva (D) of patients with ulcerative colitis (UC) or Crohn’s disease (CD). Green denotes upregulated miRNAs, and red denotes downregulated miRNAs compared to healthy controls.