MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a persistent inflammatory illness of the gastrointestinal tract (GIT) triggered by an inappropriate immune response to environmental stimuli in genetically predisposed persons. Unfortunately, IBD patients' quality of life is negatively impacted by the symptoms associated with the disease. The exact etiology of IBD pathogenesis is not fully understood, but the emerging research indicated that the microRNA (miRNA) plays an important role. miRNAs have been documented to possess a significant role in regulating pro- and anti-inflammatory pathways, in addition to their roles in several physiological processes, including cell growth, proliferation, and apoptosis. Variations in the miRNA profiles might be a helpful prognostic indicator and a valuable tool in the differential diagnosis of IBD. Most interestingly, these miRNAs have a promising therapeutic target in several pre-clinical animal studies and phase 2 clinical studies to alleviate inflammation and improve patient's quality of life. This comprehensive review discusses the current knowledge about the significant physiological role of different miRNAs in the health of the intestinal immune system and addresses the role of the most relevant differentially expressed miRNAs in IBD, identify their potential targets, and emphasize their diagnostic and therapeutic potential for future research.

Keywords: Inflammatory bowel disease (IBD); MicroRNA (miRNA); Pathogenesis; Therapy; miRNA signature.

Fig. 1

Difference between two forms of IBD. Ulcerative colitis (left side); which occurs only in the colon and rectum and is characterized by the continuous appearance of inflammation and an inner layer of the bowel is involved in inflammation. Crohn's disease (right side); which occurs in any part of GIT and characterized with the patchy appearance of inflammation and all layers of bowel involved in inflammation. Created with BioRender.com

Fig. 2

Hypothesized pathogenesis of IBD. It is speculated that IBD is a multifactorial disease and may be triggered by a complex interaction between immune, genetic, and environmental factors, including gut microbiome. In a healthy state, diversity, and eubiosis of the gut microbiome largely participate in the health of the intestinal barrier and tight junction, mainly through their metabolites. This keeps the balance between immune cells with the upregulation of anti-inflammatory Treg cells. In the IBD case, dysbiosis of gut microbiome is persistent and leads to damage to intestinal barrier and tight junctions with a subsequent increase of intestinal permeability for pathogens and triggering of immune cells and inflammatory reactions. Created with BioRender.com

Fig. 3

A schematic representation of microRNA biosynthesis. miRNA transcription is first started in the nucleus where miRNA is transcribed into primary transcript (pri-miRNA) by RNA polymerase. Then, a protein complex made up of the RNAse-III, Drosha, and DiGeorge critical region 8 (DGCR8) cleaves pri-miRNA, producing precursor miRNA (pre-miRNA), a chain of 60–70 nucleotides. After these, pre-miRNA is transported to the cytoplasm via the Exportin-5 (Exp5)—RanGTP complex. Pre-miRNA is finally cleaved into its mature state by the RNase III enzyme, dicer, which is then permanently integrated into an RNA-induced silencing complex (RISC). The RISC binds to complementary sequences in the 3′- UTR of target mRNA molecules under the guidance of the miRNA, which either causes translational suppression or mRNA destruction. Created with BioRender.com

Fig. 4

miRNAs influence cell autophagy during IBD via several molecular pathways. a miRNAs interact with autophagy genes associated with IBD, including ATG16L1, IRGM, and NOD2, to modify intestinal barrier integrity and innate intestinal immunity. b miRNAs regulate autophagy via modifying the unfolded protein response (UPR) during endoplasmic reticulum stress, which causes intestinal fibrosis in IBD patients. c miRNAs modulate NF-κB and mTOR signaling pathways that influence inflammatory mediators and intestinal autophagy. Created with BioRender.com