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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2015; 21(43): 12274-12282
Published online Nov 21, 2015. doi: 10.3748/wjg.v21.i43.12274
MicroRNA in inflammatory bowel disease: Translational research and clinical implication
Kurt Fisher, Jingmei Lin
Kurt Fisher, Jingmei Lin, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Author contributions: The authors contributed equally to this work.
Conflict-of-interest statement: The authors have no conflicts of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jingmei Lin, MD, PhD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Indianapolis, IN 46202, United States.
Telephone: +1-317-4916159 Fax: +1-317-4916419
Received: April 24, 2015
Peer-review started: April 24, 2015
First decision: July 20, 2015
Revised: August 4, 2015
Accepted: October 23, 2015
Article in press: October 26, 2015
Published online: November 21, 2015


Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis and Crohn’s disease. The pathogenesis of IBD is complex and not completely understood. MicroRNAs belong to a class of noncoding small RNAs that post-transcriptionally regulate gene expression. Unique microRNA expression profiles have been explored in IBD. In this review, we focus on the unique microRNA expression pattern in both tissue and peripheral blood from IBD patients and emphasize the potential diagnostic and therapeutic applications. The discovery of microRNAs has contributed to our understanding of IBD pathogenesis and might lead to clinical advance in new therapeutics.

Key Words: Inflammatory bowel disease, Ulcerative colitis, Crohn’s disease, MicroRNA, Pathogenesis, Gene expression

Core tip: Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis and Crohn disease. The pathogenesis of IBD is complex and not completely understood. MicroRNAs belong to a class of noncoding small RNAs that post-transcriptionally regulate gene expression. Unique microRNA expression profiles have been explored in IBD. In this review, we focus on the unique microRNA expression pattern in both tissue and peripheral blood from IBD patients and emphasize the potential diagnostic and therapeutic applications. The discovery of microRNAs has contributed to our understanding of IBD pathogenesis and might lead to clinical advance in new therapeutics.


Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis (UC) and Crohn’s disease (CD), which is a chronic and recurrent inflammatory disorder primarily involving the gastrointestinal tract. The pathogenesis of IBD is multifactorial and not completely understood, but genetic, epigenetic, infectious, physiological, and immunological factors may all play important roles in the genesis and progression of the diseases[1-3]. So far, IBD is generally accepted as a complicated consequence attributable to inadequate immunological responses to luminal factors in genetically predisposed subjects.

MicroRNAs are encoded within the genomes of a wide variety of eukaryotes, including more than 700 different microRNA genes in the human genome[4,5]. MicroRNAs are evolutionarily conserved, single-stranded non-coding RNA molecules of 19-24 nucleotides, which represent a class of regulatory RNAs that decrease stability and suppress gene expression at a post-transcriptional level. MicroRNAs concurrently modulate the expression levels of dozens or more distinct messenger RNA (mRNA) targets. Alternatively, any given mRNA sequence may be targeted by several different microRNAs[4-6]. To date, they have been predicted to target and control the expression of at least 30% of the entire mammalian genome[7]. Since their discovery in 1933, microRNAs have been found to be involved in multiple pathophysiological networks[8,9] and in the pathogenesis of a broad-spectrum of human diseases, including cancer and inflammation[10-15]. Given their potential as therapeutic targets, microRNAs have drawn a lot of attention recently.

Knowledge of microRNA in IBD has accumulated in the past seven years and has indicated that microRNAs play critical roles in the pathogenesis of chronic inflammation and oncogenic transformation. Herein, the review focuses on the current understanding of microRNA as biomarkers of pathogenesis and potential therapeutic implication in IBD.


Multiple studies have demonstrated distinct microRNA expression profiles in tissue and peripheral blood of IBD patients. Many studies have been conducted on tissue and serum of patients with active or inactive IBD in an attempt to identify biomarkers and drivers of pathogenesis.

Aberrant microRNA profiles in mucosal tissue of UC

Since 2008, dysregulated microRNAs have been identified by examining inflamed or uninflamed colonic tissue in UC patients[16-25]. As listed in Table 1, comparing to normal healthy controls aberrantly elevated microRNAs have been found including miR-7, miR-16, miR-20b, miR-21, miR-23a, miR-24, miR-29a, miR-29b, miR-31, miR-98, miR-125b-1*, miR-126, miR-126*, miR-127-3p, miR-135b, miR-146a, miR-150, miR-155, miR-195, miR-196a, miR-206, miR-223, miR-324-3p, miR-375, miR-422b, miR-548a-3p, miR-650, miR-663, miR-let-7e*, and miR-let-7f. The decreased microRNAs include miR-143, miR-145, miR-188-5p, miR-192, miR-194b, miR-196b, miR-215, miR-216b, miR-320a, miR-346, miR-375, miR-489, miR-548e, miR-559, and miR-630.

Table 1 Aberrant microRNA expression in human colonic tissue in ulcerative colitis.
StatusTissue typeControlAberrant microRNA expressionRef.
Active UCSigmoid, n = 15HealthyDecreased: miR-192 and 375Wu et al[16], 2008
Increased: miR-16, 21, 23a, 24, 29a, 126, 195, 422b and let-7f
Sigmoid, n = 12HealthyIncreased: miR-21 and 155Takagi et al[17], 2010
Sigmoid, n = 12HealthyIncreased: miR-21 and 126Feng et al[18], 2012
Colon, nonspecific, n = 10HealthyDecreased: miR-188-5p, 215, 320a and 346Fasseu et al[19], 2010
Increased: miR-7, 31, 135b and 223
Colon, nonspecific, n = 5HealthyIncreased: miR-150Bian et al[20], 2011
Colon, nonspecific, n = 8HealthyDecreased: miR-143 and 145Pekow et al[21], 2012
Colon, nonspecific, n = 20HealthyIncreased: miR-20b, 98 and let-7e*Coskun et al[22], 2013
Active or inactive UCColon, distalmost, n = 10HealthyDecreased: miR-194b, 216b, 548e and 559Lin et al[23], 2014
Increased: miR-31, 146a, 206 and 663
Inactive UCSigmoid, n = 15HealthyIncreased: miR-16, 23a, 24, 29a, 375 and 422bWu et al[16], 2008
Colon, nonspecific, n = 8HealthyDecreased: miR-188-5p, 215, 320a and 346Fasseu et al[19], 2010
Increased: miR-29a, 29b, 126*, 127-3p, 196a and 324-3p
Colon, nonspecific, n = 19HealthyIncreased: miR-20b and 125b-1*Coskun et al[22], 2013
UnknownColon, nonspecific, n = 15HealthyIncreased: miR-21Yang et al[24], 2013
Active UCColon, nonspecific, n = 20Inactive UCIncreased: miR-98Coskun et al[22], 2013
Colon, left or sigmoid, n = 9Inactive UCDecreased: miR-196b, 489 and 630Iborra et al[25], 2013
Increased: miR-548a-3p and 650

Given the variable anatomic location of colonic tissue, the diverse inflammatory status (either inflamed or uninflamed with or without treatment), the different cohorts of healthy control and analytical systems, it is not surprising that the findings are not consistent among researchers. However, three microRNA candidates, miR-21[16-18,24], miR-29a[16,19] and miR-31[19,23], have been found aberrantly elevated by at least two independent groups.

Aberrant microRNA profiles in mucosal tissue of CD

As shown in Table 2, distinct microRNA expression profiles have also been studied in patients with CD[19,23,25-29]. MiR-9, miR-9*, miR-16, miR-21, miR-22, miR-23b, miR-26a, miR-29b, miR-29c, miR-30a, miR-30b, miR-30c, miR-31, miR-34c-5p, miR-106a, miR-126, miR-126*, miR-127-3p, miR-130a, miR-133b, miR-141, miR-146a, miR-146b-5p, miR-150, miR-155, miR-181c, miR-191, miR-196, miR-196a, miR-206, miR-223, miR-324-3p, miR-375, miR-594 and miR-663 have been found significantly increased comparing to the normal controls[19,23,26,28,29]. The decreased microRNAs include miR-7, miR-18a*, miR-19b, miR140-3p, miR-194b, miR-216b, miR-548e, miR-559, miR-629, miR-629*, and miR-let-7b[23,27,30].

Table 2 Aberrant microRNA expression in human colonic tissue in Crohn’s disease.
StatusTissue typeControlAberrant microRNA expressionRef.
Active CDSigmoid, n = 5HealthyDecreased: miR-19b and 629Wu et al[26], 2010
Increased: miR-23b, 106a and 191
Terminal ileum, n = 6HealthyIncreased: miR-16, 21, 223, and 594Wu et al[26], 2010
Colon, nonspecific, n = 16HealthyIncreased: miR-9, 21, 22, 26a, 29b, 29c, 30b, 31, 34c-5p, 106a, 126, 126*, 127-3p, 130a, 133b, 146a, 146b-5p, 150, 155, 181c, 196a, 324-3p and 375Fasseu et al[19], 2010
Colon, nonspecific, n = 8HealthyDecreased: miR-7Nguyen et al[27], 2010
Colon, nonspecific, n = 120HealthyIncreased: miR-196Brest et al[28], 2011
Active and inactive CDColon, nonspecific, n = 15HealthyIncreased: miR-31 and 141Huang et al[29], 2015
Colon, distalmost, n = 9HealthyDecreased: miR-194b, 216b, 548e and 559 Increased: miR-31, 146a, 206 and 663Lin et al[23], 2014
Inactive CDColon, nonspecific, n = 8HealthyIncreased: miR-9*, 21, 22, 26a, 29b, 29c, 30a*, 30b, 30c, 31, 34c-5p, 106a, 126*, 127-3p, 133b, 146a, 146b-5p, 150, 155, 196a, 223 and 324-3pFasseu et al[19], 2010
Active CDColon, left or sigmoid, n = 9Inactive CDDecreased: miR-18a*, 140-3p, 629* and let-7b Increased: miR-328, 422a and 885-5pIborra et al[25], 2013

Among them, miR-21[19,26], miR-31[19,23,29], miR-106a[19,26], miR-146a[19,23], and miR-223[19,26] have been found dysregulated by at least two independent groups.

Aberrant microRNA in peripheral blood of UC

As summarized in Table 3, microRNA expression is also altered in the peripheral blood in patients with UC[24,25,31-34]. In studies examining microRNAs in peripheral blood mononuclear cells of patients with either active or inactive UC, miR-15b, miR-16, miR-19a, miR-20b*, miR-21, miR-22, miR-24, miR-27a, miR-27a*, miR-28-3p, miR-28-5p, miR-29a, miR-30e, miR-31, miR-92a-1*, miR-93, miR-103, miR-103-2, miR-103-2*, miR-128, miR-138, miR-140-3p, miR-142-5p, miR-143*, miR-146a-3p, miR-150*, miR-151-5p, miR-155, miR-181b, miR-188-5p, miR-196b, miR-199a-3p, miR-199a-5p, miR-221, miR-223, miR-330-3p, miR-340*, miR-345, miR-362-3p, miR-362-5p, miR-374b, miR-378, miR-378*, miR-422a, miR-423-5p, miR-500, miR-501-5p, miR-532-3p, miR-532-5p, miR-550*, miR-598, miR-720, miR-760, miR-769-3p, miR-769-5p, miR-874, miR-941, miR-1271, miR-1274b, miR-1296, miR-let-7d, miR-let-7e, miR-let-7g, miR-let-7i*, and miR-plus-E1271 are increasingly expressed comparing to the normal population[24,25,31-34]. The decreased profiles include miR-150 and miR-505* comparing to the normal controls[25,31,33].

Table 3 Aberrant microRNA expression in human peripheral blood in ulcerative colitis.
StatusTissue typeControlAberrant microRNA expressionRef.
Active UCPeripheral blood, n = 13HealthyDecreased: miR-505*Wu et al[31], 2011
Increased: miR-28-5p, 103-2*,151-5p, 199a-5p, 340*, 362-3p, 532-3p and plus-E1271
Peripheral blood, n = 88HealthyIncreased: miR-16, 21, 28-5p, 151-5p, 155 and 199a-5pParaskevi et al[32], 2012
Active and inactive UCPeripheral blood, n = 18HealthyDecreased: miR-150 Increased: miR-15b, 19a, 24, 27a, 28-3p, 29a, 30e, 93, 103, 128, 142-5p, 196b, 199a-3p, 221, 223, 345, 374b, 423-5P, 532-5p, 598, 760, let-7d, let-7e and let-7gIborra et al[25], 2013
Inactive UCPeripheral blood, n = 13HealthyDecreased: miR-505*Zahm et al[33], 2011
Increased: miR-103-2, 362-3p and 532-3p
Inactive UCPeripheral blood, n = 10HealthyDecreased: miR-505*Wu et al[31], 2011
Increased: miR-103-2*, 362-3p and 532-3p
UnknownPeripheral blood, n = 20HealthyIncreased: miR-20b*, 22, 27a*, 31, 92a-1*, 138, 140-3p, 143*, 146a-3p, 150*,181b, 188-5p, 330-3p, 362-5p, 345, 378, 378*,422a, 500, 501-5p, 532-5p, 550*, 720, 769-3p, 769-5p, 874, 941, 1271, 1274b, 1296 and let-7i*Duttagupta et al[34], 2012
Peripheral blood, n = 15HealthyIncreased: miR-21Yang et al[24], 2013

Among them, nine microRNAs, miR-21[24,32], miR-28-5p[31,32], miR-151-5p[31,32], miR-199a-5p[31,32], miR-345[25,34], miR-362-3p[31,33], miR-505*[31,33], miR-532-3p[31,33] and miR-532-5p[25,34], have been recognized by at least two independent groups.

Aberrant microRNA in peripheral blood of CD

As listed in Table 4, altered microRNA expression profiles are also found in the peripheral blood in patients with CD[25,31-33]. Compared to healthy controls, the increased microRNA profiles in the serum of patients with active CD include miR-16, miR-20a, miR-21, miR-23a, miR-27a*, miR-29a, miR-30e, miR-93, miR-106a, miR-107, miR-126, miR-140, miR-140-3p, miR-140-5p, miR-188-5p, miR-191, miR-192, miR-195, miR-199a-5p, miR-200c, miR-340*, miR-362-3p, miR-484, miR-532-3p, miR-877, miR-plus-E1271, and miR-let-7b. The significantly decreased microRNAs consist of miR-18a, miR-128, miR-140-5p, miR-145, miR-149*, miR-877, and miR-plus-F1065.

Table 4 Aberrant microRNA expression in human peripheral blood in Crohn’s disease.
StatusTissue typeControlAberrant microRNA expressionRef.
Active CDPeripheral blood, n = 14HealthyDecreased: miR-149* and plus-F1065Wu et al[31], 2011
Increased: miR-199a-5p, 340*, 362-3p, 532-3p and plus-E1271
Peripheral blood, n = 46HealthyIncreased: miR-16, 20a, 21, 30e, 93, 106a, 140, 192, 195, 484 and let-7bZahm et al[33], 2011
Peripheral blood, n = 128HealthyIncreased: miR-16, 23a, 29a, 106a, 107, 126, 191, 199a-5p, 200c, 362-3p and 532-3pParaskevi et al[32], 2012
Active and inactive CDPeripheral blood, n = 18HealthyDecreased: miR-877Iborra et al[25], 2013
Increased: miR-16, 27a*, 140-3p, 140-5p and 195
Inactive CDPeripheral blood, n = 5HealthyDecreased: miR-149*Wu et al[31], 2011
Increased: miR-340*
Active CDPeripheral blood, n = 9Inactive CDDecreased: miR-18a, 128, 140-5p and 145Iborra et al[25], 2013
Increased: miR-188-5p and 877

Among them, six microRNAs, including miR-16[25,32,33], miR-106a[32,33], miR-195[25,33], miR-199a-5p[31,32], miR-362-3p[31,32], and miR-532-3p[31,32], have been found by at least two independent groups.

MicroRNA as a differential biomarker to distinguish between UC and CD

As shown in Table 5, studies have shown that microRNAs are differentially expressed between UC and CD[19,31,35]. The panel of microRNAs that have been found differentially expressed in colonic tissue includes miR-19b, miR-23b, miR-100a-3p, miR-100b-5p, miR-106a, miR-150, miR-191, miR-196b, miR-223, miR-320a, and miR-629[19,35]. Wu and colleagues found three microRNAs (miR-3180-3p, miR-plus-E1035 and miR-plus-F1159) differentially expressed in the peripheral blood between UC and CD[31]. Although at least two groups have developed tissue microRNA panels that attempted to delineate between UC and CD, there is little overlap. Importantly, these studies vary in the activity status of IBD during sampling, which may explain the differences seen by independent groups.

Table 5 Differential microRNA expression between ulcerative colitis and Crohn’s disease.
StatusTissue typeControlAberrant microRNA expressionRef.
Inactive UCColon, nonspecific, n = 8Inactive CDDecreased: miR-100a-3p, 100b-5p, 150, 196b, 223 and 320aFasseu et al[19], 2010
Active or inactive UCColon, distalmost, n = 12Active or Inactive CDIncreased: miR-19b, 23b, 106a, 191 and 629Lin et al[35], 2013
Active UCPeripheral blood, n = 13Active CDIncreased: miR-3180-3p, plus-E1035 and plus-F1159Wu et al[31], 2011
MicroRNA in indeterminate IBD

A diagnosis of idiopathic IBD requires comprehensive analysis of clinical, radiographic, endoscopic, surgical, and histologic data. While most cases of IBD can be specifically classified as either UC or CD, 5%-10% of IBD patients bear equivocal features, falling into the category of indeterminate colitis[36-38]. The ability to better classify cases of indeterminate colitis would allow for better clinical and surgical management of these patients, especially regarding the choice of pouch procedure.

In a study by Lin and colleagues, a panel of miR-19b, miR-23b, miR-106a, miR-191 and miR-629, was evaluated in 16 patients with clinical diagnosis of indeterminate colitis. They found that 15 patients demonstrated UC-like and one CD-like microRNA expression patterns[35]. They concluded that microRNA expression pattern in indeterminate colitis are far more similar to those of UC than CD. The study of microRNA expression pattern in indeterminate colitis provides molecular evidence indicating that most indeterminate colitis are probably UC, rather than CD, which is similar to the data from long-term clinical follow-ups. Molecular testing using microRNA as promising markers to improve the classification of indeterminate IBD has the considerable advantage of being testable at the time of colectomy for improved pouch surgery selection. Before being used as a clinically validate test, clinical validation in large samples of indeterminate colitis patients, especially with correlation to pouch prognosis, is a necessity.


Despite the heterogeneity of microRNAs identified as deregulated in IBD, a few microRNAs confirm in multiple studies and may represent causative agents in disease development. Here we focus on the microRNA with the best evidence as driver of pathogenesis.

MiR-21 potentiates disease severity in IBD

As discussed above, miR-21 has been identified as being upregulated in active UC and CD, consistent with its possible role in the pathogenesis of IBD[16-18,24]. In vitro experiments have shown that the genetic deletion of DNMT1 and DNMT3b caused dysregulation of approximately 10% of microRNAs, demonstrating tight regulation by DNA methylation[39]. The use of microarray and confirmatory pyrosequencing have shown the miR-21 locus is hypomethylated, and therefore overexpressed, in samples of peripheral blood in active CD in pediatric and adult patients[40]. To determine if miR-21 was a potential driver of IBD pathogenesis, a miR-21 knockout mouse model was developed and treated with dextran sodium sulphate (DSS) to induce a chronic colitis model with an elevation of tumor necrosis factor alpha (TNF-α) that mimics human IBD[41]. In wild type mice, the addition of DSS caused a significant increase in miR-21 levels, a dramatic reduction in weight, and significant mortality while the miR-21 knockout mice were resistant to these negative effects, which supports a role of miR-21 in IBD pathogenesis.

The pathogenic effects of miR-21 overexpressing are thought to be mediated through at least 3 separate mechanisms. First, miR-21 is thought to cause increased intestinal permeability, a factor thought to initiate IBD. At baseline, no difference in intestinal permeability was seen between wild type and miR-21 knockout mice[41]. After treatment with DSS, intestinal permeability was greater in wild type mice than that of miR-21 knockout strain. Secondly, miR-21 is pro-apoptotic. Although the mechanism has not been elucidated, miR-21 knockout mice treated with DSS had less intestinal epithelial cell apoptosis[41]. Prevention of epithelial cell apoptosis may help maintain the epithelial cell barrier and limit inflammation and disease progression. Thirdly, interstitial fibrosis is a hallmark of IBD and miR-21 has been associated with fibrosis in multiple disease models. Mouse models of renal fibrosis have shown that cellular injury leads to increased levels of TNF-α and subsequent induction of miR-21[42]. Inhibition of miR-21 prevented fibrosis, presumably through preventing the recruitment of pro-fibrotic inflammatory cells[42]. Increased serum levels of miR-21 were seen in humans with idiopathic pulmonary fibrosis and may serve as a non-invasive biomarker for disease progression[43]. Analysis of serum and hepatic tissue from patients with cirrhosis has also shown that increased miR-21 levels are associated with levels of fibrosis[44]. Although miR-21 has not been experimentally linked to fibrosis in IBD yet, its role deserves further study. Interestingly, miR-21 expression was found to be high in IBD-associated dysplasia suggesting that its expression is maintained throughout the development of dysplasia and carcinogenesis, but more controlled studies are needed to define its role[45].


Longstanding IBD is a well-known risk factor for colorectal cancer, although mechanisms of carcinogenesis are poorly unknown[46,47]. Studies have shown that the risk of IBD-associated colon cancer is related to the extent of the disease, severity of inflammation, and duration[48-50]. With chronic inflammation, colonic epithelium undergoes a transformation from inflamed, but not dysplastic to progressively dysplastic, and eventually to adenocarcinoma. Colonoscopies with surveillance biopsies for IBD-associated dysplasia are used to help guide surgical timing of colectomies. Although histologic examination can reproducibly identify dysplasia, IBD-associated dysplasia cannot be distinguished from sporadic dysplasia based on histologic appearance alone. Histologic examination of IBD-associated adenocarcinomas has characteristic features and demographics which may indicate a specific pathway to carcinogenesis[51]. Molecular alterations have been shown to lead to this histological progression[52-58]. Previous studies have demonstrated molecular abnormalities in normal-appearing non-dysplastic mucosa from patients with UC who had a remote dysplastic lesion[55-57,59-61]. Aneuploidy, chromosomal alterations, p53 mutation, loss of heterozygosity, and chromosome instability are present in normal-appearing mucosa before the development of dysplasia[55-57,59-61].

Studies of microRNAs may elucidate distinct pathways that may help reliably identified IBD-associated dysplasia and subsequent carcinogenesis. Recent studies demonstrate that microRNAs are largely involved in oncogenesis via their regulation of tumor suppressors and oncogenes[62]. In a study by Olaru et al[63], microRNA arrays were performed on tissue from eight patients with IBD-associated dysplasia. Twenty two microRNAs (miR-31, miR-31*, miR-96, miR-135b, miR-141, miR-183, miR-192, miR-192*, miR-194, miR-194*, miR-200a, miR-200a*, miR-200b, miR-200b*, miR-200c, miR-203, miR-215, miR-224, miR-375, miR-424*, miR-429, and miR-552) were significantly upregulated and 10 microRNAs (miR-122, miR-139-5p, miR-142-3p, miR-146b-5p, miR-155, miR-223, miR-490-2p, miR-501-5p, miR-892b, and miR-1288) were downregulated in dysplastic epithelium compared to the non-dysplastic inflamed tissue.

MiR-31 identifies IBD-associated dysplasia

MiR-31 is upregulated in UC and CD, but not in other non-IBD colitis, such as microscopic colitis, that have no association with dysplasia or malignancy[64]. As early as 2007, miR-31 was found to be upregulated in sporadic colorectal adenocarcinomas[65-67]. However, the role of miR-31 in IBD-associated dysplasia or malignancy has only recently been examined. An assessment of the baseline miR-31 expression in normal tissue regardless the different anatomic locations of the colon allows for comparison of all colon specimens equally[63]. In addition, no difference of miR-31 expression level was seen between IBD-associated dysplasia and IBD-associated carcinomas. Importantly, the levels of miR-31 were found 11-fold higher in IBD-associated dysplasia or carcinoma when compared to that of IBD tissue without dysplasia[63]. Although in a smaller study set, these findings were not replicated and a link between microRNAs and p53 dysregulation was indicated[68] Taken together, these findings suggest that miR-31 alteration might happen early in carcinogenesis and may be used a biomarker for IBD-associated dysplasia or malignancy.


Understanding the underlying mechanisms that regulate gene expression and the complex interplay of factors is essential to develop novel therapeutics in IBD. The post-transcriptional regulation of gene expression is unique and is becoming increasingly important.

The ability of microRNAs to target multiple genes and biological signaling pathways has drawn great attention in potential clinical utility as innovative therapeutic agents in treatment. Antisense oligonucleotides complementary to microRNAs, namely anti-microRNA oligonucleotides, can target specific microRNAs abolishing their function in in vitro cultured cells, or in vivo in animal models. For example in the achievement of cancer research, recent accumulating preclinical studies have shown the feasibility of slowing tumor progression by either overexpressing tumor suppressive microRNAs, or by neutralizing the activities of oncogenic microRNAs in cell- or animal-based cancer models[69-72]. In addition, a number of clinical drugs have shown to modulate the microRNA expression as anticancer effect in vitro[73,74].

Particularly in the field of IBD, the mechanisms to modify microRNAs that might activate or inactivate pathways required for the inflammation progress are worth investigating. Potential therapeutic application targeted on microRNA is to block inflammatory progression to improve sensitivity to conventional therapies. The pharmacologic targeted tissue delivery consists of two general strategies: (1) antisense oligonucleotides complementary to specific mature microRNAs to inactivate the overexpressed pro-inflammatory process; and (2) to replace the expression of suppressive microRNAs.

To date, no therapeutic manipulation of microRNAs in IBD has been published in either cell lines or animal models yet. Although recent study has shown that inhibition of miR-21, a promising pathogenetic driver in IBD, slows the proliferation and progression in a nasopharyngeal carcinoma cell line[75]. The similar approach is expected to be tested in IBD cell line or animal model. Although side effects are another essential issue to be considered before an effective drug enters the markets, we can’t help speculating that a new therapeutic concept, targeted microRNA drug for IBD, maybe emerges in the near future.


During the past 7 years, the identification of microRNA in IBD has broadened our knowledge. However, the lack of a standardized approach often leads to inconsistent or even conflicting results.

The nomenclature for microRNA has continued to evolve since its discovery in 1993[8,9]. MicroRNAs were named in the order they were discovered, leading to identical microRNAs being given different names by different groups. As the microRNA field continues to expand, significant efforts have been made to clarify nomenclature using a unified system. Recent data added from deep genome sequencing has pushed the number of annotated microRNAs to roughly 1900 in the most recently nomenclature database, miRBase version 21[76]. The complicated historical nomenclature of microRNA makes literature evaluation difficult and diligent effort to confirm sequence identity of each in the literature must be made.

One of the most commonly encountered problems is when we attempt to verify microRNA’s role in IBD pathogenesis. Recent developments in microarrays have led to numerous attempts to identify microRNAs associated with a diverse set of disease processes. Despite the ability of candidate microRNAs to be validated by additional RT-PCR, there has been little reproducibility between groups. Differences in samples obtained from various anatomic locations, treatment regimens, and activity level of disease may account for discrepancies seen between studies. Additionally, microRNAs with the same sequence identity are given modifiers in their name based on their location within the genome. Most techniques do not distinguish microRNAs that have the same sequence but at different locations in the genome[76]. A more clear understanding of the genetic loci associated with microRNAs can provide insight into how they are regulated and become deregulated in pathogenesis.


In summary, the accumulating knowledge of microRNA has significantly expanded our understanding of the pathogenesis of IBD and has demonstrated the usefulness of microRNAs as biomarkers with emerging clinical utility and the potential for personalized therapies.


P- Reviewer: Maric I S- Editor: Yu J L- Editor: A E- Editor: Liu XM

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