Table 1.
Dysregulated miRNAs in DGBIs.
| Disease | miRNA (Expression) |
Target | Key Findings | References | ||
|---|---|---|---|---|---|---|
| Gene | Cell | Pathophysiological Mechanisms | ||||
| Gastroparesis, STC | miR-10b ↓ | KLF11, KIT |
ICCs | GI dysmotility | Deficiency of miR-10b in ICCs led to gastroparesis and STC, while injection of miR-10b rescued the dysmotility. | [28] |
| STC | miR-222 ↑ | KIT, SCF | ICCs | GI dysmotility | Overexpression of miR-222 in ICCs diminished ICC proliferation and accelerated autophagy, whereas inhibition of miR-222 prevented apoptosis of ICCs. |
[55] |
| Delayed gut transit | miR-551b ↓ | KIT | ICCs | GI dysmotility | miR-551b mimic increased intracellular Ca2+ concentration in ICCs. | [56] |
| STC | let-7f ↑ | NaV1.5 | SMCs | GI dysmotility | Upregulation of let-7f resulted in decreased NaV1.5 expression, current density, and reduced motility of GI smooth muscle. | [23] |
| Delayed gut transit | miR-143/145 ↓ | SRF | SMCs | GI dysmotility | Deficiency of Dicer in SMCs resulted in degeneration of SMCs in GI smooth muscle. SRF-induced miR-143 and miR-145 expression promoted GI SMC differentiation and suppression of proliferation. | [57] |
| Delayed gut transit | miR-28 ↑ | NRF2 | Enteric neurons |
GI dysmotility | Elevated miR-28 levels in enteric neurons delayed gastric motility by modulating nNOSα dimerization. | [58] |
| Delayed gut transit | miR-375 ↑ | Pdk1 | Enteric neurons |
GI dysmotility | Overexpression of miR-375 in enteric neurons resulted in neuronal cell apoptosis while injection of a miR-375 inhibitor prevented the neuronal cell apoptosis and improved gut motility. | [59] |
| IBS-D | miR-490 ↑ | Tryptase, PAR-2 |
Mast cells | Gut immune dysfunction |
Overexpression of miR-490 in mast cells resulted in increased proliferation of mast cells while inhibition of miR-490 expression promoted apoptosis and inhibited proliferation of mast cells. | [60] |
| IBS model | miR-181c ↓ | IL-1A | Colonic biopsy |
Gut immune dysfunction |
Inhibition of miR-181c resulted in increased IL-1A levels while overexpressed miR-18c silenced IL-1A and inhibited low-grade inflammation in IBS rats. | [61] |
| STC | miR-128 ↑ | MAPK-14 | Colonic macrophages |
Gut immune dysfunction |
miR-128 expression negatively correlated with macrophage number, suggesting a miR-128 inhibitor might be a potential therapeutic candidate for a subset of patients with STC having gut immune dysfunction. | [62] |
| IBS-D | miR-16, miR-103/107 ↓ |
5HTR4 | Jejunal biopsy |
Altered serotonin signaling |
miR-16 and miR-103/107 were downregulated in jejunum biopsies from IBS-D patients and were negatively correlated with IBS symptoms. | [63] |
| IBS-D | miR-510 ↑ | 5HTR3E | IECs | Altered serotonin signaling |
miR-510 expression was upregulated in enterocytes and myenteric plexuses of colon sections from patients with IBS-D and resulted in altered serotonin signaling via 5HTR3. | [64] |
| IBS | miR-24 ↑ | SERT | IECs | Altered serotonin signaling/visceral hypersensitivity |
miR-24 expression was upregulated in colonic biopsies from IBS patients. Treatment with a miR-24 inhibitor increased nociceptive threshold levels and reduced MPO activity in the proximal colon of IBS mice, and upregulated expression levels of SERT in IECs. | [65] |
| IBS-D | miR-199a/b ↓ | TRPV1 | Colonic biopsy |
Visceral hypersensitivity |
Decreased colonic miR-199a/b correlated with visceral pain in patients with IBS-D. Administration of miR-199 (lenti-miR-199 precursor) reversed visceral nociception in a rat model of visceral hypersensitivity. | [26] |
| IBS-D | miR-495 ↓ | PI3K, AKT, PKB |
Rectal biopsy |
Visceral hypersensitivity |
miR-495 upregulation reduced visceral sensitivity in IBS-D mice via inhibition of the PI3K/AKT signaling pathway by targeting PKIB. | [66] |
| IBS-D | miR-200a ↑ | CNR1, SERT | Colonic biopsy |
Visceral hypersensitivity |
Upregulation of miR-200a induced visceral hyperalgesia by targeting CNR1 and SERT. A miR-200a mimic markedly inhibited the expression of CNR1/SERT in IBS-D rats. | [67] |
| IBS | miR-338 ↓ | MAPK, threonine kinase |
IECs | Visceral hypersensitivity |
Inhibition of miR-338 increased MAPK or protein serine/threonine kinase pathway genes leading to increased visceral sensation. | [29] |
| IBS-D | miR-29a ↑ | ZO-1, CLDN1 |
Colonic biopsy |
Intestinal barrier dysfunction |
Upregulation of miR-29a downregulates ZO-1 and CLDN1 expression resulting in leaky gut. Treatment with miRNA-29a inhibitor downregulated D-LA and DAO activity, and increased the expression of ZO-1 and CLDN1 in the intestinal mucosal epithelium. | [68] |
| IBS-D | miR-29a ↑ | GLUL | Colonic and duodenal biopsy |
Intestinal barrier dysfunction |
Upregulation of miR-29a led to reduced GLUL levels resulting in impaired intestinal membrane permeability in patients with IBS-D. | [69] |
| IBS | miR-219a ↓ | TJP1/ZO-1, E-CDH1, CEACAM5, CTNND1 |
IECs | Intestinal barrier dysfunction |
Inhibition of miR-219a-5p in intestinal epithelial cells led to hyperpermeability as TEER was reduced and dextran flux was increased. | [29] |
| IBS model | miR-122a ↑ | TNF-α | IECs | Intestinal barrier dysfunction |
miR-122a upregulation led to intestinal barrier dysfunction via TNF-α-mediated degradation of occludin. | [70] |
| IBS model | miR-144 ↑ | OCLN, ZO-1 |
Colonic biopsy |
Intestinal barrier dysfunction |
miR-144 upregulation led to intestinal hyperpermeability, while inhibition of miR-144 improved intestinal barrier function in IBS-D rat colonic epithelial cells. | [71] |
| IBS model | miR-21 ↓ | PTEN, PDCD4, ARF4 |
IECs | Intestinal barrier dysfunction |
Inhibition of miR-21-5p in IECs led to intestinal epithelial hyperpermeability. | [72] |
| IBS-D | miR-125b, ↑ miR-16 |
CGN, CLDN2 |
IECs | Intestinal barrier dysfunction |
Upregulation of miR-125b and miR-16 downregulated CGN and CLDN2 and resulted in intestinal barrier dysfunction. | [27] |
| IBS | miR-148b ↑ | RGS2 | HT-29 cells cultured with IBS-derived serum exosomes |
Intestinal barrier dysfunction |
miR-148b overexpression increased cell permeability and downregulated RGS2 expression. | [73] |
Abbreviations: AKT/PKB, protein kinase B; ARF4, ADP-ribosylation factor-4; CDH1, cadherin-1; CEACAM5, carcinoembryonic antigen-related cell adhesion molecule-5; CGN, cingulin; CLDN1, claudin-1; CNR1, cannabinoid receptor-1; CTNND1, catenin delta-1; GI, gastrointestinal; GLUL, glutamine synthetase; HFD, high fat diet; IBS-D, diarrhea-predominant irritable bowel syndrome; ICCs, interstitial cells of Cajal; IECs, intestinal epithelial cells; IL-1, interleukin-1; KIT, receptor tyrosine kinase; KLF11, krüppel-like factor-11; nNOS, neuronal nitric oxide synthase; MAPK, mitogen-activated protein kinase; miRNA, microRNA; NaV1.5, voltage-gated sodium channel subunit 1.5; NRF2, nuclear factor erythroid 2-related factor; OCLN, occludin; PAR-2, protease activated receptor-2; PDCD4, programmed cell death-4; PDK1, 3-phosphoinositide-dependent protein kinase-1; PI3K phosphoinositide-3-kinase; PTEN, phosphatase and tensin homolog; RGS2, regulator of G-protein signaling-2; SCF, stem cell factor; SERT serotonin transporter; SMCs smooth muscle cells; SRF, serum response factor; STC, slow transit constipation; TEER, trans-epithelial electrical resistance; TJP, tight junction protein; TNF-α, tumor necrosis factor-alpha; TRPV1, transient receptor potential vanilloid-1 receptor; ZO-1, zonula occludens-1; 5-HTR3E, 5-hydroxytryptamine receptor 3 isoform E.