Table 4.
Impact of drugs on epigenome in intestinal inflammation. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; circRNA, circular RNA; CpG, CpG, cytosine–phosphate–guanine; DNA, deoxyribonucleic acid; DNMT, DNA methyltransferase; DSS, dextran sulfate sodium; EEN, Exclusive enteral nutrition; EMT, epithelial-to-mesenchymal-transition; EV, extracellular vesicle; HDAC, histone deacetylases; HPM, Herb-partitioned moxibustion; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; IFN, interferon; IL, interleukin; lncRNA, long non-coding RNA; LPS, lipopolysaccharide; miR, micro-RNA; MSC, mesenchymal stem cell; PPAR-γ, peroxisome proliferator-activated receptor γ; RNA, ribonucleic acid; SCFAs, short-chain fatty acids; SNIP1, Smad Nuclear Interacting Protein 1; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TNF, tumor necrosis factor; TNBS, 2,4,6-Trinitrobenzene sulfonic acid; UC, ulcerative colitis; VEGF, Vascular Endothelial Growth Factor; ZO, zonula occludens.
| Drug | Activity | Epigenetic Mechanism | Tissue/Cells | Mechanism | Model | Author |
|---|---|---|---|---|---|---|
| IBD medication | ||||||
| Mesalamine | Anti-inflammatory activity | miR-206 | IECs and colonic tissues | Long-term treatment donw-regulates miR-206 which confer a protective effect in inducing and maintaining histologic remission | HT29 colon cells; UC patients (n = 10) | Minacapelli CD, et al. (2019) [258] |
| 5-ASA | Anti-inflammatory activity | miR-125b, miR-150, miR-155, miR-346 and miR-506 | IECs | 5-ASA suppressed the levels of miR-125b, miR-150, miR-155, miR-346 and miR-506 in IECs and inhibition of these miR were associated with significant inductions of their target genes such as vitamin D receptor (VDR), suppressor of cytokine signaling (SOCS1), Forkhead box O (FOXO3a) and DNA methyltransferase 1 (DNMT1) | Caco-2 cells | Adamowicz M, et al. (2021) [259] |
| Infliximab | Anti-inflammatory activity | miR-10a | DCs | Anti-TNF mAb treatment significantly promote miR-10a expression, whereas it markedly inhibited NOD2 and IL-12/IL-23p40 in the inflamed mucosa | Human monocyte-derived dendritic cells (DC); IBD patients | Wu W, et al. (2015) [127] |
| Infliximab | Anti-inflammatory activity | miR-301a | T cells | Decreases miR-301a expression in IBD CD4+ T cells by decreasing Th17 cell differentiation through upregulation of SNIP1 | Peripheral blood mononuclear cells (PBMC); inflamed mucosa of patients with IBD | He C, et al. (2016) [260] |
| Infliximab | Anti-inflammatory activity | lnc-ITSN1-2 | T cells | Lnc-ITSN1-2 promotes IBD CD4+ T cell activation, proliferation, and Th1/Th17 cell differentiation by serving as a competing endogenous RNA for IL-23R via sponging miR-125a | Intestinal mucosa from IBD patients (n = 6) and healthy controls (n = 6) | Nie J, et al. (2020) [261] |
| Infliximab | Anti-inflammatory activity | miR-30 family | IECs | Decreases circRNA_103765 expression, which act as a molecular sponge to adsorb the miR-30 family and impair the negative regulation of Delta-like ligand 4 (DLL4) and protect human IECs from TNF-α-induced apoptosis | IBD patients; PBMCs | Ye Y, et al. (2021) [262] |
| Infliximab | Anti-inflammatory activity | miR-146a and miR-146b | Serum and intestinal mucosae | Decreases miR-146a and miR-146b levels in serum. miR-146a probably promotes colitis through TLR4/MyD88/NF-κB signaling pathway | Serum of 19 IBD patients | Batra SK, et al. (2020) [263] |
| Infliximab (IFX) therapy and longer-term steroids (weeks) | Anti-inflammatory activity | miR-320a | Decreases miR-320a serum level. miR-320a could play a role in sensitization of the quiescent mucosa to environmental factors | Serum of 19 IBD patients | ||
| Anti-TNF and glucocorticoids | Anti-inflammatory activity | let-7c | let-7c serum level decreases, thus reduces M2 macrophage polarization (anti-inflammatory) and promote M1 (proinflammatory) polarization | Serum of 19 IBD patients | ||
| Anti-TNF | Anti-inflammatory activity | miR-10a | DCs | Blockade TNF with anti-TNF mAb markedly enhances miR10a expression in the intestinal mucosa. miR-10a could block intestinal inflammation and reduce the differentiation Th1 and Th17 | C57BL/6 (B6) mice | Xue X, et al. (2011) [125] |
| Anti-TNF | Anti-inflammatory activity | miR-378a-3p, miR-378c | Colonic mucosae | Increases levels of miR-378a-3p and miR-378c. Over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence β-gal-reporter gene | Active UC patients (n = 24); inactive UC (n = 10); controls (n = 6); HEK293 cells | Dubois-Camacho K, et al. (2019) [264] |
| Enemas containing short chain fatty acids (SCFA) such as butyrate, propionate, and acetate | Anti-inflammatory activity | Histone acetylation | IECs | SCFAs increase histone acetylation states and inhibit the production of proinflammatory substances, such as IL-8, by the intestinal epithelium | Caco-2 cells | Huang N, et al. (1997) [288] |
| N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), a butyrate-releasing derivative | Anti-inflammatory activity | Histone deacetylase-9 and H3 histone acetylation | Colonic mucosae | FBA, similar to its parental compound sodium butyrate, inhibited histone deacetylase-9 and restored H3 histone acetylation, exerting an anti-inflammatory effect through NF-κB inhibition and the upregulation of PPARγ | DSS-induced colitis in mice | Simeoli R, et al. (2017) [289] |
| Exclusive enteral nutrition (EEN) | Anti-inflammatory activity | hsa-miR-192-5p, hsa-miR-423-3p, hsa-miR-99a-5p, hsa-miR-124-3p, hsa-miR-301a-5p, hsa-miR-495-5p, and hsa-let-7b-5p | Intestinal mucosae | EEN induces mucosal miRNAs expression profile (altered expressions of hsa-miR-192-5p, hsa-miR-423-3p, hsa-miR-99a-5p, hsa-miR-124-3p, hsa-miR-301a-5p, hsa-miR-495-5p, and hsa-let-7b-5p) after EEN therapy was significantly changed compared with inflamed mucosa before treatment | CD patients (n = 30) | Guo Z, et al. (2016) [265] |
| ABX464 | Anti-inflammatory activity | miR-124 | Immune cells | Upregulates miR-124 in human immune cells, which is a negative regulator of inflammation and was shown to target RNAs, such as STAT and TLR | Tazi J, et al. (2021) [290] | |
| MSCs | Anti-inflammatory activity | miR-181a | IECs | MSC-derived exosomal miR-181a could alleviate colitis by promoting intestinal barrier function decreased (increasing level of Claudin-1, ZO-1, and IκB) | DSS-induced colitis in mice and induced human colonic epithelial cell (HCOEPIC) | Gu L, et al. (2021) [266] |
| MSCs | Anti-inflammatory activity | H3K27me3 | T cells | Extracellular vesicles from MSCs could inhibit the differentiation of Th17 cells by regulating H3K27me3 | TNBS-induced colitis in mice | Chen Q, et al. (2020) [291] |
| IFN-γ pretreated bone marrow mesenchymal stem cells | Anti-inflammatory activity | miR-125a and miR-125b | T cells | Increases the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation | DSS-induced colitis in mice | Yang R, et al. (2020) [267] |
| Vascular endothelial growth factor-C-treated adipose-derived stem cells (ADSCs) | Anti-inflammatory activity | miR-132 | Lymphatic endothelial cells | VEGF-C-treated ADSCs have a higher level of miR-132, which promotes lymphangiogenic response by directly targeting Smad-7 and regulating TGF-β/Smad signaling | Lymphatic endothelial cells (LECs) | Wang X, et al. (2018) [292] |
| Supplementation | ||||||
| Iron | Proinflammatory activity | TET1 induction; NRF2, NQ01, GPX2 demethylation | IECs and intestinal mucosae | Chronic iron exposure leads to induction of TET1 expression leading to demethylation of NRF2 (nuclear factor erythroid 2-related factor 2) pathway targets (including NAD(P)H Quinone Dehydrogenase 1 (NQO1) and Glutathione peroxidase 2 (GPX2). NQO1 and GPX2 hypomethylation led to increased gene and protein expression, and could be a route by which cells overcome persistent and chronic oxidative stress | Caco-2 cells and wild-type C57BL/6 mice | Horniblow RD, et al. (2022) [293] |
| Antibiotics | ||||||
| Isotretinoin | Anti-inflammatory activity | miR | T cells | 3 miR overexpressed in naive T-cells and potentially downregulate 777 miR targets (cytoskeleton remodelling and the c-Jun N terminal kinase (JNK) signaling pathway) | Balb/c mice | Becker E, et al. (2016) [268] |
| Metronidazole | Anti-inflammatory activity | miR | 5 miR were significantly lower in naive T-cells resulting in the prediction of 340 potentially upregulated miR targets associated with IL-2 activation and signaling, cytoskeleton remodelling and epithelial-to-mesenchymal-transition (EMT). | |||
| Doxycycline | Anti-inflammatory activity | miR-144-3p | Overexpression of miR-144-3p that resulted in the prediction of 493 potentially downregulated miR targets involved in protein kinase A (PKA), protein kinase B and nuclear factor of activated T-cells (NFAT) signaling pathways | |||
| Tetracyclines | Anti-inflammatory activity | miR-150, miR-155, miR-375 and miR-146 | Colonic tissues | Reduce miR-150 and miR-155 expression, upregulate miR-375 and miR-142 | DSS-induced colitis in mice and bone marrow-derived macrophages | Garrido-Mesa J, et al. (2018) [269] |
| Antibiotics treatment | Anti-inflammatory activity | DNA demethylation | IECs | Suppresses aberrant DNA methylation of three marker CpG islands (Cbln4, Fosb, and Msx1) induced by chronic inflammation | AOM/DSS-induced colitis in mice | Hattori N, et al. (2019) [270] |
| Probiotics | ||||||
| Probiotic bacterium Escherichia coli Nissle 1917 (EcN) | Anti-inflammatory activity | miR-203, miR-483-3p, miR-595 | IECs | Increases miR-203, miR-483-3p, miR-595 targeting tight junction (TJ) proteins; these miRNAs are involved in the regulation of barrier function by modulating the expression of regulatory and structural components of tight junctional complexes. | T84 cells | Veltman K, et al. (2012) [271] |
| Bifidobacterium longum | Anti-inflammatory activity | DNA demethylation | Peripheral blood mononuclear cells | B. Longum treatment significantly demethylates several CpG sites in Foxp3 promoter | TNBS-induced colitis in rat; spleen peripheral blood mononuclear cells (PBMC) cells was extracted | Zhang M, et al. (2017) [272] |
| Lactobacillus fermentum and Lactobacillus salivarius | Anti-inflammatory activity | miR-155, miR-223, miR-150 and miR-143 | Colonic tissues | They increase the expression of miR-155 and miR-223, and miR-150 and miR-143 for L. fermentum, involved in the immune response (restoration of Treg cell population and the Th1/Th2 cytokine balance) and in the intestinal barrier function | C57BL/6J mice | Rodríguez-Nogales A, et al. (2017) [273] |
| Saccharomyces boulardii | Anti-inflammatory activity | miR-155 and miR-223; miR-143 and miR-375 | Colonic tissuess | Increasing the expression of miR-155 and miR-223, whereas decreasing the expression miR-143 and miR-375 | DSS-induced colitis in mice | Rodríguez-Nogales A, et al. (2018) [274] |
| Bifidobacterium bifidum ATCC 29521 | Anti-inflammatory activity | miR-150, miR-155, miR-223 | Colonic mucosae | Restorates miR-150, miR-155, miR-223, upregulates anti-inflammatory cytokines (IL-10, PPARγ, IL-6), tight junction proteins (such as ZO-1, MUC-2, Claudin-3, and E Cadherin-1) and downregulates inflammatory genes (TNF-α, IL-1β) | DSS-induced colitis in mice | Din AU, et al. (2020) [275] |
| Lactobacillus casei LH23 probiotic | Anti-inflammatory activity | Histone H3K9 acetylation | Colonic tissues | Modulates the immune response and ameliorates colitis via suppressing JNK/p-38 signal pathways and enhancing histone H3K9 acetylation | DSS-induced colitis in mice; LPS-induced RAW264.7 cells | Liu M, et al. (2020) [294] |
| Lactic Acid-Producing Probiotic Saccharomyces cerevisiae | Anti-inflammatory activity | Histone H3K9 acetylation and histone H3K18 lactylation | Macrophages | Promotes histone H3K9 acetylation and histone H3K18 lactylation and attenuates intestinal inflammation via suppressing macrophage pyroptosis | DSS-induced colitis in mice | Sun S, et al. (2021) [276] |
| Other medication | ||||||
| Telmisartan (angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-receptor-γ agonist) | Anti-inflammatory activity | miR-155 | Mesenteric adipocytes | Restorates the mesenteric adipose tissue adipocyte morphology and the expression of adipokines by suppressing the neurotensin/miR-155 pathway | IL-10(−)/(−) mice; cultured mesenteric adipose tissue from Crohn’s disease patients | Li Y, et al. (2015) [295] |
| Melatonine | Anti-inflammatory activity | Prevent DNA methylation | IECs | Prevents DNA demethylation, reduces NF-κB activation, decreases the levels of inflammatory mediators (including IL-6, IL-8, COX-2, and NO), and reduces increase in paracellular permeability, attenuating the inflammatory response | Caco-2 cells | Mannino G, et al. (2019) [296] |
| Morphine | Proinflammatory activity | Let7c-5p | Macrophages, DCs | Opioid treatment can disrupt gut immune homeostasis by inhibiting packaging of miR into EVs secreted by intestinal crypt cells (with a decreased amount of Let7c-5p) | C57BL/6J mice; organoid culture | Zhang Y, et al. (2021) [297] |
| Artesunate | Anti-inflammatory activity | miR-155 | Macrophages | Inhibits the expression of miR-155 to inhibit the NF-κB pathway | LPS-induced RAW264.7 cells; BALB/c mice model | Yang ZB, et al. (2021) [298] |
| Valproic acid treatment | Anti-inflammatory activity | HDAC inhibition | Intestinal tissue | Inhibits HDAC activity and increases H3K27ac levels and reduced expression of IL6, IL10, IL1B, and IL23 | DSS-induced colitis in mice | Felice C, et al. (2021) [299] |
| Tetrandrine | Anti-inflammatory activity | miR-429 | IECs | Tetrandrine can attenuate the intestinal epithelial barrier defects in colitis through promoting occludin expression via the AhR/miR-429 pathway | DSS-induced colitis in mice | Chu Y, et al. (2021) [300] |
| Chinese medicine | ||||||
| Sinomenine, a pure alkaloid isolated in Chinese medicine | Anti-inflammatory activity | miR-155 | Colonic tissues | Downregulates the levels of miR-155 and several related inflammatory cytokines | TNBS-induced colitis in mice | Yu Q, et al. (2013) [277] |
| Tripterygium wilfordii Hook F (TWHF) | Anti-inflammatory activity | miR-155 | Ileocolonic anastomosis | Triptolide could suppress miR-155/SHIP-1 signaling pathway and attenuated expression of inflammatory cytokines after ileocaecal resection | IL-10(−/−) mice | Wu R, et al. (2013) [278] |
| Herb-partitioned moxibustion (HPM) | Anti-inflammatory activity | miR-147 and miR-205 | Colonic tissues | Upregulates the expression of miR-147 and miR-205 and then further regulate some of their target genes, thereby indirectly inhibiting the inflammatory signal pathways mediated by TLR, NF-κB, and so forth and decreasing the production of downstream inflammatory cytokines such as TNF-α and IL-1β, so as to alleviate intestinal inflammation in CD | Experimental CD rat models | Wei K, et al. (2015) [280] |
| Salvianolic acid B (Sal B) is isolated from the traditional Chinese medical herb Salvia miltiorrhiza | Anti-inflammatory activity | miR-1 | IECs | Sal B restores barrier function by miR-1 activation and subsequent myosin light chain kinase (MLCK) inactivation | TNBS-induced rat colitis model | Xiong Y, et al. (2016) [281] |
| Herb-partitioned moxibustion (HPM) | Anti-inflammatory activity | miR-184 and miR-490-5p | Colonic tissue | HPM regulates miR-184 and miR-490-5p expression, act on the transcription of their target genes to regulate inflammatory signaling pathways, and attenuate inflammation and tissue injury in the colons of rats with DSS-induced UC | DSS-induced colitis in mice | Huang Y, et al. (2017) [282] |
| Triptolide (TPL) | Anti-inflammatory activity | miR-16-1 | Ileocolonic anastomosis | TPL reduces miR-16-1 levels aggravating anastomotic inflammation and fibrosis | IL-10−/− mice | Hou HW, et al. (2017) [283] |
| Norisoboldine (NOR), a natural aryl hydrocarbon receptor (AhR) | Anti-inflammatory activity | H3K9me3 modification | T cells | NOR promoted Treg differentiation and then alleviated the development of colitis by regulating AhR (aryl hydrocarbon receptor)/glycolysis axis and decreases NAD+ and SIRT1 (sirtuin 1), facilitates the ubiquitin-proteasomal degradation of SUV39H1, which is a major member of histone KMTs and catalyses the H3K9me3 modification, which is associated with transcription repression of Foxp3 | Lv Q, et al. (2018) [284] | |
| Triptolide (TPL), the most potent bioactive substance in TWHF (Tripterygium wilfordii Hook F) extract | Anti-inflammatory activity | miR-16-1 | Fibroblasts | Inhibits migration and proliferation of fibroblasts from ileocolonic anastomosis of CD patients via regulating the miR-16-1/HSP70 pathway | Fibroblasts from strictured anastomosis tissue (SAT) samples and matched anastomosis-adjacent normal tissue (NT) samples of CD patients (n = 10) | Chen M, et al. (2019) [285] |
| Polysaccharide RAMPtp from Atractylodis macrocephalae Koidz | Anti-inflammatory activity | lncRNA ITSN1-OT1 | IECs | Induces lncRNA ITSN1-OT1, which blocks the nuclear import of phosphorylated STAT2 and prevents the decrease of expression and structural destroy of tight junction proteins | DSS-induced colitis in mice | Zong X, et al. (2021) [286] |
| Dendrobium officinale polysaccharide (DOP) | Anti-inflammatory activity | miR-433-3p | IECs, macrophages | DOP interfered with the secretion of small extracellular vesicles (DIEs) by IEC, with increased miR-433-3p expression. When delivered to macrophages, miR-433-3p targeted the MAPK8 gene, leading to inhibition of the MAPK signaling pathway and reduced production of inflammatory cytokines | IECs, macrophages | Liu H, et al. (2021) [287] |
| Huangqin-Tang decoction (HQT) | Anti-inflammatory activity | miR-185-3p | IECs | HQT could upregulate miR-185-3p, thereby affecting the myosin light chain kinase (MLCK)/myosin light chain phosphorylation (p-MLC) pathway and leading to increased expression of occludin protein, which ultimately protected the intestinal epithelial barrier function | Balb/c mice | Changlin Z, et al. (2021) [279] |