Table 3.
Impact of the diet on the epigenome in intestinal inflammation. ADAM17, a disintegrin and metalloprotease-17; AIEC, Adherent-invasive Escherichia coli; CD, Crohn’s disease; CEACAM6, carcinoembryonic antigen-related cell adhesion molecule 6; CREB, C-AMP response element-binding protein; DNA, deoxyribonucleic acid; DNMT, DNA methyltransferase; DSS, dextran sulfate sodium; HDAC, histone deacetylase; HMGB1, high mobility group box 1; HRE, HIF-1-responsive elements; IBD, inflammatory bowel disease; ICAM, intercellular adhesion molecule; IEC, intestinal epithelial cell; IFN, interferon; IL, interleukin; lncRNA, long non-coding RNA; LPS, lipopolysaccharide; miR, microRNA; MMP9, Matrix Metallopeptidase 9; PBMC, peripheral blood mononuclear cell; PTEN, phosphatase and tensin homolog; NF-κB, nuclear factor-kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; PECAM, Platelet endothelial cell adhesion molecule; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; SCFAs, short-chain fatty acids; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TNBS, 2,4,6-trinitrobenzenesulfonic acid; TNF, tumor necrosis factor; UC, ulcerative colitis; VCAM, vascular cell adhesion molecule 1; WT, wild-type; ZO, zonula occludens.
| Food | Activity | Epigenetic Mechanism | Tissue/Cells | Mechanism | Model | Author |
|---|---|---|---|---|---|---|
| Diet | ||||||
| Western diet | Proinflammatory activity | miR-143, miR-145A, miR-148a, miR-152 | IECs | Leads to a decrease in miR-143/145a, miR-148a and miR-152 in colonocytes with a consequent increase in ADAM17 expression protein (these miRs regulating ADAM17) and aggravates colitis. | DSS-induced colitis in mice | Dougherty U, et al. (2021) [164] |
| High fat diet | Proinflammatory activity | miR-155 | Visceral adipocytes | High fat diet changes the miR profile (among which miR-155) of the visceral adipose exosomes, switching the exosomes from anti-inflammatory to a proinflammatory phenotype. | Macrophages | Wei M, et al. (2020) [193] |
| High fat diet rich in n-6 linoleic acid | Proinflammatory activity | DNA methylation | Colonic mucosae | Epigenetically modifies farnesoid-X-receptor (FXR), leading to the activation of downstream factors that participate in bile acid homeostasis and epigenetically activates prostaglandin-endoperoxide synthase-2 (Ptsg-2) coupled accumulation of c-JUN and proliferative cyclin D1(Ccnd1) and increase the risk of inflammation | C57BL/6J mice; Human colonic foetal cells | Romagnolo DF, et al. (2019) [194] |
| Methyl-deficient diet | Proinflammatory activity | Sirtuin 1 | IECs | Reduces sirtuin 1 (SIRT1) expression level and promotes greater acetylation of (heat shock factor protein 1) HSF1, in relation with a dramatic decrease of chaperones (binding immunoglobulin protein (BIP), heat shock protein (HSP)27 and HSP90) | DSS-induced colitis in mice; Caco-2 cells | Melhem H, et al. (2016) [165] |
| Low-methyl diet | Proinflammatory activity | DNA methylation | IECs | Low-methyl diet-dependent HRE demethylation led to abnormal gut expression of CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6), favouring AIEC colonisation and subsequent inflammation | Transgenic mice; Caco-2, T-84 and sh-HIF1-α-T-84 cells | Denizot J, et al. (2015) [166] |
| Methyl-donnor supplemented diet (folate, B12 vitamin) | Anti-inflammatory activity | DNA methylation | IECs | Methyl-donor supplemented diet contributes to hypermethylation of CEACAM6 promoter in IECs, associated with a significant decrease in CEACAM6 expression contributing to less adherence of AIEC bacteria to the enterocytes | CEABAC10 mice | Gimier E, et al. (2020) [195] |
| Isolated food | ||||||
| Cow’s milk (commercial) | Anti-inflammatory activity | miR-21, miR-29b and miR-125b | Colonic mucosae | Extracellular vesicles (EVs) concentrated from commercial cow’s milk downregulates miR-21, miR-29b and miR-125b. MiR-125b was associated with a higher expression of the NF-κB inhibitor TNFAIP3 (A20) | DSS-induced colitis in mice | Benmoussa A, et al. (2019) [178] |
| Human milk derived exosomes | Anti-inflammatory activity | miR-320, miR-375, and Let-7 and DNMT1 and DNMT3 | Colonic mucosae | MiR highly express in milk, such as miR-320, 375, and Let-7, were found to be more abundant in the colon of milk derived exosomes-treated mice compared with untreated mice. These miR downregulate their target genes, mainly DNA methyltransferase 1 (DNMT1) and DNMT3 | DSS-induced colitis in mice; PBMC | Reif S, et al. (2020) [179] |
| Dietary depletion of milk exosomes and their microRNA cargos | Proinflammatory activity | miR-200a-3p | Cecum mucosae | Elicits a depletion of miR-200a-3p and elevated intestinal inflammation and chemokine (C-X-C Motif) ligand 9 expression | Mdr1a−/− mice | Wu D, et al. (2019) [180] |
| Saccharin sodium, Stevioside, and Sucralose (three common sweeteners) | Anti-inflammatory activity | miR-15b | IECs | Upregulate the expression of E-cadherin through the miR-15b/RECK/MMP-9 axis to improve intestinal barrier integrity. Saccharin exerts the most pronounced effect, followed by Stevioside and Sucralose | DSS-induced colitis in mice | Zhang X, et al. (2022) [181] |
| Galacto-oligosaccharides (GOS) | Anti-inflammatory activity | miR-19 | IECs | GOS increases of cell viability, the decrease of apoptosis, as well as the suppressed release of TNF-α, IFN-γ and IL-1β by upregulating miR-19b | Human colon epithelial FHC cells; Helicobacter hepaticus induced colitis in rats | Sun J, et al. (2019) [182] |
| Cinnamaldehyde (a major active compound from cinnamon) | Anti-inflammatory activity | miR-21 and miR-155 | Macrophages | Cinnamaldehyde inhibits NLRP3 inflammasome activation as well as miR-21 and miR-155 level in colon tissues and macrophage. The decrease in miR-21 and miR-155 suppresses levels of IL-1β and IL-6; | DSS-induced colitis in mice; macrophage cell line RAW264.7 and human monocytes U937 | Qu S, et al. (2018) [185] |
| Cinnamaldehyde | Anti-inflammatory activity | lncRNAs H19 | T cells | Cinnamaldehyde inhibits Th17 cell differentiation by regulating the expression of lncRNA H19 | DSS-induced colitis in mice and naïve CD4+ T cells | Qu SL, et al. (2021) [101] |
| Limonin (a triterpenoid extracted from citrus) | Anti-inflammatory activity | miR-124 | IECs | Downregulates p-STAT3/miR-214 signaling pathway and represses the productions of proinflammatory cytokines (such as TNF-α and IL-6) | DSS-induced colitis in mice; cultured normal colonic epithelial cells | Liu S, et al. (2019) [186] |
| Edible ginger | Anti-inflammatory activity | Contained around 125 miRNAs | IECs | Increases the survival and proliferation of IECs, reduces the proinflammatory cytokines (such as TNF-α, IL-6 and IL-1β), and increases the anti-inflammatory cytokines (including IL-10 and IL-22) in colitis | DSS-induced colitis in mice | Zhang M, et al. (2016) [187] |
| Ginsenoside Rh2 (active ingredient of ginseng) | Anti-inflammatory activity | miR-124 | IECs | Inhibits IL-6-induced STAT3 phosphorylation and miR-214 expression (which is an inflammatory effector molecule acting through NF-κB-IL6 pathway) | DSS-induced colitis in mice; cultured normal colonic epithelial cells | Chen X, et al. (2021) [188] |
| Black raspberries (BRBs) | Anti-inflammatory activity | Demethylation the promoter of dkk3; correction of promoter hypermethylation of suppressor genes | Colonic mucosae | BRBs exert their anti-inflammatory effects is through decreasing NF-κB p65 expression leading to decrease of DNMT3B expression (but also histone deacetylases 1 and 2 (HDAC1 and HDAC2) and methyl-binding domain 2 or MBD2), which in turn reverse aberrant DNA methylation of tumor suppressor genes, e.g., dkk2, dkk3, in the Wnt pathway, resulting in their enhanced mRNA expression locally in colon and systematically in spleen and bone marrow and thus in decreased translocation of β-catenin to the nucleus prohibiting the activation of the pathway | DSS-induced colitis in mice; splenocytes and bone marrow cells | Wang LS, et al. (2013) [189] |
| Black raspberries | Anti-inflammatory activity | Demethylation | Colonic mucosae | BRBs decreas the methylation of wif1, sox17, and qki gene promoters and thus increase their mRNA expression (contributing to Wnt signaling) | Interleukin-10 knockout mice | Wang LS, et al. (2013) [190] |
| Mastiha | Anti-inflammatory activity | miR-155 | T cells | Plays a role in circulating levels of miR-155, a critical player in T helper-17 (Th17) differentiation and function | UC patients (n = 35) | Amerikanou C, et al. (2021) [196] |
| Isoliquiritigenin | Anti-inflammatory activity | HDACs inhibition | IECs | Suppresses acetylated HMGB1 release via the induction of HDAC activity, which is one of the critical mediators of inflammation, which is actively secreted from inflammatory cytokine-stimulated immune or non-immune cells | HT-29 cells | Chi JH, et al. (2017) [197] |
| Chronic ethanol exposure | Proinflammatory activity | miR-122a | IECs | Increases the intestinal miR-122a expression, which decreased occludin (OCLN) expression leading to increased intestinal permeability | HT-29 cells | Chen Y, et al. (2013) [191] |
| Chronic alcohol feeding (but not acute alcohol binge) | Proinflammatory activity | miR-155 | Intestinal tissue | Increases miR-155 in the small bowel, which is a modulator of cytokine and T-cell immune response in the gut, leading to intestinal TNFα, and NF-κB activation | WT-mice | Lippai D, et al. (2014) [192] |
| Polyphenol | ||||||
| Polyphenolic red wine extract | Anti-inflammatory activity | miR-126 | Fibroblasts | Polyphenolic red wine extract downregulates miR-126, leading to downregulation of NF-kB, ICAM-1, VCAM-1, and PECAM-1 | CCD-18Co myofibroblasts cells | Angel-Morales G, et al. (2012) [198] |
| Polyphenolic extracts from cowpea (Vigna unguiculata) | Anti-inflammatory activity | miR-126 | Fibroblasts | Cowpea may exert their anti-inflammatory activities at least in part through induction of miR-126 that then downregulate VCAM-1 mRNA and protein expressions | CCD-18Co myofibroblasts cells | Ojwang LO, et al. (2015) [199] |
| Mango (Mangifera indica L.) polyphenolics | Anti-inflammatory activity | miR-126 | Fibroblasts | Mango polyphenols attenuates inflammatory response by modulating the PI3K/AKT/mTOR pathway at least in part through upregulation of miR-126 expression | CCD-18Co cells; DSS-induced colitis in rats | Kim H, et al. (2017) [200] |
| Baicalin (flavone) | Anti-inflammatory activity | miR-191a | IECs | Exerts a protective effect on IECs against TNF-α-induced injury, which is at least partly via inhibiting the expression of miR-191a, thus increasing ZO-1 expression | IEC-6 cells | Wang L, et al. (2017) [170] |
| Pomegranate (Punica granatum L.) polyphenolics | Anti-inflammatory activity | miR-145 | Myofibroblasts | Pomegranate polyphenols attenuate colitis by modulating the miR-145/p70S6K/HIF1α axis | DSS-induced colitis in rats; CCD-18Co colon-myofibroblastic cells | Kim H, et al. (2017) [201] |
| Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata | Anti-inflammatory activity | miR-302 | T cells | Activates Aryl hydrocarbon receptor (AhR), promoting expression of miR-302, downregulating expression of DNA methyltransferase 1 (DNMT-1), reducing methylation level of Foxp3 promoter region, facilitating combination of CREB and promoter region of Foxp3, and upregulating the expression of Foxp3. Alpinetin ameliorates colitis in mice by recovering Th17/Treg balance. | DSS-induced colitis in mice | Lv Q, et al. (2018) [168] |
| Fortunellin, a citrus flavonoid | Anti-inflammatory activity | miR-374a | IECs | Fortunellin targets miR-374a, which is a negative regulator of PTEN, known to induce cell apoptosis | TNBS-induced colitis in rats | Xiong Y, et al. (2018) [169] |
| Quercetin (flavonoid) | Anti-inflammatory activity | miR-369-3p | DCs | Quercetin-induced miR-369-3p which reduce C/EBP-β, TNF-α, and IL-6 production | LPS-stimulated DCs | Galleggiante V, et al. (2019) [171] |
| Resveratrol (a natural plant product) | Anti-inflammatory activity | miR-31, Let7a, miR-132 | T cells | Resveratrol decreases the expression of several miRs (miR-31, Let7a, miR-132) that targets cytokines and transcription factors involved in anti-inflammatory T cell responses (Foxp3 and TGF-β). MiR-31 regulates the expression of Foxp3 with increase of CD4+ Foxp3+ regulatory T cells (Tregs) | TNBS-induced colitis in mice | Alrafas HR, et al. (2020) [176] |
| Resveratrol (an anti-oxidant) | Anti-inflammatory activity | HDACs inhibition | T cells | Inhibits HDACs, increases anti-inflammatory CD4+ FOXP3+ (Tregs) and CD4+ IL10+ cells, and decreases proinflammatory Th1 and Th17 cells | AOM and DSS-induced colitis in mice | Alrafas HR, et al. (2020) [175] |
| Chlorogenic acid (found in the coffee) | Anti-inflammatory activity | miR-155 | Macrophages | Downregulates miR-155 expression, inactivates the NF-κB/NLRP3 inflammasome pathway in macrophages and prevent colitis | DSS-induced colitis in mice; LPS/ATP-induced RAW264.7 cells | Zeng J, et al. (2020) [177] |
| Lonicerin (constituant of herb Lonicera japonica Thunb.) | Anti-inflammatory activity | H3K27me3 modification | Macrophages | Binds to enhancer of zeste homolog 2 (EZH2) histone methyltransferase, which mediate modification of H3K27me3 and promotes the expression of autophagy-related protein 5, which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation | DSS-induced colitis in mice and isolated colonic macrophages and IECs; bone marrow-derived macrophages | Lv Q, et al. (2021) [174] |
| Pristimerin (Pris), which is a natural triterpenoid compound extracted from the Celastraceae plant | Anti-inflammatory activity | miR-155 | Colonic mucosae | Pris may reduce DSS-induced colitis in mice by inhibiting the expression of miR-155 | Blood and colon tissue of IBD patients; DSS-induced colitis in mice | Tian M, et al. (2021) [202] |
| Cardamonin is a naturally occurring chalcone (majorly from the Zingiberaceae family incluging a wide range of spices from India) | Anti-inflammatory activity | Modulation of miR expression | Macrophages | Cardamonin modulates miR expression, protects the mice from DSS-induced colitis, decreases the expression of iNOS, TNF-α, and IL-6, and inhibited NF-kB signaling which emphasizes the role of cardamonin as an anti-inflammatory molecule | RAW 264.7 Cells (monocyte/macrophage-like cells); DSS-induced colitis in mice | James S, et al. (2021) [172] |
| Berberine | Anti-inflammatory activity | miR-103a-3p | IECs | Represses Wnt/β-catenin pathway activation via modulating the miR-103a-3p/Bromodomain-containing protein 4 axis, thereby refraining pyroptosis and reducing the intestinal mucosal barrier defect induced via colitis | DSS-induced colitis in mice; Caco-2 cells and human NCM460 cells | Zhao X, et al. (2022) [173] |