Table 1.

Impact of the microbiota on the epigenome in intestinal inflammation. AIEC, adherent-invasive Escherichia coli; CpG, cytosine–phosphate–guanine; DCs, dendritic cells; DNA, deoxyribonucleic acid; DNMT, DNA methyltransferase; DSS, dextran sulfate sodium; ETBF, Enterotoxigenic Bacteroides fragilis; HDAC, histone deacetylases; IECs, intestinal epithelial cells; IL, interleukin; KO, knockout; LPS, lipopolysaccharide; lncRNAs, long non-coding RNAs; MAP, Mycobacterium avium subspecies paratuberculosis; miR, micro-RNA; NF-κB, nuclear factor-kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; NOD2, nucleotide-binding oligomerization domain 2; PSC, primary sclerosing cholangitis; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TNBS, 2,4,6-trinitrobenzenesulfonic acid; UC, ulcerative colitis; WT, wild-type; ↑, increase; ↓ decrease.

Germ	Activity	Epigenetic Mechanism	Tissue/Cells	Mechanism	Model	Author
Commensal bacteria
Commensal bacteria	Anti-inflammatory activity	miR-10a	DCs	Negatively regulates host miR-10a expression, which contribute to the intestinal homeostasis maintenance by targeting IL-12/IL-23p40 expression	C57BL/6 (B6) mice	Xue X, et al. (2011) [125]
Commensal flora	Proinflammatory activity	miR-107	DCs and macrophages	Downregulates miR-107 expression, known to represses the expression of IL-23p19, thereby favouring IL-23 expression	IECs, lamina propria CD11c+ myeloid cells including dendritic cells and macrophages, and T cells; DSS-induced colitis in mice	Xue X, et al. (2014) [126]
Commensal bacteria	Anti-inflammatory activity	miR-10a	DCs	Inhibits human DCs miR-10a expression, which downregulates mucosal inflammatory response through inhibition of IL-12/IL-23p40 and NOD2 expression, and blockade of Th1/Th17 cell immune responses	Human monocyte-derived dendritic cells	Wu W, et al. (2015) [127]
Commensal microbiome-dependent (Bacteroides acidifaciens and Lactobacillus johnsonii	Anti-inflammatory activity	miR-21-5p	IECs	Commensal microbiome-dependent miR-21-5p expression in IECs regulates intestinal epithelial permeability via ADP Ribosylation Factor 4 (ARF4)	HT-29 and Caco-2 cells	Nakata K., et al. (2017) [128]
Cluster(s)
↓ of Bacteroidetes and ↑ of protective Firmicutes and Clostridia	Anti-inflammatory activity	miR-21	Colonic mucosae	Leads to miR-21 reduction, known to influence the pathogenesis of intestinal inflammation by causing propagation of a disrupted gut microbiota	WT and miR-21−/− mice	Johnston DGW, et al. (2018) [129]
Cluster enriched in Bacteroides fragilis	-	DNA methylation	Intestinal mucosa	Induces 33 and 19 significantly hyper-methylated or hypomethylated sites, including hyper-methylated signals in the gene body of Notch Receptor 4 (NOTCH4)	50 CD; 80 UC; 31 controls	Ryan FJ, et al. (2020) [130]
Cluster enriched in Escherichia/Shigella/Klebsiella and Ruminococcus gnavus	Proinflammatory activity	DNA methylation	Intestinal mucosa	Larger number of differentially methylated CpG sites (131 hyper- and 475 hypomethylated), including hypomethylation in CCDC88B (recently correlated with risk of CD) and Transporter 2 (TAP2), involved in genetic heterogeneity of CD
Cluster enriched in B. vulgatus	-	DNA methylation	Intestinal mucosa	Induces 23 hyper- and 18 hypomethylated sites, significant hyper-methylation was observed in the gene body of DNA Damage Regulated Autophagy Modulator 1 (DRAM1)
Specific germ
Adherent-invasive Escherichia coli (AIEC)	Proinflammatory activity	miR-30c and miR-130a	IECs	Upregulates levels of miR-30c and miR-130a in IECs (by activating NF-κB), reducing the levels of ATG5 and ATG16L1 and inhibiting autophagy, leading to increased numbers of intracellular AIEC and an increased inflammatory response	Cultured IECs and mouse enterocytes	Nguyen HT, et al. (2014) [115]
AIEC	Proinflammatory activity	let-7b	IECs	Instigates excessive mucosal immune response against gut microbiota via miR let-7b/TLR4 signaling pathway	WT and IL-10 KO mice; T84 cells	Guo Z, et al. (2018) [117]
AIEC	Proinflammatory activity	miR-30c and miR-130a	IECs	AIEC-infected IECs secretes exosomes that can transfer specific miRs (miR-30c and miR-130a) to recipient IECs, inhibiting autophagy-mediated clearance of intracellular AIEC	T84 cells	Larabi A, et al. (2020) [116]
Mycobacterium avium subspecies paratuberculosis (MAP)	Proinflammatory activity	miR-21	Macrophages	MAP upregulates miR-21 in macrophages, a change that results in diminished macrophages clearance ability and favours pathogens survival within the cells	THP-1 cells	Mostoufi-Afshar S, et al. (2018) [119]
Lactobacillus rhamnosus GG	Anti-inflammatory activity	miR-146a and miR-155	DCs	Induces a significant downregulation of miR-146a expression, a negative regulator of immune response, and upupregulation of on miR-155	Cultured DCs	Giahi L., et al. (2012)
Lactobacillus acidophilus	Anti-inflammatory activity	miRs	Colonic mucosae	L. acidophilus induce miRs expression	DSS-induced colitis in mice	Kim WK, et al. (2021) [131]
Faecalibacterium prausnitzii	Anti-inflammatory activity	HDAC1 inhibition	T cells	Inhibits HDAC1, promotes Foxp3 and blocks the IL-6/STAT3/IL-17 downstream pathway contributing to the maintain of Th17/Treg balance	IBD patients (n = 9) and healthy control (n = 6); DSS-induced colitis in mice	Zhou L, et al. (2018) [132]
Faecalibacterium prausnitzii	Anti-inflammatory activity	HDAC3 inhibition	T cells	Produces butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells	IBD patients; TNBS-induced colitis in mice	Zhang M, et al. (2019) [133]
Trichinella spiralis	Anti-inflammatory activity	miRs	T cells	Extra-vesicles-derived miR are involved in the regulation of the host immune response, including inflammation, including increase of Th2 and Treg cells	TNBS-induced colitis in mice	Yang Y, et al. (2020) [134]
Enterotoxigenic Bacteroides fragilis (ETBF)	Proinflammatory activity	miR-149-3p	T cells	Downregulates miR-149-3p, which play a role in modulation of T-helper type 17 cell differentiation (with increased number of T-helper type 17 cell contributing to intestinal inflammation)	ETBF cells	Cao Y, et al. (2021) [135]
Bacterial component
Roseburia intestinalis-derived flagellin	Anti-inflammatory activity	lncRNA	IECs	Flagellin induces p38-stat1 activation, activated HIF1A-AS2 promotor, induced HIF1A-AS2 (a lncRNA) expression in gut epithelium in a dose- and time-dependent manner. HIF1A-AS2 inactivates NF-κB/Jnk pathway and thus inhibits inflammatory responses	DSS/Flagellin-challenged mice; Caco-2 cells	Quan Y, et al. (2018) [124]
Roseburia intestinalis-derived flagellin	Anti-inflammatory activity	miR-223-3p	Macrophages	Flagellin inhibited activation of the NLRP3 inflammasome and pyroptosis via miR-223-3p/NLRP3 signaling in macrophages	DSS-induced colitis model in C57Bl/6 mice and the LPS/ATP-induced THP-1 macrophages	Wu X, et al. (2020) [123]
LPS	Proinflammatory activity	H3K4me1, H3K4me3, and H3K27ac histone	Macrophages	Increases H3K4me1, H3K4me3, and H3K27ac histone marks, particularly in genes associated with an inflammatory response such as IL-12a and IL-18	IL-10-deficient (Il10(−/−)) mice	Simon JM, et al. (2016) [136]
LPS and flagellin	Anti-inflammatory activity	miR-146	IECs	Stimulate miR-146a overexpression in IECs, induces immune tolerance, inhibiting cytokine production (MCP-1 and GROα/IL-8)	TNBS and DSS-induced colitis in mice	Anzola A, et al. (2018) [137]
LPS	Proinflammatory activity	lncRNA H19	IECs	Increases levels of H19 lncRNA in epithelial cells in the intestine. H19 lncRNA bound to p53 and miR (miR-34a and let-7) that inhibit cell proliferation (alters regeneration of the epithelium)	Intestinal tissues of UC patients and mice	Geng H, et al. (2018) [138]
LPS	Proinflammatory activity	miR-19b	IECs	LPS significantly induces cell inflammatory injury, downregulated miR-19b expression and activates NF-κB and PI3K/AKT pathway	Caco2 cells	Qiao CX, et al. (2018) [120]
LPS	Proinflammatory activity	lncRNA	Monocytes/macrophages	LPS promotes a downregulation of the lncRNA growth arrest-specific transcript 5 (GAS5), could mediate tissue damage by modulating the expression of matrix metalloproteinases	IBD patients (n = 25)	Lucafò M, et al. (2019) [139]
LPS	Proinflammatory activity	miR-215	Fibroblasts	LPS upregulates the expression of miR-215, increases oxidative stress in LPS-treated intestinal fibroblast by downregulating GDF11 (Growth differentiation factor 11) expression and activating the TLR4/NF-κB and JNK/p38 signaling pathways	CCD-18Co cells	Sun B, et al. (2020) [122]
LPS	Proinflammatory activity	miR-506 and DNMT1 modification	IECs	LPS inhibits miR-506, leading to reduced expression of anion exchange protein 2 and inositol-1,4,5-trisphosphate-receptor but was accompanied by a substantial increase in DNMT1 and SPHK1 (sphingosine kinase 1) expression. The enhanced levels of kinase SPHK1 resulte in upregulation of bioactive sphingosine-1-phosphate (S1P) which led to further activation of S1P-dependent signaling pathways. The net effect of these responses is severe inflammation	Patients with PSC, PSC with concurrent UC (PSC  +  UC), UC alone, and healthy controls (n  =  10 each); Caco2 cells	Kempinska-Podhorodecka A, et al. (2021) [140]
LPS	Proinflammatory activity	miR-497	Macrophages	Reduces miR-497, promotes the activation of NF-κB pathway and the release of cytokines	IBD patients, mice with colitis and LPS-treated RAW264.7 cells	Zhang M, et al. (2021) [121]