Table 1.

Summary of genetic and epigenetic factors and their mechanisms in intestinal fibrosis.

Genetic and Epigenetic Factors	Site of Action	Role in Fibrosis
NOD2 (nucleotide-binding oligomerization domain-containing 2)	Is expressed, e.g., in goblet cells, Paneth cells, enterocytes; immune system cells present in the lamina propria; monocytes, macrophages, and dendritic cells [37]	Shifting T lymphocytes toward the production of tissue growth factor beta (TGF-β) cytokines and increasing the deposition of collagen by smooth muscle cells and fibroblasts in the intestine [37] Reduced expression of alpha-defensin in the mucosa [37] Carriers of the 1007fs variant are at risk of intestinal stenosis; the 007fs variant is associated with impaired interleukin-1b production and dendritic cell function [37]
TGF-β (transforming growth factor β)	Can be found in all tissues and can be produced or released by infiltrating cells such as lymphocytes, monocytes/macrophages, and platelets after wounding or inflammation [103]	TGF-β1-directed epithelial–mesenchymal transition [47] Altered Smad3 transduction protein activity and elevated Smad7 levels as a result of impaired TGF-β1 signaling [48] Induction of myofibroblast accumulation by promoting EMT and Endo-MT [47] Increasing the proliferation of myofibroblasts and making them resistant to apoptosis [47] Myofibroblasts promote fibrosis by inducing collagen and MMP under TGF-β simulation [47] ECM remodeling by increasing TIMP expression [47]
TLRs (toll-like receptors)	Are expressed in myeloid cells [37]	Increased expression of TLR4 in cells of the ileal crypt [50]
Il23R (interleukin 23 receptor)	Is highly expressed on the cell membrane of memory T cells and other immune cells such as monocytes, natural killer cells, and dendritic cells [37]	The association of IL23R variants with CD and UC inflammation was observed [37]
ATG16L1 (autophagy-related 16-like 1)	Is expressed in intestinal epithelial cells, as well as in macrophages and leukocytes [104]	Impairment of autophagic function and anti-inflammatory activity (possibly reduced ability to generate a specific type of macrophage (Mφind) [37] Stimulation of mesenchymal cells to produce large amounts of collagen and other fibrogenic particles [37] Changing the reactions of immune cells to bacterial components [37] Variant T300a increases the production of cytokines driven by NOD2 [37]
DNA (deoxyribonucleic acid) methylation	It occurs primarily occurs on CpG dinucleotides, with most CpGs concentrated in CpG islands [73]	Specific gene hypermethylation and general methylation alterations have been observed in organs during IBD [75,76,77] Differentially methylated position (DMP) (cg16176675) was found to be significantly hypermethylated in patients with IBD [81] DNA methylation abnormalities in the intestinal mucosa were identified in the HLA-DRB1, YPEL5, and CBLB genes in CD patients [82,83]
Histone modifications	Histones	H3K27me3 can potentially control the outer follicles for the regulation of Th17 in patients with UC [91] The silencing of SETD8 regulates the expression of the p62 protein, thereby blocking the inflammatory response of the colon. SETD8 could potentially be used as a therapy for patients with IBD in the future [92] Protein arginine methyltransferase (PRMT) exhibits [94]
RNA (ribonucleic acid) interference	RNA	Increased expression of miR-21 in muscle cells and myofibroblasts in CD patients leads to continuous activation of TGF-β1 signaling, resulting in excessive production of collagen and extracellular matrix, leading to fibrosis [101] The Wnt-β-catenin signaling pathway is activated during intestinal fibrosis [102]