Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases

Table 3 Current therapeutic approaches in inflammatory bowel diseases focused on intestinal epithelial cells

Effects on IECs	Drug type	Drug name/approach	Mechanism of action	Ref.
Promotes physical barrier functions (by increasing proliferation and survival of IECs)	Anti-IL-22BP	Infliximab or adalimumab	Anti-TNF-α therapy may block the expression of IL-22BP, the endogenous inhibitor of IL-22 (IL-22 is known to promote IEC proliferation via STAT3 activation in ISCs)	[108-111]
	ER stress reducers	TUDCA, PBA	Reduce apoptosis by increasing protein folding capacity of ER	[112]
	Human recombinant EGF	Enema	Promotes proliferation and reduces apoptosis of ISCs	[113,114]
Promotes physical barrier functions (by promoting expression and assembly of TJ proteins)	Inhibitor of para-cellular permeability	AT-1001	Inhibits TJ disassembly by interfering with cytoskeletal rearrangement	[115]
	Vitamin D	Calcitriol, vitamin D3 analogue	Induces expression of TJ proteins and E-cadherin	[117,179]
	Sex hormone	Estradiol, diarylpropionitrile (estrogen receptor-β agonist)	Induces expression of TJ proteins (occludin, junctional adhesion molecule-A)	[118]
	AMPK activator	Metformin	Induces expression and assembly of TJ proteins via AMPK dependent pathway	[119]
Promotes biochemical barrier functions (by promoting mucus secretion or production)	PGE2 receptor (subtype EP4) agonist	KAG-308, AGN205203	Promotes mucus secretion and proliferation of goblet cells (Promotes proliferation and reduces apoptosis of IECs)	[120,123,145,180,181]
	Short chain fatty acid	Butyrate	Stimulates mucin production by HDAC inhibitor activity	[121,124]
	Recombinant anti-microbial peptide	Cathelicidin	Stimulates mucin production by MAPK dependent pathway	[122,182]
	Phosphatidylcholine (PC)	LT-02	Mucus component supplement for UC patients who have reduced PC in rectal mucus	[125,126,183]
Promotes biochemical barrier functions (by promoting anti-microbial peptide secretion or production)	TLR7 ligand	Imiquimod	Promotes anti-microbial peptide (defensin) production in IECs	[127]
	Probiotics	Escherichia coli Nissle 1917	Promotes anti-microbial peptide (defensin) production in IECs by NF-kB activation	[128,184]
Corrects innate immune barrier dysfunctions (by inhibiting the retention of T cells in inflamed site)	Gut specific anti-integrin	Etrolizumab (anti-β7)	Blocks the interaction between αEβ7 integrin on T cells with E-cadherin on IECs (Neutralizing antibody against integrin)	[129]

IECs: Intestinal epithelial cells; IL-22BP: Interleukin-22 binding protein; STAT3: Signal transducer and activator of transcription 3; ISCs: Intestinal stem cells; ER: Endoplasmic reticulum; TUDCA: Tauroursodeoxycholate; PBA: 4-phenyl butyrate; EGF: Epidermal growth factor; TJ: Tight junction; AMPK: Adenosine monophosphate-activated protein kinase; PGE2: Prostaglandin E2; EP4: Prostaglandin E2 receptor 4; HDAC: Histone deacetylase; MAPK: Mitogen activated protein kinase; UC: Ulcerative colitis; TLR7: Toll-like receptor 7; NF-kB: Nuclear factor kappa B; IECs: Intestinal epithelial cells.