Table.

Candidates for epithelial wound healing-targeted therapy in IBD

	Agent	Proposed mechanism of action+	Delivery / Formulation	Preclinical or Clinical Evidence	Example References
Growth factors, restitutive signals, and stem cells	EGF	Epithelial migration, proliferation, and survival through EGFR signaling	Enema	Induces clinical remission in 10/12 UC patients	[44, 48, 77]
	FGF10/KGF-2	Epithelial restitution through FGFR2	Systemic injection	Promotes healing of indomethacin-induced small-intestinal ulcerations in rats	[83]
	TFF3	Essential for epithelial restitution, but details of molecular mechanism unknown	Enema	Mild improvement in symptoms in a minority of 8 enrolled UC patients, comparable to mesalamine	[54]
	IGF-1	Epithelial cell proliferation and goblet cell regeneration through extracellular signal-related kinase (ERK) signaling	Systemic injection	Improved recovery from DSS-induced colitis in rodents	[80, 81]
	HGF	Epithelial proliferation	Systemic injection	Accelerated healing of inflammatory ulcers in rats	[78, 79]
	Mongersen	Migration of epithelial cells through inhibition of SMAD7 (i.e., potentiation of TGFbeta signaling) via antisense targeting	Oral	Clinical remission in ~50% of 83 enrolled CD patients receiving higher doses	[104]
	GB004	Epithelial integrin expression and migration through inhibition of prolyl hydroxylase, resulting in stabilization of HIF-1alpha	Oral	Accelerated wound closure in TNBS-induced colitis in rodents	[88]
	Organoids	Direct engraftment of new epithelium onto injured area	Enema or endoscopic	Improved outcomes in mice with DSS-induced colitis	[107]
Cytokine-inspired	Interleukin 10	Epithelial proliferation through Wnt-inducible signaling protein 1 (WISP1); design of IL-10 variants with specific receptor affinities	Systemic injection	Accelerates closure of biopsy-induced wounds in mice; specific IL-10 variants decouple anti- and proinflammatory signaling	[139, 140]
	Interleukin 2	Activation of Tregs and epithelial restitution	Low-dose systemic injection	Ameliorates DNBS-induced and DSS-induced colitis in mice	[142, 143]
	Interleukin 22	Epithelial wound closure through activation of STAT3	Local gene delivery; treatments with variants to specifically activate STAT3	Attenuates TCRalpha−/− colitis in mice; variants provide selective tissue healing without inflammation	[133, 134, 140]
	STAR2	Selective targeting of TNF receptor 2 to promote colonic epithelial proliferation in injury	Systemic injection	Ameliorates graftvs-host disease in mice	[145, 148]
	IL-36R ligands	Epithelial proliferation and secretion of antimicrobial proteins	Local submucosal injection	Accelerates ulcer closure in biopsy-induced wounds in mice	[132]
	Rivenprost (ONO-4819CD)	Selective activation of EP4 prostaglandin receptor involved in adaptive differentiation of wound-associated epithelia	Intravenous	Improved histological score in 4 UC patients	[27, 55]
Microbe-derived	Butyrate	Promotes epithelial tight junction integrity	Enema	Reduces stool frequency and endoscopic score in trial with 10 UC patients	[50, 51, 53]
	p40 protein from Lactobacillus rhamnosus GG	Activates host EGFR signaling for wound healing	Oral delivery of p40 on hydrogel bead system	Improved preclinical outcomes and epithelial cell survival in DSS-induced and oxazolone-induced murine colitis	[173]
	Faecalibacterium prausnitzii	Preserves epithelial stem cell pool, proliferation, and barrier function	Intragastric delivery of F. prausnitzii strain A2–165	Protects murine colons from radiation-induced damage	[176]
	Microbiome purine reconstitution	Epithelial cell metabolism, proliferation, and mucin secretion	E. coli K12	Monocolonized mice are resistant to DSS-induced colitis compared to germ-free	[174]
	VSL #3	Treatment of dysbiosis	Lactobacilli (4 strains), Bifidobacteria (3 strains), Streptococcus thermophilus	Remission in ~40% of 77 enrolled UC patients	[177, 178, 185]

⁺Agents can have multiple mechanisms of actions complementing their wound healing activity; only the wound healing-relevant mechanism is listed here.