Mucosal healing and inflammatory bowel disease: Therapeutic implications and new targets

Table 1 Summary of inflammatory bowel disease therapeutics

Treatment type	Available therapeutics	Mucosal healing relevance/ Success
Corticosteroids	Prednisone/ Prednisolone/ Methylprednisone	Prednisone treatment for 14 d (20 mg/day) decreased mucosal inflammation indicating a possible role in developing short-term MH[139]. 29% of patients in one study displayed endoscopic remission after steroid treatment[140].
Nutritional therapy	Enteral nutrition (EN)/ Partial enternal nutrition (PEN)	EN/PEN induce MH in both adults and children[14].
Aminosalicylates (5-ASA)	Sulfasalazine/ Mesalamine/ Olsalazine/ Balsalazide	On average induce MH in 43.7% of patients[141].
Immunomodulators	Azathioprine/ 6-mercaptopurine	Azathioprine alone has achieved MH in 16.5% of cases and in 43.9% when used in combination with antibody therapies[18]. After 16 wk of mercaptopurine treatment, patients in remission showed a 47.1% rate of MH[142].
	Cyclosporine	Shown to induce MH when used in conjunction with Vendolizumab[143].
	Tacrolimus	Shown to induce MH when used in conjunction with Vendolizumab[143].
	Methotrexate	After 36 wk, methotrexate treatment had a MH rate of 47.4%[142].
Monoclonal antibody/ Biologic therapies	Adalimumab	Induced MH in 24% of patients treated[24].
	Certolizumab	Clinical response rate at weeks 2 and 12 was 29.7% and 52.8% (respectively) in CD[25].
	Infliximab	Treatment induced MH in up to 60.3% of patients in phase 2 clinical trials[23].
	Natalizumab	MH achieved by 42.3% of patients after 14.1 mo of treatment[144].
	Risankizumab-rzaa	Endoscopic response and deep remission observed in 55% and 29% of patients (respectively), indicating MH[27].
	Ustekinumab	Treatment of individuals with moderate to severe CD showed MH via a reduced disease score after 8 wk[19].
	Vedolizumab	Has shown to induce MH in up to 50% of UC patients and 29% of CD patients in clinical trials[26,27].

MH: Mucosal healing; EN: Enteral nutrition; PEN: Partial enteral nutrition; 5-ASA: Aminosalicylates; CD: Chron’s Disease; UC: Ulcerative colitis.

Table 2 Summary of molecular pathways involved in mucosal healing

Pathways/ Mechanism of action	Associated models studied	Ref.
EGFR signaling	In vitro, colorectal cancer mice, EGFR mutant mice	[43,116]
Hippo/YAP signaling	In vitro, YAP-1 transgenic mice	[36,59]
Notch signaling	Villin-Claudin-1 transgenic mice	[41,42]
Wnt/β-catenin signaling	In vitro and In vivo models of injury/repair	[44,60,61]
Vitamin D receptor (VDR) signaling	In vitro, VDR knockout mice	[45]
Src/focal adhesion kinase	In vitro, Mechanical colonic wound in mice, Nox1 and AnxA1 knockout mice, oral gavage in mice	[76-78]
Autophagy/ATG16L1	Patient biopsies; ATG16L1 T300A knock-in mice; Atg5-manipulated mice	[6,7,104]
SCFA-mediated signaling [acetate, propionate, butyrate, etc.]	In vitro, Patient biopsies, oral gavage in mice. T-cell induced colitis, trinitrobenzenesulphonic acid (TNBS) colitis	[83-85,91,93,100,101,114]
TLR-mediated signaling	DSS colitis	[109,110,112]
MyD88 mediated bacterial sensing	Mechanical colonic wound, MyD88 knockout mice	[111]
Prostaglandin-endoperoxidase synthase 2 enzyme (PGE2)	In vitro, mechanical colonic wound, Ptgs2 knockout mice, Ptger4 knockout mice	[111,112]
Mucin 2 signaling	In vitro, DSS colitis, EGFR mutant mice	[80,116]
IL-6/IL-22/IL-23/STAT3 signaling	DSS colitis, Th2-mediated colitis, cytokine deficient mice, bone marrow transplant mice, T-cell induced colitis, human and mouse intestinal organoid culture	[94,97,98,136-138]
TGF-β signaling	In vitro, DSS colitis, TGF-β transgenic mice	[50,130,131]
IL-10 signaling	In vitro, mechanical colonic wound in mice, IL-10-deficient mice	[132,133]

EGFR: Epidermal growth factor receptor; YAP: Yes-associated protein 1; ATG16L1: Autophagy related 16 like 1 protein; Atg5: Autophagy related 5; SCFA: Short chain fatty acid; TNBS: Trinitrobenzenesulphonic acid; TLR: Toll-like receptor; DSS: Dextran sodium sulfate; PGE2: Prostaglandin-endoperoxidase synthase 2 enzyme; IL: Interleukin; STAT3: Signal transducer and activator of transcription 3; TGF-β: Transforming growth factor-β.