Therapeutic peptides in inflammatory bowel disease: From mechanistic rationale to clinical translation

Table 1 Potential peptide-based therapies in inflammatory bowel disease with current clinical data

Peptide	Class/mechanism	Route	IBD population	Highest evidence	Study design /n/comparator	Duration	Principal result	Evidence maturity/source
Anti-inflammatory peptides
Icotrokinra[48,49]	Selective IL-23 receptor antagonist; inhibits IL-23 mediated inflammatory signaling	Oral	Moderate-to-severe UC	Phase 2b human interventional study	Phase 2b randomized, double-blind, placebo-controlled, dose ranging RCT (n = 252). 100 mg, 200 mg or 400 mg daily vs placebo	Primary assessment 12 weeks. Exploratory follow up to week 28	All doses met week-12 endpoint (clinical response vs placebo). Clinical, endoscopic and biomarker responses persisted through exploratory week-28 analyses	Level 1: Human interventional. Conference abstract/trial reporting
K(D)PT[50-52]	Tripeptide derivative of α-melanocyte-stimulating hormone; anti-inflammatory and epithelial barrier-supportive effects	Oral	Mild-to-moderate UC	Phase 2a human interventional study	Multicentre phase 2a randomized double-blind, placebo-controlled RCT (n = 162). 20 mg, 50 mg or 100 mg twice daily vs placebo as add-on therapy	12 weeks	Pooled K(D)PT improved remission at weeks 2 and 4 and CAI response at week 8. Remission later converged with placebo because of a high placebo response	Level 1: Human interventional. Peer-reviewed
CGMP[53-55]	Bovine milk-derived glycopeptide; proposed anti-inflammatory, microbiome modifying and barrier-supportive effects	Oral	Active distal UC	Pilot human interventional study	Randomized open-label pilot study (n = 24). CGMP vs mesalamine escalation	4 weeks comparative treatment; follow-up to 8 weeks	At week 4, there were no significant between-group differences in SCCAI improvement or stability, with broadly similar changes in endoscopic disease extent and severity	Level 1: Human interventional. Peer-reviewed
Barrier protective and mucosal healing peptides
GLP-1 receptor agonists (e.g., semaglutide, liraglutide, dulaglutide, exenatide)[96,99,100]	GLP-1 receptor agonist; proposed anti-inflammatory and intestinal barrier-supportive effects, alongside established metabolic actions	Subcutaneous	UC and CD. Predominantly concomitant T2DM and/or obesity	Human observational evidence	Multiple retrospective studies. Largest cohort (n = 3737). Exposed vs non-exposed with adjustment	Longitudinal follow-up; study dependent	GLP-1 agonist exposure was associated with lower composite risk of hospitalisation, surgery, steroid dependence, treatment escalation, mortality	Level 3: Human observational. Peer reviewed observational studies/systematic review
Teduglutide[108-110]	GLP-2 analogue; promotion of intestinal epithelial growth, repair and barrier integrity	Subcutaneous	Moderate-to-severe CD	Phase 2 human interventional study	Pilot randomized, double-blind, placebo-controlled, dose-ranging (n = 100). Teduglutide vs placebo	8 weeks placebo-controlled treatment; optional 12-week extension	Greater clinical remission and response compared to placebo; differences were not statistically significant	Level 1: Human interventional. Peer-reviewed
EGF[111-113]	Growth-factor peptide; promotes epithelial restitution, proliferation and mucosal healing	Topical enema	Mild-to-moderate left sided UC or proctitis	Human interventional RCT	Randomized, double-blind, placebo-controlled RCT (n = 24). EGF vs placebo in conjunction with oral mesalamine	14 days treatment; follow-up to 12 weeks	Week-2 remission was more frequent with EGF than placebo; clinical, endoscopic and histologic outcomes also favoured EGF, with initial response maintained through 12 weeks	Level 1: Human interventional. Peer-reviewed
TFF3[111,112,114]	Intestinal repair peptide; promotes epithelial restitution, mucus integrity and mucosal barrier repair	Topical enema	Mild-moderate left-sided UC	Human interventional RCT	Randomized, double-blind, placebo-controlled RCT (n = 16). TFF3 vs saline placebo in conjunction with oral mesalamine	14 days treatment; follow-up to 12 weeks	No treatment benefit over placebo noted	Level 1: Human interventional. Peer reviewed

CAI: Colitis activity index; CD: Crohn’s disease; CGMP: Casein glycomacropeptide; EGF: Epidermal growth factor; GLP: Glucagon-like peptide; IBD: Inflammatory bowel disease; IL: Interleukin; RCT: Randomized controlled trial; SCCAI: Simple clinical colitis activity index; T2DM: Type 2 diabetes mellitus; TFF3: Trefoil factor 3; UC: Ulcerative colitis.