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

Abstract

Although therapeutic advancements have transformed treatment of inflammatory bowel disease (IBD), many patients fail to achieve a durable corticosteroid-free remission, highlighting an apparent therapeutic ceiling. This has prompted interest in novel treatment strategies that target pathways not yet fully addressed by existing therapies. Therapeutic peptides represent an emerging and mechanistically diverse class of agents with potential applications in IBD. Occupying an intermediate space between small molecules and biologics, peptides offer theoretical advantages including high target specificity, structural adaptability, capacity to modulate protein-protein interactions and relatively predictable metabolism. This narrative review summarises the rationale for the development of therapeutic peptides in IBD and evaluates key candidates across major mechanistic classes including anti-inflammatory, antimicrobial and barrier supportive peptides. Although preclinical findings and early clinical data are encouraging, substantial barriers to translation remain, including limited stability and bioavailability, delivery challenges, manufacturing complexity, incomplete long-term safety and efficacy data and regulatory considerations. Well-designed clinical trials are therefore required to establish efficacy, safety and optimal positioning of peptide-based therapies within existing treatment paradigms. Therapeutic peptides are unlikely to replace established therapies in the near term but may ultimately complement current IBD management by targeting additional disease pathways and expanding the therapeutic armamentarium.

Key Words: Peptides; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Drug delivery; Translational medicine

Core Tip: Therapeutic peptides represent a promising but still largely unproven class of agents in inflammatory bowel disease (IBD). Therapeutic peptides offer potential advantages over small molecules and biologic therapies and may provide clinicians with novel therapeutic options for IBD. This review highlights the rationale for peptide-based therapies in IBD, summarises key candidates across major classes of peptides and potential barriers to widespread use in IBD.

INTRODUCTION

Inflammatory bowel disease (IBD) refers to chronic relapsing and remitting inflammatory conditions of the gastrointestinal tract affecting over 6.8 million people globally[1], with incidence rising in both developed and developing countries[2]. IBD is primarily subdivided into Crohn’s disease (CD) and ulcerative colitis (UC) based on symptoms, disease location and histologic characteristics[3].

The pathogenesis of IBD is likely multifactorial, arising from a complex interplay between genetic susceptibility and environmental exposures, which together promote gut microbial dysbiosis, disruption of the intestinal epithelial barrier followed by dysregulated innate and adaptive immune responses[4,5]. This complex pathophysiology provides several opportunities for targeted therapeutic intervention and disease modification.

Historically, management of IBD has prioritised clinical remission, with a step-up approach to treatment escalation following disease flare[6,7]. This therapeutic paradigm is shifting to target deeper remission with endoscopic healing and normalisation of inflammatory parameters, with a move to treat-to-target and top-down therapy in patients who are identified at high risk of disease complications[7,8]. Despite the expansion and optimisation of advanced therapies, a substantial proportion of patients do not achieve durable corticosteroid-free remission because of primary non-response or secondary loss of response to treatment. Treatment intolerance, safety considerations and limitations in access further reduce overall effectiveness in clinical practice. Collectively, these factors contribute to a persistent gap between current treat-to-target objectives and achievable long-term disease control, representing a possible therapeutic ceiling[9].

In this context, there is increasing interest in novel therapeutic approaches to raise the efficacy of therapies, either through combining existing advanced therapies or adding novel adjuncts or classes of drugs[9]. Therapeutic peptides represent one such emerging class. Peptides are short chains of amino acids that can be engineered to have antimicrobial, anti-inflammatory, metabolic, immunomodulatory and structural functions[10]. Advances in peptide chemistry, molecular engineering and drug delivery have driven rapid development of peptide-based therapies across a broad range of clinical applications, including potential use in IBD[11].

Alongside scientific interest in peptide therapeutics, several investigational peptides have gained substantial public and social media attention outside of conventional clinical pathways, including through unregulated ‘grey-market’ suppliers[12-14]. Although many such products have not been investigated specifically in IBD, patients may nevertheless encounter claims regarding gastrointestinal, anti-inflammatory or tissue repair benefits. It is therefore important that clinicians caring for patients with IBD are familiar with the potential therapeutic role of peptides, as well as their inherent advantages, limitations and safety considerations.

With the rapid expansion of this field, there is a need for an updated, clinically oriented appraisal of therapeutic peptides that distinguishes mechanistic promise from direct human evidence and considers the practical barriers to translation. This narrative review evaluates therapeutic peptide candidates across anti-inflammatory, antimicrobial and barrier-restorative mechanisms, with particular emphasis on evidence maturity, clinical readiness, safety and regulatory considerations. In doing so, we aim to provide a translational framework for assessing which peptide strategies are most likely to progress from experimental models toward meaningful clinical evaluation in IBD. This focus distinguishes the present review from recent related work. Existing reviews have considered therapeutic peptides in digestive inflammation broadly[10], the chemistry of peptide-based therapeutic and delivery strategies[15], smart oral delivery systems for IBD[16], and the wider pipeline of gut-restricted oral therapies, of which peptides form only one component[17]. In contrast, the present review is restricted to peptide therapeutics in IBD, applies an explicit evidence maturity classification to every candidate discussed, and separates direct human evidence in IBD from indirect, observational and preclinical data, so that claims of therapeutic promise can be weighed against the strength of the data supporting them.

SEARCH STRATEGY

A narrative literature review was undertaken to identify relevant studies examining therapeutic peptides in IBD. PubMed was searched on 1^st May 2026 using a combination of keywords and Medical Subject Headings related to IBD and peptide-based therapies including “inflammatory bowel disease”, “Crohn’s disease”, “ulcerative colitis”, “therapeutic peptides”, “peptide therapy”, and names and mechanisms of action of specific peptide candidates identified during the review process (including abbreviations of such). A representative search strategy was: (“inflammatory bowel disease” OR “Crohn’s disease” OR “ulcerative colitis”) AND (“peptide” OR “therapeutic peptide” OR “peptide therapy”). Additional targeted searches combined IBD terms with names, abbreviations and mechanisms of action of individual peptide candidates identified during the review. Reference lists of relevant articles were also screened to identify additional studies of interest. The literature search was updated in June 2026. Given the scope of this review, studies were prioritised based on relevance to peptide use in IBD. Human interventional studies were prioritised where available followed by observational human studies, animal models and in vitro studies. Regulatory documents and trial registries were assessed where relevant to determine safety, regulatory status and ongoing clinical development for peptide candidates. Conference abstracts were considered where peer-reviewed data were unavailable. Given the narrative design of this review, study identification and selection were not performed according to formal systematic review methodology and incomplete retrieval or selective citation remains a potential limitation.

To allow transparent comparison between candidates at very different stages of development, each agent discussed in this review has been assigned an evidence maturity level, which is applied consistently in the narrative and in Table 1. Level 1 denotes human interventional evidence, comprising randomized or otherwise controlled clinical trials conducted in patients with IBD. Level 2 denotes indirect human interventional evidence, comprising early-phase human pharmacology studies or interventional data derived from conditions other than IBD. Level 3 denotes human observational evidence, comprising retrospective, cohort or case-control studies in patients with IBD. Level 4 denotes preclinical evidence only, comprising in vitro studies and animal models of colitis. For each candidate, the source of the supporting data is additionally identified as peer-reviewed, conference abstract, or regulatory and trial registry material, because publication status materially affects the confidence that can be placed in a reported result. Table 1 is restricted to candidates for which human data are available; agents supported only by experimental data are identified as Level 4 within the text.

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.

CURRENT THERAPEUTIC LANDSCAPE AND UNMET NEED IN IBD

The therapeutic landscape for IBD has expanded considerably over the last two decades. Available pharmacological therapies can be broadly categorized into three major groups: Conventional therapies, biologic therapies and small molecules.

Conventional therapies include non-specific agents that reduce inflammation and immune activation, such as corticosteroids[18], 5-aminosalicylic acid compounds[19,20] and immunomodulators such as thiopurines and methotrexate[21].

Advanced therapies comprise biologic agents and small molecules. Biologic therapies refer to monoclonal antibodies that bind receptors on the cell surface and act through two major mechanisms. The first involves the inhibition of pro-inflammatory cytokines which play central roles in the initiation and propagation of intestinal inflammation, including tumour necrosis factor (TNF)[22], interleukin (IL)-12 and IL-23[23]. Anti-TNF agents include infliximab, adalimumab, golimumab and certolizumab, while IL-targeted therapies include ustekinumab, risankizumab, guselkumab and mirikizumab. The second mechanism involves targeting lymphocyte trafficking. Integrins are cell-surface glycoprotein receptors involved in lymphocyte adhesion and migration. Vedolizumab inhibits α4β7 integrin binding to mucosal cell adhesion molecules in the intestine, thereby preventing lymphocyte migration into gut tissue and limiting intestinal inflammation[24].

Small molecules represent the third major therapeutic group and act intracellularly predominantly through two mechanisms. First, JAK inhibitors, including tofacitinib, filgotinib and upadacitinib, inhibit intracellular signaling pathways responsible for downstream transduction of inflammatory cytokine signals, thereby reducing cytokine-mediated immune activation[25]. Second, S1P receptor modulators, including ozanimod and etrasimod, limit lymphocyte egress from lymphatic tissue into the systemic circulation, thereby reducing lymphocyte trafficking to sites of intestinal inflammation[26].

There is now growing preference for upfront use of advanced therapies as opposed to step-up therapy and treatment targets have changed from primarily clinical response to aiming for deeper remission with endoscopic and histologic healing, particularly in individuals with moderate to severe IBD, given the limited response to conventional therapies and potential for adverse events[27,28]. Despite attempts to optimise the use of advanced therapies, a substantial proportion of patients experience primary non-response and secondary loss of response to these treatments, with up to 60% of patients unable to achieve a durable corticosteroid free remission[9,29,30]. In addition, adverse effects or treatment-limiting safety concerns further limit the efficacy of these treatments. This persistent therapeutic ceiling has prompted interest in alternative and adjunctive strategies capable of targeting pathways not fully addressed by current treatments. Peptide-based therapies represent one such emerging class, with potential to address this unmet need for novel treatment strategies.

THERAPEUTIC PEPTIDES: BRIDGING SMALL MOLECULES AND BIOLOGICS

Physicochemical properties of therapeutic agents

Peptides are short chains of amino acids linked by amide bonds typically up to 50 residues in length, with a molecular weight often between 500 Daltons to 5000 Daltons[31]. Therapeutic peptides, or peptide-based drugs, possess properties intermediate between those of small molecule drugs and biologic therapies and share some key advantages associated with both classes of therapies (Table 2).

Table 2 Comparison between therapeutic peptides, small molecules and biologics.

	Therapeutic peptides	Small molecule drugs	Biologics
Advantages	High affinity binding	High oral bioavailability	High affinity binding
	High specificity	High membrane permeability	High specificity
	Modulate protein-protein interactions without well-defined binding pocket	High gastric stability	Minimal off-target effects
	Wide range of targets	Lower manufacturing costs
	Predictable degradation products	Low immunogenicity
	Minimal off-target toxicities
	Low immunogenicity
Weaknesses	Low oral bioavailability	Risk of off-target effects	Requires parenteral administration
		Require a well-defined binding pocket
	Short half-life & rapid serum clearance		High immunogenicity-risk of anti-drug antibody formation
	Low membrane permeability		Low membrane permeability
	Low gastric stability		High manufacturing costs

Small molecule therapy

Small molecule drugs are low molecular weight compounds, typically less than 500 Daltons, with relatively simple chemical structures, so many are able to withstand gastric metabolism and passively diffuse across cell membranes, enabling effective oral absorption[32]. Their simple structure also makes them relatively easy to manufacture compared with larger agents such as monoclonal antibodies[33]. Furthermore, because they are generally below the immunogenic threshold, small molecules are associated with lower risk of immunogenicity and allergic reactions[34]. The therapeutic potential for small molecules relies on well-defined binding pockets to exert their biological effects. This limits their ability to modulate protein-protein interactions, which often involve broad, shallow and dynamic interaction surfaces, thereby restricting their applicability across certain therapeutic targets[11].

Biologic therapy

Biologic therapies are large, complex molecules derived from living systems, most commonly monoclonal antibodies or fusion proteins, with molecular weights substantially greater than those of small molecule drugs[33]. Their size and structural specificity allow high-affinity binding to extracellular targets, including cytokines, cytokine receptors and cell surface molecules, with minimal off-target effects. This has made biologics particularly useful in immune-mediated diseases such as IBD, where they can selectively inhibit key inflammatory pathways. However, their large molecular size limits membrane diffusion, and their complex structure makes biologics susceptible to gastrointestinal degradation[35]. As such, biologics require parenteral administration, limiting their ease of use and patient acceptability. The complex structure and reliance on recombinant manufacturing also contribute to higher production costs[31]. Finally, biologics are highly immunogenic, leading to anti-drug antibody formation and associated allergic and infusion reactions[36].

Therapeutic peptides

Therapeutic peptides combine several favourable properties of both small molecules and biologics. Like biologics, peptides can be designed to bind therapeutic targets with high affinity and specificity. Unlike small molecules, therapeutic peptides can also engage broad, relatively flat protein-protein interaction surfaces without requiring a well-defined binding pocket, often by mimicking endogenous protein motifs[11], increasing the number of possible therapeutic targets. However, most unmodified peptides exhibit poor membrane permeability and limited intracellular access, restricting their application predominantly to extracellular targets[11,32]. As peptides are composed of amino acids, their degradation products are generally predictable and may be associated with fewer off-target toxicities when compared with the metabolism of small molecule drugs. In addition, their smaller size may confer lower immunogenic potential than larger biologic therapies, reducing the risk of anti-drug antibody formation[34].

Strategies to improve peptide stability and delivery

A key advantage of small molecules is their suitability for oral delivery. By contrast, oral delivery has historically been a major limitation for therapeutic peptides and biologics. Peptides are susceptible to enzymatic and chemical degradation within the gastrointestinal tract and generally exhibit poor membrane permeability resulting in low oral bioavailability[37]. Following absorption or parenteral administration, many peptides also exhibit short systemic half-lives because of rapid glomerular filtration and enzymatic degradation within the circulation and peripheral tissues. These processes can result in low or variable systemic exposure, necessitate frequent or higher dosing and make it difficult to maintain therapeutic concentrations[38,39]. Aggregation and poor solubility may further affect formulation stability, dose consistency and bioavailability[40,41]. Collectively, these properties have complicated the development of peptide-based therapies[42].

Strategies to overcome these limitations broadly involve molecular engineering and formulation-based delivery approaches. Backbone modifications, including amino-acid substitution with D-amino acids or non-natural amino acids and N-methylation, can reduce protease recognition and improve stability. Terminal modification and peptide cyclisation and stapling can further protect against enzymatic cleavage and stabilise the bioactive conformation[11,38,43,44]. Conjugation strategies, including lipidation, PEGylation, glycosylation and fusion to albumin or immunoglobulin Fc domains, may prolong systemic exposure and serum half-life by increasing molecular size, promoting albumin binding or utilising receptor-mediated recycling. Modern peptide therapeutics increasingly combine several of these modifications to optimise stability, permeability and pharmacokinetics while preserving biological activity[11,43,44].

Formulation-based approaches aim to protect peptides during gastrointestinal transit and facilitate their absorption across the intestinal mucosa. Enteric coatings, emulsions, nanoparticles and liposomes can shield encapsulated peptides from acidic conditions and enzymatic degradation while enabling site-specific or controlled release[32]. Surface-modified nanoparticles may also improve mucus penetration and promote uptake into the intestinal epithelium, whereas mucoadhesive systems and hydrogels can prolong residence at the intestinal mucosa and maintain a local concentration gradient to enhance absorption. These carrier systems may be combined with protease inhibitors or permeation enhancers that transiently increase epithelial permeability[38,43,44]. Oral semaglutide provides an important example of successful clinical translation. It is co-formulated with the absorption enhancer salcaprozate sodium, which provides local buffering of the gastric environment, reducing pepsin-mediated degradation and promoting transcellular absorption across the gastric epithelium[45].

Recent delivery strategies have also focused on targeting peptides to specific tissues or cellular populations. Active targeting approaches including cell-targeting peptides and ligand-functionalised nanoparticles, nanovesicles or liposomes that recognise receptors expressed on disease cells may allow more targeted release of peptides[43,44,46]. In IBD, pH-responsive coatings and enzyme-, microbiota- or inflammation-responsive carriers may exploit features of inflamed colonic and intestinal microenvironment to provide localised peptide release[16,17,46].

Collectively, these characteristics and advances in delivery provide a strong rationale for investigating therapeutic peptides in IBD. Their target specificity, biological compatibility and increasingly adaptable delivery have supported the development of a broad range of peptide-based therapies, which are discussed in the following sections.

MECHANISTIC CLASSES OF THERAPEUTIC PEPTIDES IN IBD

The pathogenesis of IBD is multifactorial and incompletely understood. It is postulated that, in those with genetic predisposition, disruption of the intestinal barrier and dysbiosis may promote inappropriate immune activation, leading to chronic inflammation and resultant intestinal injury[4,5,39]. These interconnected pathways provide multiple potential therapeutic targets for peptide-based therapies, including by targeting inflammation, the gut microbiome or promoting gut barrier function and healing[41]. These groups are described further below. Summary of peptide-based therapies with translational or clinical data can be found in Table 1.

However, the maturity of evidence varies substantially between these therapeutic classes. Most candidates are supported predominantly by in vitro studies or chemically induced animal models of colitis, which do not fully reproduce the chronic, relapsing and heterogeneous nature of human IBD. Human evidence is limited to a small number of early-phase studies, frequently characterized by small sample sizes, short follow up, concomitant treatment and heterogeneous clinical endpoints. Accordingly, biological plausibility and efficacy in experimental colitis should not be interpreted as evidence of clinical effectiveness.

Anti-inflammatory peptides

Several anti-inflammatory peptide therapies are in development for the treatment of IBD. Among these, icotrokinra is among the most clinically advanced peptide candidates currently being evaluated specifically for IBD, with phase 2 data in UC and progression into phase 3 clinical development. However, these findings do not yet establish long-term efficacy, comparative effectiveness or safety in broader IBD populations. Other agents, including tripeptide K(D)PT and casein glycomacropeptide (CGMP), have shown encouraging preliminary signals in early clinical studies, although larger confirmatory trials are currently lacking.

Icotrokinra: Icotrokinra is a targeted oral peptide, currently being trialled for use in moderate to severe UC. It selectively antagonises the IL-23 receptor, inhibiting IL-23 mediated inflammatory signaling. In preclinical and phase 1 studies, icotrokinra demonstrated oral systemic activity with a serum half-life of 9 to 16 hours and reduction of IL-23 induced inflammatory signaling[47]. Preliminary results from the phase 2b ANTHEM-UC randomized, double-blind, placebo-controlled, dose-ranging trial of 252 patients with moderate to severe active UC, reported to date in conference abstracts, indicate that icotrokinra met the week 12 primary endpoint of clinical response across all evaluated doses (once daily doses of 100 mg, 200 mg and 400 mg)[48]. Compared to placebo, treatment was associated with reduction in inflammatory biomarkers, with reduction in C-reactive protein and faecal calprotectin (FCP), as well as reduction in IL-23 pathway cytokines and tissue inflammatory gene-expression signatures, with the greatest responses at the 200mg and 400mg once daily doses. There was improvement over placebo in secondary endpoints of endoscopic and histologic-endoscopic mucosal improvement scores, defined by Mayo endoscopic subscore and Geboes histologic criteria, with greater response at higher dose options, although these results did not all reach statistical significance. Exploratory week 28 data suggested sustained clinical, endoscopic and biomarker responses, supporting further evaluation in phase 3 trials[48,49]. Adverse event rates through week 28 were broadly similar between the icotrokinra and placebo groups. Overall, these results provide an encouraging phase 2 efficacy signal; however, the inconsistent statistical significance of secondary endpoints and exploratory nature of the week 28 findings mean that durable efficacy, safety and comparative effectiveness against other therapies remain to be established. Evidence for icotrokinra in IBD is therefore Level 1 (human interventional), although the supporting phase 2b results are currently reported in conference abstract form rather than as a full peer-reviewed publication.

K(D)PT: K(D)PT is a tripeptide derivative of the α-melanocyte stimulating hormone, which can be given orally and has demonstrated anti-inflammatory and epithelial barrier protective effects, including stabilisation of tight junction proteins and preservation of intestinal barrier integrity in experimental colitis models[50,51]. In a proof-of-concept phase 2a randomized double-blind, placebo-controlled trial of 162 adult patients with mild to moderate UC on 5-aminosalicylates, oral corticosteroids and/or azathioprine, patients treated with add on oral K(D)PT therapy demonstrated earlier remission compared to placebo, as defined by colitis activity index (CAI) ≤ 3, at weeks two and four. However, rates of CAI-defined remission converged at later time points, with no difference between placebo and all K(D)PT dose groups at weeks six, eight and 12. Due to high placebo response rates, the authors suggest that conditions for the statistical evaluation of time to sustained response were violated[52]. Although early benefit was noted with K(D)PT treatment, these findings require cautious interpretation. The early separation from placebo and absence of sustained separation in remission rates mean that the findings should be regarded primarily as hypothesis-generating. No confirmatory phase 3 trials have been reported, and further adequately powered studies incorporating contemporary clinical, biomarker, endoscopic and histologic endpoints are required to establish the therapeutic role of K(D)PT in UC. Evidence for K(D)PT in IBD is therefore Level 1 (human interventional), derived from a single peer-reviewed phase 2a trial.

CGMP: CGMP is a large bioactive peptide derived from bovine milk. Preclinical studies suggest that it may exert anti-inflammatory effects and modulate the gut microbiome, although human data in IBD remain limited[53,54]. In a small randomized open-label randomized pilot study, 24 patients with active distal UC-defined by a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3, FCP ≥ 200 mg/kg, a Mayo endoscopic subscore ≥ 1 and disease extending 10-40 cm from the anal verge were randomized to receive either adjunctive oral CGMP (30 g daily) or escalation of oral mesalamine to 4.8 g daily[55]. CGMP was well tolerated and associated with improvements in clinical disease activity, as measured by SCCAI, as well as endoscopic disease extent and severity. These improvements appeared comparable to those observed with mesalamine dose escalation. However, the small sample size, open-label design and absence of a placebo control preclude firm conclusions regarding efficacy and should not be interpreted as evidence of non-inferiority to mesalamine. No adverse events were reported in the study. Evidence for CGMP in IBD is therefore Level 1 (human interventional), derived from a single small peer-reviewed open-label pilot study without a placebo control.

Other anti-inflammatory peptides: Beyond these clinically studied peptides, several anti-inflammatory peptide candidates remain at an earlier stage of development. Vasoactive intestinal peptide (VIP), cortistatin-based peptides and hydrostatin-SN1 (H-SN1) and the Arthrospira platensis-derived peptide P1 have demonstrated immunomodulatory effects in vitro and in animal models of intestinal inflammation. VIP is a naturally occurring neuropeptide that has broad anti-inflammatory and immunomodulatory effects, impacting both the innate and adaptive immune systems[56]. VIP and its receptors are downregulated during intestinal inflammation, supporting a potential homeostatic role in mucosal immune regulation[57]. In IBD animal models, VIP has been shown to attenuate chemically induced colitis, with reductions in pro-inflammatory cytokine expression, improvement in histologic inflammation and preservation of epithelial barrier function[58]. However, therapeutic translation has been limited by poor stability of free VIP, with rapid systemic degradation. Nanomedicine-based delivery strategies have demonstrated improved efficacy over free VIP in murine colitis models[58]. Although lacking human data, VIP shows mechanistic potential as a peptide-based anti-inflammatory therapy for IBD. Evidence for VIP in IBD remains Level 4 (preclinical only).

Cortistatin is an endogenously produced neuropeptide structurally related to somatostatin that is expressed within the central nervous system as well as by innate and adaptive immune cells. Through its action on immune cell differentiation and activation, cortistatin appears to have broad immunomodulatory properties[59-61]. In preclinical murine models of colitis, cortistatin administration was associated with improved clinical symptoms, histologic features of inflammation, attenuated weight loss and improved survival, supporting its potential role as an anti-inflammatory peptide[62]. However, the therapeutic application of native cortistatin is limited by its poor serum stability. A more stable cortistatin analogue, A5, was subsequently developed and retained anti-inflammatory activity in vitro and in murine colitis models, with efficacy comparable to reference treatments within the experimental setting, including anti-TNF therapy[63]. These findings support cortistatin-based peptides as promising anti-inflammatory candidates in the management of IBD, although their therapeutic relevance has yet to be established in human studies and experimental models do not support equivalent efficacy in humans. Evidence for cortistatin-based peptides in IBD remains Level 4 (preclinical only).

H-SN1 is a peptide that is derived from snake venom from Hydrophis cyanocinctus and acts as a TNF receptor 1 antagonist. Given the established efficacy of anti-TNF therapy in IBD, H-SN1 has been investigated as a potential anti-inflammatory agent in both in vitro and in vivo models. Across two preclinical studies, H-SN1 suppressed TNF-α mediated inflammatory signaling and was associated with reduced disease activity and histologic features of inflammation in murine colitis models. These effects were accompanied by reduced pro-inflammatory cytokine expression and inhibition of TNF receptor 1 associated signaling at the messenger ribonucleic acid (mRNA) and protein levels[64,65]. Although H-SN1 remains at an early preclinical stage, its mechanism is therapeutically relevant. Selective TNF receptor 1 antagonism could potentially suppress proinflammatory TNF signaling while preserving potentially beneficial TNF receptor 2 mediated functions, thereby providing an alternative approach to non-selective TNF inhibition. However, this proposed advantage remains unproven, and clinical translation will require further evaluation of pharmacokinetics, peptide stability and the consideration of immunogenic potential of this toxin-derived peptide. Evidence for H-SN1 in IBD remains Level 4 (preclinical only).

P1 is a heptapeptide derived from the cyanobacterium Arthrospira platensis. In a recent DSS-induced murine colitis study, concurrent administration of P1 was associated with reduced disease activity and histologic injury, reductions in pro-inflammatory cytokine expression, oxidative stress, epithelial apoptosis and preservation of mucin and tight junction protein expression. Integrated transcriptomic and proteomic analysis implicated activation of PPARα/γ and suppression of NF-κB signaling[66]. However, these mechanistic findings remain associative, and P1 was administered during induction of acute colitis rather than as treatment for established disease. Given the small sample sizes for individual outcomes and absence of human data, P1 remains an early preclinical anti-inflammatory and barrier-supportive peptide candidate. Evidence for P1 in IBD remains Level 4 (preclinical only).

Together, these candidates highlight the spectrum of development in anti-inflammatory peptide therapies, ranging from clinically advanced targeted cytokine inhibition to early preclinical approaches that modulate immune activation, epithelial barrier function and inflammatory signaling. In the absence of direct comparative trials, their efficacy cannot yet be reliably compared with one another or with established IBD therapies. Although most remain distant from clinical translation, they may ultimately provide adjunctive or alternative strategies for controlling intestinal inflammation in IBD.

Antimicrobial peptides

The intestinal microbiome is increasingly recognized as a central regulator of intestinal function[67]. In the pathogenesis and progression of IBD, environmental exposures may alter the composition and function of the gut microbiota and disrupt the balance between commensal microorganisms and enteric pathogens. This dysbiosis can impair mucosal homeostasis, drive dysregulated immune activation and contribute to chronic intestinal inflammation and ongoing tissue injury[68,69].

Given the central role of host-microbe interactions, antimicrobial peptides may represent a therapeutically beneficial group in IBD. Antimicrobial peptides are naturally occurring peptides that form an integral arm of the innate immune system and are found across a diverse range of organisms[70]. In IBD, they may support host defence, limit microbial translocation, modulate intestinal dysbiosis and contribute to preservation of epithelial barrier integrity[71]. Although many antimicrobial peptides remain at early stages of development, they may have a role in the treatment of IBD. The broad classes of peptides in this group are defensins, cathelicidins and protease inhibitors.

Defensins: Human defensins, a class of antimicrobial peptides, have been described and are categorised into α- and β-defensins based on structural differences. They are expressed by neutrophils and at epithelial surfaces, including the skin and gastrointestinal mucosa. Within the gastrointestinal tract, defensins exert bactericidal effects through disruption of bacterial cell membranes and are thought to contribute to maintenance of commensal microbiota, prevention of bacterial overgrowth and limitation of bacterial translocation[72,73]. Aberrant expression of both α- and β-defensins have been reported in ileal and colonic CD and UC, suggesting that defensin-mediated host defence may reflect and contribute to IBD pathogenesis[72,74]. A human defensin-5 producing probiotic, NZ9000SHD-5, when given orally to a murine colitis model demonstrated significant reduction in histologic inflammatory changes and preservation of colonic barrier integrity, supporting possible novel therapeutic application in UC[75]. These early findings support the potential therapeutic relevance of defensin based IBD therapies. Evidence for defensin-directed strategies in IBD remains Level 4 (preclinical only).

Cathelicidins: Cathelicidins represent another major family of antimicrobial peptides, alongside defensins. LL-37, the only human cathelicidin, demonstrates possible direct antibacterial, antiviral and endotoxin-neutralising activity, in addition to immunomodulatory effects, including immune cell chemotaxis and modulation of chemokine responses[76]. In patients with UC, LL-37 mRNA expression is significantly increased in both inflamed and non-inflamed colonic mucosa[77]. In contrast, LL-37 expression does not appear to be altered within the ileum or colon of patients with CD, although circulating neutrophils demonstrate upregulation of LL-37, mirroring bacterial DNA concentrations[77,78]. These observational findings do not establish whether LL-37 expression has a protective or pathogenic role or whether it simply reflects mucosal inflammation. Nevertheless, preclinical animal studies suggest that cathelicidins, including mCRAMP (murine homologue of LL-37) and synthetic LL-37 analogues, may attenuate colonic inflammation and support mucosal healing, including through effects on mucin gene expression[79-81]. More recently, an orally administered bacteriocin transport-inspired platform combining LL-37 with a Lactobacillus probiotic within an alginate coating was evaluated in murine models including models of acute colitis and colitis-associated intestinal fibrosis. The formulation protected LL-37 from proteolytic degradation, enhanced intestinal retention and mucosal penetration and was associated with improvements in disease activity, histologic inflammation, epithelial barrier integrity and extracellular matrix deposition. LL-37 also demonstrated anti-fibrotic effects[82]. Although cathelicidin-based therapy has yet to reach clinical translation in IBD, its combined antimicrobial, immunomodulatory and barrier-supportive properties make it a biologically plausible therapeutic candidate, while engineered delivery platforms may help overcome the poor gastrointestinal stability and rapid clearance of orally administered LL-37. Evidence for cathelicidin-based therapy in IBD remains Level 4 (preclinical only), supported by Level 3 human observational data describing altered LL-37 expression in inflamed mucosa.

GPR15 L: GPR15 L is an endogenous host-defence peptide produced predominantly by colonic epithelial cells and is the ligand for the GPR15 receptor; a receptor involved in lymphocyte trafficking to the large intestine[83]. A recent preclinical study demonstrated that GPR15 L may protect against intestinal inflammation through selective antimicrobial activity, similar to that of defensins and cathelicidins, independent of GPR15-mediated T-cell recruitment[84]. Genetic deletion of Gpr15 L increased the severity of experimental colitis, whereas transgenic overexpression was protective. Under intestinal conditions, GPR15 L inhibited potentially pathogenic bacteria including Escherichia coli, Salmonella typhimurium and Enterococcus faecalis, while sparing several potentially beneficial commensal species. Importantly, rectal supplementation with recombinant GPR15 L in Gpr15 L-deficient mice reduced clinical, endoscopic and histologic disease activity and shifted the intestinal microbiome. In observational human cohorts, mucosal GPR15 L expression was reduced during active IBD flares, while higher expression in patients with UC in endoscopic remission was associated with longer flare-free survival. Although these findings support GPR15 L as a potential locally delivered antimicrobial peptide therapy, evidence remains limited to preclinical and observational studies. Further studies are required to establish efficacy and evaluate optimal delivery, dose-response, safety and effects on the human microbiome. Evidence for GPR15 L in IBD therefore comprises Level 4 preclinical data supported by Level 3 human observational findings, with no interventional human studies reported to date.

Serine protease inhibitors: Proteases have increasingly been recognized as important mediators in the chronic mucosal injury and inflammation seen in IBD. In active intestinal inflammation, proteases derived from neutrophils, epithelial cells and microbiota exceed endogenous anti-protease capacity, leading to intestinal barrier failure, increased permeability and amplification of mucosal inflammatory signaling[85]. Elafin, a serine protease inhibitor, is produced by intestinal mucosal cells, macrophages and neutrophils and is markedly upregulated in UC, demonstrating an inverse correlation with disease activity; higher elafin serum concentrations are associated with decreased inflammatory activity[86]. In murine colitis models, exogenous elafin appears to improve markers of intestinal inflammation, modulate gut microbiota and increase concentrations of beneficial short-chain fatty acids[87,88]. In addition to inhibition of neutrophil-derived serine proteases, elafin may also modulate microbial-driven inflammation by binding lipopolysaccharides and attenuating associated Toll-like receptor 4-mediated inflammatory signaling, which has previously been implicated in the pathogenesis of IBD[89-91]. Evidence for elafin in IBD therefore comprises Level 4 preclinical data alongside Level 3 human observational data, with no interventional human studies reported to date.

Barrier protective and mucosal healing peptides

Beyond direct anti-inflammatory and immunomodulatory action and antimicrobial activity, peptides have shown capacity to support intestinal homeostasis, barrier integrity, mucosal repair and healing. Disruption of the intestinal barrier is a pathogenic step in IBD, facilitating bacterial translocation, immune activation and persistent inflammation and injury[92]. Peptides that enhance epithelial healing, promote tight junction integrity, maintain the mucus barrier or support mucosal regeneration may represent a novel therapeutic approach in IBD.

Glucagon-like peptides

Glucagon-like peptides (GLP)-1 is an incretin hormone that is produced predominantly by enteroendocrine L cells. GLP-1 receptor agonists have entered widespread clinical use after revolutionising management of diabetes, obesity and associated metabolic diseases[93]. Their established clinical actions are principally metabolic and include stimulation of insulin secretion, suppression of glucagon release, delayed gastric emptying, appetite suppression and weight loss[94].

Beyond their metabolic actions, preclinical evidence suggests that GLP-1 receptor signaling may modulate pathways relevant to intestinal homeostasis. In experimental models, GLP-1 receptor agonist exposure has been associated with reduced epithelial injury, improved intestinal epithelial cell survival, altered intestinal microbial composition and reduction in proinflammatory cytokine expression including TNF-α and interferon-gamma[95]. These findings provide biological plausibility for a gut-directed effect, although they remain limited to in vitro and animal models, and do not establish that GLP-1 receptor activation directly suppresses intestinal inflammation in humans independent of weight loss, improvement in glycaemic control or other systemic metabolic changes.

Clinical evidence in IBD is currently limited to observational studies that have not been able to distinguish between direct intestinal activity and metabolic benefits. In a large retrospective study of 3737 patients with IBD and type 2 diabetes mellitus (T2DM), GLP-1 analogue use was associated with reduced risk of a composite adverse outcome including hospitalisation, surgery, steroid dependence, treatment escalation and mortality [adjusted hazard ratio of 0.74 (confidence interval 0.62-0.89)]. However, subgroup analysis demonstrated that this effect was primarily observed in patients with obesity (body mass index ≥ 30 kg/m²) and hospitalisation was the individual component of the composite outcome that was significantly reduced[96]. These findings suggest that at least part of the observed benefit may be mediated through weight loss, reduced visceral adiposity, improvement in metabolic health or attenuation of obesity-associated systemic inflammation. Obesity has been shown to influence IBD outcomes through chronic low-grade inflammation, intestinal dysbiosis, altered pharmacokinetics and treatment response, and increased perioperative risk[97,98].

In a recent case-control study, 580 patients with IBD treated with GLP-1 receptor agonists demonstrated lower rates of corticosteroid use, intestinal resection and mortality than matched controls, with similar findings in both UC and CD[99]. However, the study did not report on subsequent weight loss or changes in metabolic status, nor did it incorporate objective biochemical or endoscopic measures of intestinal inflammation. Consequently, these findings cannot establish a direct disease-modifying effect in IBD. These findings are broadly consistent with a recent systematic review investigating efficacy and safety of GLP-1 receptor agonists in immune-mediated inflammatory diseases, which included 20 IBD studies[100]. Although some studies reported lower rates of corticosteroid use, hospitalisation, surgery and IBD-related complications with GLP-1 use, most were retrospective, with substantial heterogeneity, overlapping database populations, variable definitions of IBD activity and limited objective inflammatory assessment. These limitations precluded meta-analysis and causal interpretation. Prospective trials incorporating objective inflammatory endpoints and analyses adjusted for achieved weight loss and metabolic improvement are required to determine whether GLP-1 receptor signaling modifies IBD activity independently of its metabolic effects. Evidence for GLP-1 receptor agonists in IBD is therefore Level 3 (human observational), and is derived predominantly from populations selected for coexisting T2DM or obesity rather than for IBD activity.

In IBD, malnutrition and sarcopenia are highly prevalent, affecting a large proportion of patients. While malabsorption and increased energy expenditure contribute to the development of malnutrition, reduced oral intake is a major determinant, driven by anorexia, symptom-related food avoidance and the use of restrictive dietary interventions[101]. In this context, GLP-1 analogues warrant careful consideration. By suppressing appetite and promoting weight loss, these agents may exacerbate existing malnutrition or sarcopenia in vulnerable patients with IBD, noting loss of both adipose tissue and lean muscle mass[102]. Clinicians should also consider the potential impact of GLP-1 analogues on concomitant IBD therapies. GLP-1 associated changes in body composition may alter drug pharmacokinetics through changes in volume of distribution and drug clearance. In addition, alteration to gastrointestinal transit may impact absorption and delivery of orally administered therapies such as modified release 5-aminosalicylic acid formulations[103]. Although the clinical significance of these interactions remains uncertain, they warrant consideration when initiating GLP-1 based therapies in patients with IBD.

GLP-2 is also a peptide hormone produced by enteroendocrine L cells, with barrier supportive effects on the intestinal mucosa[104]. GLP-2 modulates intestinal epithelial growth by stimulating proliferation and reducing apoptosis. It also aids digestion and nutrient absorption, improves mesenteric blood flow and supports epithelial barrier integrity through upregulation of tight junctions[105]. In preclinical models of both enteritis and colitis, GLP-2 and GLP-2 analogues attenuate intestinal injury, reduce inflammatory cytokine expression and improve histologic inflammation[106,107]. However, clinical evidence for GLP-2 analogues in IBD remains limited. Teduglutide, an injectable GLP-2 analogue, was evaluated in a phase 2 randomized controlled trial including 100 patients with moderate to severe CD, defined by CD Activity Index (CDAI) of 220 to 450 points, with the primary endpoint of remission (defined by CDAI ≤ 150 points) or response (defined by CDAI decrease by ≥ 100 points) at week eight. Although clinical remission and response rates were numerically higher with teduglutide than with placebo (12% over placebo in both), differences were not statistically significant. The largest numerical effect was observed with the highest dose of 0.2 mg/kg/day, with response rates of 44% vs 32% and remission rates of 32% vs 20% for placebo[108]. These findings should therefore be regarded as hypothesis generating rather than evidence of established efficacy. Interpretation is further limited by substantial participant attrition and reliance on symptom-based CDAI outcomes without contemporary biochemical, endoscopic or histologic measures of disease activity. At present, GLP-2 agonists remain largely used in the management of intestinal failure and short gut syndrome rather than inflammatory disorders such as IBD[109]. Furthermore, given the trophic effects of GLP-2 on intestinal mucosa, long-term use requires consideration of the potential impact on dysplasia risk and polyp surveillance, as well as possible implications in stricturing disease[110]. Overall, GLP-2 agonism may represent a barrier restorative adjunct to immune targeted therapies in IBD, although further clinical trials are required to define its therapeutic role. Evidence for teduglutide in CD is therefore Level 1 (human interventional), derived from a single peer-reviewed phase 2 trial that did not meet its primary endpoint.

Epidermal growth factor and trefoil factor peptides

Among barrier-protective peptides, epidermal growth factor (EGF) and trefoil factor (TFF) peptides are of particular interest due to their involvement in epithelial restitution, mucosal repair and maintenance of intestinal barrier integrity. EGF primarily stimulates epithelial cell migration, restitution and proliferation, while TFF peptides additionally support mucin layer integrity and intestinal tight junction expression[111,112]. A small randomized double-blind placebo-controlled trial of 24 patients with mild to moderate left sided UC was conducted. Patients were included with active left colitis, defined as St. Marks index ≥ 5 and with an endoscopic subscore of ≥ 1 and excluded if inflammation extended proximally to the splenic flexure, therapy change within 3 months or utilising topical or systemic corticosteroids. A 14-day course of daily EGF enemas, used as an adjunct to 5-aminosalicylic acid therapy (either commencement or dose escalation), were associated with rapid improvement in clinical and endoscopic endpoints in over 80% of patients, in comparison to placebo arm with only 8% of patients achieving the same endpoints. The initial response to EGF enemas was maintained at four and 12 weeks[113]. In a similarly designed randomized controlled trial including 16 patients with mild to moderate left sided UC, a 14-day course of daily TFF3 enema was not observed to provide additional benefit over commencement or dose-escalation of 5-aminosalicylic acid therapy. Due to lack of efficacy the study was discontinued[114]. Evidence for both EGF and TFF3 enemas in UC is therefore Level 1 (human interventional), in each case derived from a single small peer-reviewed randomized trial.

Despite their potential reparative benefits, proliferative agents such as EGF raise theoretical safety concerns, particularly regarding carcinogenesis, given that dysregulated EGF signaling is implicated in multiple malignancies and is therapeutically targeted in several cancers. Given their complementary roles in epithelial restitution, barrier repair and mucosal healing, combination TFF and EGF therapy may represent a promising approach, with such strategies theoretically enhancing reparative efficacy while reducing the need for higher dose proliferative stimulation, possibly reducing the safety concerns, although further studies are required to define both clinical benefit and long-term safety in IBD[115].

Overall, the evidence supporting therapeutic peptides in IBD remains heterogeneous and predominantly preclinical. Human evidence is limited to a small number of early-phase trials involving different disease phenotypes, routes of administration, concomitant therapies and outcome definitions, preventing meaningful indirect comparison between agents. No peptide candidate has yet demonstrated superiority or equivalence to established IBD therapies in an adequately powered active-comparator trial, and long-term safety data remain limited. Future clinical trials should be adequately powered, incorporate objective biochemical, endoscopic and histologic endpoints, assess corticosteroid-free durable remission and include sufficiently long follow-up to identify uncommon or delayed adverse effects.

TRANSLATIONAL, SAFETY AND REGULATORY CHALLENGES OF PEPTIDE-BASED THERAPIES

Although therapeutic peptides offer several theoretical advantages, including high target specificity, biologic versatility and capacity to modulate novel pathways not currently addressed by conventional IBD therapies, their translation into clinical practice is accompanied by important pharmacological, safety, production and regulatory challenges.

Despite advances in peptide engineering and delivery, achieving predictable and therapeutically meaningful peptide levels remains difficult. Most orally administered peptides have low and variable bioavailability, while reliance on parenteral administration may reduce patient acceptability, feasibility and long-term adherence[42]. Locally acting intestinal peptides may be less reliant on systemic bioavailability; however, their efficacy still requires reproducible delivery to, and sufficient retention at affected mucosal sites[32,116]. In IBD, variations in intestinal pH, transit time, mucus composition and epithelial integrity according to disease location and activity may further influence site-specific release, peptide stability and mucosal exposure[16,17]. Structural modifications and carrier systems may also alter receptor affinity, biological activity, tissue distribution and clearance, complicating dose selection and extrapolation from preclinical models.

Beyond these pharmacokinetic and delivery challenges, safety remains an important consideration. Therapeutic peptides may have advantages over both small molecules and biologic therapies, including relatively low immunogenic potential and degradation into generally predictable amino acid products[34]. Nevertheless, their safety profiles are incompletely characterized, particularly because many investigational candidates lack long-term human exposure data.

Although therapeutic peptides generally have lower immunogenic potential than larger biologic therapies, they are not inherently non-immunogenic. Immunogenicity is specific to each peptide and may be influenced by peptide sequence and structural modifications including non-native amino acids, conjugation, peptide aggregation or degradation, synthesis-related impurities, formulation characteristics, route of administration and repeated or prolonged exposure. Resulting anti-drug antibodies may be clinically silent but can alter peptide pharmacokinetics, reduce or neutralise therapeutic activity, or contribute to hypersensitivity reactions. For peptides with endogenous homologues, cross-reactive antibodies may also interfere with physiological function of the corresponding endogenous peptide[34,43,117].

Other safety considerations are likely to depend on the peptide’s mechanism of action. Anti-inflammatory peptides with immunomodulatory or immunosuppressive effects may increase susceptibility to infection, impair host defence or interfere with normal healing pathways. Conversely, antimicrobial peptides may have unintended effects on commensal microbiota, potentially disrupting host-microbe homeostasis, noting significant complexities that are unexplored in the importance and relevance of the gastrointestinal microbiome in physiological and pathological processes. Peptides that promote epithelial proliferation, angiogenesis or tissue repair also require long-term evaluation for potential effects on dysplasia, carcinogenesis, fibrosis and stricture formation. These risks remain largely theoretical for many candidates but are particularly relevant to chronic administration in a population already at increased risk of immune dysregulation, dysbiosis, intestinal neoplasia and fibrostenotic complications.

Delivery strategies designed to improve peptide stability, bioavailability, mucosal retention and tissue penetration may introduce platform-specific safety and quality considerations in addition to those associated with the peptide itself[118]. In the context of oral or locally acting peptide therapies for IBD, nanoparticle-, liposome- and advanced mucoadhesive-based formulations remain predominantly at the early translational stage[16,119,120]. Their clinical development requires careful evaluation of formulation complexity, manufacturing scalability and batch-to-batch consistency, stability and release kinetics, biocompatibility and immunogenicity of carrier materials[15,121,122]. Given the limited long-term human data regarding their use in chronic intestinal disease, future studies should evaluate the safety and efficacy of the therapeutic peptide and delivery platform as an integrated product before widespread clinical implementation.

The production and synthesis of therapeutic peptides represent further barriers to clinical translation. Although peptides are generally less structurally complex than biologic therapies, their manufacturing is more challenging than that of conventional small molecules[11]. Peptides can be produced through various methods including chemical and enzymatic synthesis, recombinant DNA technology, cell-free expression and use of microbial cell factories[38,116], although optimal manufacturing process may differ from peptide to peptide. Manufacturing costs, consistency, scalability and stringent quality control are therefore important practical considerations, particularly if peptide therapies are to progress from early-phase studies into broader clinical use.

These regulatory and quality control challenges are amplified by the growing availability of unapproved and clinically unproven peptides through wellness clinics, online suppliers and grey market ‘biohacking’ platforms[13,123]. BPC-157, an investigational peptide in tissue repair, provides a pertinent example of the regulatory challenge posed by grey-market peptides; despite limited human safety and efficacy data, it is widely promoted within the wellness space for tissue repair, anti-ageing and sports recovery, despite lacking approval from major regulatory bodies[124]. Clinicians should therefore remain vigilant by enquiring about non-prescribed peptide use, educate patients on distinction between investigational compounds and evidence-based regulated therapies and their potential risks, while also maintaining awareness of this rapidly evolving therapeutic field.

DISCUSSION

Therapeutic peptides in IBD are often considered as a single emerging class. However, the three mechanistic groups differ substantially in their proximity to clinical use, in their delivery requirements and in their associated risks. The following section compares these groups directly and considers how peptide therapies might be positioned within IBD care.

Comparative clinical readiness across peptide classes

Anti-inflammatory peptides are the most clinically advanced group (Table 3). Icotrokinra has completed phase 2b evaluation in UC and has progressed into phase 3 development, and both K(D)PT and CGMP have been assessed in peer-reviewed randomized studies, placing the class at Level 1 evidence. Barrier-protective and mucosal healing peptides occupy an intermediate position. Teduglutide, EGF and TFF3 have each been studied in small randomized trials in IBD and therefore also carry Level 1 evidence. However, none demonstrated efficacy sufficient to support continued development for this indication, and the TFF3 study was discontinued for lack of efficacy. GLP-1 receptor agonists are widely used clinically but are supported in IBD only by Level 3 observational data that cannot be separated from the effects of weight loss and metabolic improvement. Antimicrobial peptides are the least mature. Defensin-directed strategies, cathelicidins and GPR15 L remain at Level 4, supported by experimental colitis models and, for some candidates, human observational expression data. On current evidence, orally delivered targeted cytokine inhibition appears the peptide strategy most likely to reach clinical use in IBD in the near term.

Table 3 Clinical trials of peptide-based therapies in inflammatory bowel disease.

Agent	Mechanism	Phase and design	Population	Primary endpoint	Status
Icotrokinra	Oral interleukin-23 receptor antagonist	Phase 2b randomized, double-blind, placebo-controlled, dose-ranging (ANTHEM-UC)	Moderate-to-severe ulcerative colitis	Clinical response at week 12	Completed; reported in conference abstract form
Icotrokinra	Oral interleukin-23 receptor antagonist	Phase 3 programme	Moderate-to-severe ulcerative colitis	Not yet reported	Ongoing; recruiting
K(D)PT	Tripeptide derivative of alpha-melanocyte stimulating hormone	Phase 2a randomized, double-blind, placebo-controlled	Mild-to-moderate ulcerative colitis	Time to sustained clinical remission (colitis activity index 3 or less)	Completed; no confirmatory trial reported
Casein glycomacropeptide	Bovine milk-derived immunomodulatory peptide	Randomized open-label pilot study	Active distal ulcerative colitis	Change in simple clinical colitis activity index and endoscopic activity	Completed
Teduglutide	Glucagon-like peptide-2 analogue	Phase 2 randomized, double-blind, placebo-controlled, dose-ranging	Moderate-to-severe Crohn’s disease	Remission or response by Crohn’s disease activity index at week 8	Completed; not progressed for this indication
Epidermal growth factor enema	Growth-factor peptide promoting epithelial restitution	Randomized, double-blind, placebo-controlled	Mild-to-moderate left-sided ulcerative colitis	Clinical and endoscopic remission	Completed
Trefoil factor 3 enema	Trefoil peptide supporting mucosal repair	Randomized, double-blind, placebo-controlled	Mild-to-moderate left-sided ulcerative colitis	Clinical improvement	Terminated for lack of efficacy

Delivery feasibility, benefits and risks by class

The classes also differ in what their delivery demands and in their characteristic risks. Anti-inflammatory peptides directed at systemic cytokine pathways require reproducible systemic exposure, historically the principal obstacle to oral peptide therapy. Icotrokinra demonstrates that this is achievable through molecular engineering, but the same requirement means the class carries the immunosuppressive risks common to cytokine-directed therapy, including infection and impaired mucosal healing. Antimicrobial peptides act at the mucosal surface and may not require systemic absorption, which simplifies delivery and favours topical or colonic-release formulations. Their principal risk is disruption of the commensal microbiota, the long-term consequences of which are unknown in a population in whom dysbiosis is already implicated in pathogenesis. Barrier-protective peptides likewise act locally, and rectal administration has proven feasible for EGF and TFF3, but their reparative mechanism raises theoretical concerns regarding epithelial proliferation, dysplasia and fibrostenotic complications that would require long-term surveillance. The agents that are most straightforward to deliver locally are therefore those for which long-term safety data are most limited.

Potential target populations

Defining the populations most likely to benefit in advance of larger trials would improve the efficiency of future development. Orally delivered IL-23 receptor antagonists would be expected to target moderate-to-severe UC, and potentially CD, in patients seeking an oral alternative to parenteral biologic therapy, including both biologic-naive patients and those with prior inadequate response. Locally acting barrier-protective and antimicrobial peptides are better suited to distal disease, where topical administration can achieve adequate mucosal concentrations. They may be of particular relevance in refractory proctitis, or in patients with limited disease extent in whom systemic immunosuppression is undesirable. GLP-1 receptor agonists, were a direct intestinal effect to be confirmed, would most plausibly be evaluated in patients with IBD and coexisting obesity or T2DM, in whom the metabolic indication is independently established. In patients with active or extensive disease, however, the risk of exacerbating malnutrition and sarcopenia would need to be weighed carefully.

Combination strategies and comparative trial design

Given their mechanistic diversity and generally favourable theoretical safety profile, peptide therapies may prove more useful as adjuncts than as replacements for established treatments. Combining a barrier-protective peptide with an immune-directed advanced therapy is mechanistically attractive because the two would address different components of disease, and combined TFF and EGF administration has shown synergy in experimental models[115]. No combination strategy has, however, been evaluated in a controlled trial in IBD, and additive immunosuppression, overlapping toxicity and pharmacokinetic interaction would each require formal assessment. Trial design should also move beyond placebo comparison alone. Placebo-controlled studies remain appropriate for the first demonstration of efficacy, but the high placebo response rates observed in the K(D)PT trial illustrate the limitations of this design in mild-to-moderate disease. Active-comparator or add-on designs, in which a peptide is compared against or added to an established advanced therapy, would provide more clinically useful information. Such trials should incorporate objective biochemical, endoscopic and histologic endpoints, together with corticosteroid-free durable remission, rather than symptom-based indices alone.

Cost, access and healthcare system considerations

The practical value of a new therapeutic class ultimately depends on whether it can be delivered at scale. Manufacturing peptides is more demanding than that of small molecules but less demanding than recombinant biologic production, and peptides do not generally require cold-chain distribution to the same degree as monoclonal antibodies. An orally administered peptide with room-temperature stability would therefore hold clear advantages in settings where infusion capacity, refrigerated supply chains or specialist infrastructure are limited, and where the incidence of IBD is rising most rapidly[2]. These advantages are not guaranteed, however. Complex delivery platforms such as nanoparticle and liposomal carriers add manufacturing cost and regulatory complexity that may offset them, and regulatory capacity for such combination products varies considerably between jurisdictions. Whether peptide therapies improve access to effective treatment, rather than adding a further high-cost option within well-resourced health systems, will depend on decisions made about formulation and pricing during development. This warrants explicit consideration alongside efficacy and safety.

CONCLUSION

Therapeutic peptides comprise a mechanistically diverse and evolving group of potential therapies for IBD. Their high target specificity, structural adaptability and capacity to modulate inflammation, support host microbial defence, promote mucosal repair and maintain intestinal barrier integrity make them potentially attractive candidates in the management of IBD. However, the available evidence remains predominantly preclinical, and no peptide candidate has established routine efficacy as an IBD-directed therapy through adequately powered comparative clinical trials. Existing human studies are generally small, early-phase, observational or preliminary, and should therefore be regarded as hypothesis-generating.

The future development of peptide-based therapies should focus on several key priorities (Figure 1). First, continued investigation into the underlying pathophysiology of IBD is required to identify novel therapeutic targets and refine understanding of established inflammatory, microbial and epithelial repair pathways. Second, greater emphasis should be placed on overcoming translational barriers, including improving drug delivery and route of administration, enhancing peptide stability, addressing bioavailability limitations and ensuring scalable and reproducible manufacturing. Third, rigorous evaluation of short- and long-term safety will be essential. Finally, it will be important to define the optimal clinical role of peptide therapies, whether as adjunctive treatments, steroid-sparing strategies or therapeutic alternatives to advanced therapies, and to determine how they may be integrated into existing treat-to-target paradigms, including precision and personalized approaches.

Figure 1 Translational considerations for therapeutic peptides in inflammatory bowel disease. This is a conceptual framework devised based on the findings from this narrative review. The figure summarises important barriers including pharmacokinetic and pharmacodynamic limitations, disease and patient heterogeneity, limited efficacy and long-term safety data, manufacturing complexity and regulatory concerns. Addressing these factors is essential to allow effective and safe translation of peptide-based therapies into the management of inflammatory bowel disease. IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis. This figure was created by BioRender.com (Supplementary material).

Although peptide-based therapies are unlikely to replace established IBD treatments in the immediate future, they may prove to be additional therapies targeting pathways not yet adequately addressed by current therapies. With careful translational development and well-designed clinical trials, therapeutic peptides have the potential to expand the therapeutic armamentarium to manage patients with IBD.