Beyond gluten-free diet: Novel therapeutic frontiers in celiac disease armamentarium

Abstract

Celiac disease is a chronic, immune-mediated enteropathy triggered by dietary gluten ingestion in a genetically susceptible individual. While a strict gluten-free diet remains the most effective treatment, many patients face persistent challenges, including inadvertent gluten exposure, difficulties in long-term adherence, and incomplete mucosal recovery despite clinical or serological remission. This article briefly outlines the pathophysiological basis of celiac disease and highlights the limitations of current monitoring approaches based on symptoms and serology. It also discusses the recent advancements in biomarker-based monitoring and explores novel therapeutic options that target key immunological and molecular pathways, offering promise as adjuncts or potential alternatives to the traditional gluten-free diet.

Key Words: Celiac disease; Gluten-free diet; Celiac disease pathophysiology; Celiac disease treatment; Novel therapies in celiac disease

Core Tip: Celiac disease is managed with a gluten-free diet, which is difficult to sustain and often fails to achieve full mucosal recovery. Advances in disease pathogenesis have led to novel therapies, including gluten-detoxifying enzymes, gluten-sequestering polymers, barrier stabilizers, tissue transglutaminase-2 inhibitors, human leukocyte antigen-DQ antagonists, cytokine-directed biologics, and tolerance-inducing strategies such as nanoparticle-based therapies. This review summarizes the current therapeutic pipeline, discusses the challenges of translating emerging therapies into routine practice, and highlights how future management is likely to evolve towards personalized, multimodal approaches that integrate dietary management with safe and effective adjunctive therapies.

INTRODUCTION

Celiac disease (CeD) is a lifelong disorder of gluten sensitivity. In genetically susceptible individuals, exposure to wheat gluten or related rye and barley proteins triggers a maladaptive, T cell-mediated autoimmune cascade within the small intestinal mucosa, culminating in villous atrophy and subsequent signs and symptoms of malabsorption[1]. Clinically, CeD may present with gastrointestinal symptoms such as diarrhea, abdominal pain, flatulence or steatorrhea; extraintestinal manifestations such as anaemia, osteoporosis, infertility, hepatitis, neurological symptoms, or growth failure in children; or remain entirely asymptomatic, underscoring the need for heightened clinical awareness and appropriate screening[2]. Detection of CeD-specific antibodies most commonly, IgA tissue transglutaminase (tTG) in the serum serves as the initial screening tool in patients with suspected disease. Duodenal biopsy, the diagnostic gold standard, confirms the presence of characteristic histopathological changes of CeD[2,3]. Gluten-free diet (GFD) or removing gluten from the diet achieves clinical improvement, a progressive decline in antibody titers and recovery of the duodenal mucosa to normal[2,4]. But maintaining a strict lifelong GFD is often challenging, and many celiac patients continue to experience symptoms and intestinal damage despite their best efforts at dietary restriction[2]. This highlights the unmet need for alternative, non-dietary treatment options that can enhance both clinical outcomes and quality of life in affected patients. This review outlines the historical development and mechanistic basis of CeD, examines shortcomings of the GFD, evaluates emerging biomarkers and targeted therapeutics with corresponding trial evidence, and provides a brief critical appraisal of these interventions.

LITERATURE SEARCH

This narrative review was conducted through comprehensive literature searches in PubMed and Google Scholar from January 2000 to October 2025. Search terms included “celiac disease”, “celiac disease pathophysiology”, and keywords related to emerging therapies such as “glutenases”, “tight junction modulators”, “tTG2 inhibitors”, “immunotherapy”, “tolerance induction”, “biologics”, “nanoparticle therapies”, and “emerging biomarkers”. Additional references were identified from trial registries (clinicaltrials.gov) to capture completed, ongoing, and terminated studies. Although the review primarily focused on English-language human studies, relevant in vitro and ex vivo mechanistic studies were included when they provided essential insight into drug targets or disease pathways. High-quality narrative reviews, systematic reviews, and meta-analyses were also consulted to ensure comprehensive coverage and cross-verification of evidence. Reference lists of key articles were manually screened to identify further pertinent publications.

ORIGIN OF CeD: HISTORICAL TIMELINE AND RISING GLOBAL PREVALENCE

The earliest record of CeD is attributed to Aretaeus of Cappadocia, who in the second century, described a chronic malabsorption syndrome that he referred to as the “Coeliac Diathesis”[5]. A major breakthrough came in the 1940s, when Dutch paediatrician Dicke et al[6] established a link between the protein component of wheat (gluten) and CeD through careful clinical observation and detailed dietary studies conducted over several years. His hypothesis was further strengthened when during the Second World War and the Dutch Famine, bread became unavailable in the Netherlands; Dicke et al[6] noticed that throughout this time, the mortality rate for CeD dropped dramatically in his hospital[5,6]. Dicke et al’s work[6] laid the foundation for the GFD as the cornerstone of therapy. In 1954, Paulley described the characteristic mucosal changes in the small intestine, and by 1956, peroral small intestinal biopsy techniques introduced by Shiner allowed direct visualization of villous atrophy and crypt hyperplasia[7]. The 1970s brought the first serological tools, anti-gliadin antibodies, followed by the introduction of more specific markers such as anti-endomysial antibodies (EMA) and anti-tTG antibodies in the 1980s and 1990s, revolutionizing screening and enabling detection of silent and atypical forms[7]. In the 1980s, the strong association of CeD with human leukocyte antigen (HLA)-DQ2/DQ8 haplotypes were established, confirming its genetic predisposition[7].

Over the past two decades, CeD has emerged as a major global public health concern with considerable geographic variation rather than a rare, region-specific disorder[8]. According to a 2024 population-level analysis and burden review, the estimated prevalence in the general population now ranges between 0.7% and 2.9%, with higher rates among at-risk groups (first-degree relatives, patients with autoimmune comorbidities) and a clear female predominance[9]. Despite this high prevalence, a substantial proportion of cases remain undiagnosed, contributing to a considerable hidden burden with nutritional, skeletal, and quality-of-life implications. In regions like South Asia, including India, emerging data suggest increasing recognition of CeD with a striking north-south gradient within India (significantly higher prevalence in the wheat-consuming northern states compared with the predominantly rice-based southern regions). This divergence, observed despite similar HLA-DQ2/DQ8 carriage rates, underscores the key role of environmental exposure, particularly gluten intake, in shaping disease expression[9]. This evolving epidemiology, together with the large “undiagnosed iceberg”, emphasizes the urgent need for enhanced disease awareness, early diagnosis, population-based screening strategies, and the development of novel therapeutic approaches beyond a GFD.

PATHOGENESIS AND IMMUNOPATHOLOGY OF CeD

The development of novel, non-dietary therapies for CeD requires a detailed understanding of its underlying pathogenic mechanisms (Figure 1)[10,11]. At the broadest level, CeD results from a complex interplay of genetic predisposition, environmental triggers, and immune dysregulation[12]. Approximately 95% of patients carry HLA-DQ2 or -DQ8 alleles, which are necessary but not sufficient for disease development. The key environmental driver is dietary gluten, a protein rich in glutamine and proline, rendering it resistant to complete degradation by gastrointestinal proteases. As a result, partially digested immunogenic gluten peptides cross the intestinal epithelium through paracellular leakage due to altered tight junctions (TJs) or via active transcellular transport. In the lamina propria, these peptides undergo deamidation by tTG2, which increases their binding affinity for HLA-DQ2/DQ8 molecules expressed on antigen-presenting cells (APCs). This process initiates the adaptive immune response, activating gluten-specific CD4⁺ T-helper cells[2,10-12].

Figure 1 Immunopathogenesis of celiac disease. Schematic representation summarizing the key steps from gluten ingestion to immune activation and enterocyte injury. IFN-γ: Interferon-γ; IL-21: Interleukin-21; TNF-α: Tumor necrosis factor-α; tTG: Tissue transglutaminase; HLA-DQ: Human leukocyte antigen-DQ; APCs: Antigen-presenting cells; NK: Natural killer; Th: T helper.

Activated Th1 cells secrete interferon-γ (IFN-γ) and other proinflammatory cytokines that drive recruitment and activation of CD8⁺ intraepithelial lymphocytes (IELs) and natural killer (NK)-like cells, which mediate direct cytotoxicity against enterocytes. In parallel, some gluten-reactive CD4⁺ T cells differentiate into Th2 cells, secreting interleukin (IL)-4 and IL-5, which stimulate B-cell activation and antibody production (anti-gliadin, anti-EMA, and anti-tTG antibodies). Although these antibodies are critical for CeD diagnosis, their precise pathogenic role remains incompletely defined[2,10-12].

In addition to adaptive immunity, the innate immune system plays a central role in CeD pathogenesis. Gluten exposure induces production of IL-15 in both the lamina propria and intestinal epithelium. IL-15 promotes expansion and activation of IELs, enhances natural killer group 2 member D expression, and drives cytotoxic responses through recognition of stress-induced ligands such as MHC class I chain–related protein A and MHC class I chain–related protein B on epithelial cells. IELs in CeD also aberrantly express CD94/natural killer group 2 member C, which recognizes HLA-E, upregulated by IFN-γ signalling, further amplifying epithelial cell destruction[10,12].

This combined immune assault leads to the classic histological triad of villous atrophy, crypt hyperplasia, and increased IELs. Persistent gluten exposure perpetuates mucosal inflammation, resulting in malabsorption, nutritional deficiencies, and - in severe cases - complications such as refractory CeD, ulcerative jejunitis, or enteropathy-associated T-cell lymphoma[2]. Beyond T-cell-mediated pathways, emerging evidence also implicates regulatory T-cell dysfunction, altered gut microbiota, and epithelial barrier defects as contributors to disease pathogenesis, highlighting the multifactorial nature of CeD and underscoring the rationale for targeted non-dietary therapeutic strategies[2].

Beyond localized intestinal injury, CeD exhibits systemic immunological effects that contribute to a wide spectrum of extraintestinal manifestations[13]. Neurological involvement, including cerebellar ataxia and peripheral neuropathy, is linked to autoantibodies targeting tTG6[14]. In untreated patients, neurophysiological studies have demonstrated cerebral hypoperfusion, altered cortical excitability, and gluten-related neuroinflammation, with partial reversibility following long-term adherence to a GFD, reflecting the systemic immune activation characteristic of CeD[14,15]. Similar immune-mediated mechanisms underlie other extraintestinal manifestations, including reduced bone mineral density driven by chronic inflammation and malabsorption, dermatitis herpetiformis resulting from IgA-tTG3-mediated immune complex deposition, and hepatic abnormalities ranging from mild transaminase elevation (“celiac hepatitis”) to associations with chronic liver disease linked to shared autoimmune pathways[13]. Recognition of these systemic effects not only broadens the understanding of CeD pathophysiology but also reinforces the need for therapeutic approaches that extend beyond mucosal healing to address whole-body immune dysregulation.

GFD

The term “gluten-free” does not imply total absence of gluten but generally refers to an amount of gluten that is thought to be harmless. Codex Alimentarius (http://www.codexalimentarius.net) states that gluten free foods are foods or ingredients naturally free of gluten, in which the measured gluten level is ≤ 20 mg/kg or 20 ppm in total[3].

While most patients tolerate trace gluten under the 20 ppm threshold, a subgroup might react even more sensitively. It has therefore been suggested that a more-than-strict GFD regimen has the potential to induce mucosal recovery in these patients[16]. The gluten contamination elimination diet is a diet that was developed to remove even minute amount of gluten from the diet, consisting of a more restrictive dietary regimen focusing on the use of naturally gluten-free products rather than processed gluten-free food[16,17].

GFD ADHERENCE-CHALLENGES

Lifelong strict GFD is not easy, due to the ubiquity of gluten in homemade and processed foods, as well as in some pharmaceuticals; the risk of cross-contamination from contact with gluten-containing food, surface, or utensils; improper labelling; and social constraints[18,19]. Strict GFD adherence is particularly challenging when consuming food prepared outside the home, such as in restaurants, cafeterias, during travel, or at social gatherings[4]. Certain groups, including the elderly, illiterate, those with mental or psychological impairments, and individuals with limited financial resources, are especially vulnerable to poor adherence[19]. Figure 2 presents a schematic summary of nutritional, practical and psychosocial challenges faced by patients on a lifelong GFD.

Figure 2 Limitations of the gluten-free diet. GFD: Gluten-free diet.

Numerous studies have investigated the factors influencing the compliance to a GFD, showing that adherence rates in patients with CeD are well below optimal. A systematic review of literature from 1980 to 2007 reported strict adherence rates ranging from 42% to 91%, depending on the definition and method of assessment[20]. Among adults with CeD on a GFD, 62% experienced food insecurity, struggling to access or afford gluten-free foods[21]. In a cohort of 1162 patients, 71.9% reported poor health-related quality of life, closely linked to food insecurity and diet adherence[22]. Even with strict GFD adherence, health-related quality of life often remains below that of the general population, particularly in social, emotional, and mental health domains[23]. These observations underscore the ongoing burden of disease despite dietary therapy and highlight the need for novel therapeutic strategies to further improve long-term quality of life in CeD.

CONCEPT OF MUCOSAL HEALING IN CeD

Overall, only 1^st/3^rd of adults achieve normal villous architecture after 2 years on a GFD and about 2^nd/3^rd after 5 years[24,25]. These estimates are based on duodenal biopsies only, so the proportion of patients achieving complete mucosal recovery of the entire small intestine remains unknown. A United States study reported a median healing time of 3 years after starting GFD[26]. The long-term benefit of achieving mucosal healing after starting a GFD is controversial. While seroconversion (negative celiac antibodies) increases the likelihood of mucosal healing, correlation is poor and currently a repeat intestinal biopsy remains the only reliable method to confirm mucosal recovery[26].

Risks of persistent villous atrophy include increased risk of lymphoproliferative malignancy [hazard ratio (HR) = 2.81, 95% confidence interval (CI): 2.10-3.67][27], increased hip fracture risk (HR = 1.67; 95%CI: 1.05-2.66)[28] and risk of refractory CeD (RCD) in GFD adherent patients who continue to be symptomatic. In a Swedish study, patients with normal follow-up histology had no excess lymphoma risk (HR = 0.97; 95%CI: 0.44-2.14), suggesting that mucosal healing might be a worthwhile follow-up goal[29]. Evidence on mortality is inconsistent - one study suggested a borderline reduction with healing, though not statistically significant (HR = 0.13; 95%CI: 0.02-1.06)[26], whereas a larger Swedish cohort found no benefit[30]. Mucosal healing also did not reduce risks of serious infections[31], cardiovascular disease[32], or adverse pregnancy outcomes[33]. Given these mixed findings and lack of randomized controlled trials (RCTs), the value of routine follow-up biopsy remains uncertain, and decisions should be individualized through shared decision-making.

MONITORING ON GFD

Long-term monitoring in CeD is essential to ensure clinical remission, assess dietary adherence, detect complications and manage associated conditions. Gluten-induced symptoms typically subside within a few weeks of starting a GFD[34,35]. Persistent symptoms may indicate ongoing gluten exposure (intentional or inadvertent); coexistent conditions like irritable bowel syndrome, microscopic colitis, small intestinal bacterial overgrowth and other food intolerances; or complications such as RCD or malignancy[2]. Dietary assessment using standardized dietician evaluation or validated GFD adherence questionnaires (e.g., Biagi score, celiac dietary adherence test) helps identify inadvertent gluten exposure[36]. Serology, mainly anti-tTG IgA, is also used to assess compliance, though normalization does not guarantee mucosal healing[37-39]. In strict GFD adherence, antibody titres usually normalize within 6-12 months; slower in adults or severe disease[38]. Gluten immunogenic peptide (GIP) testing in stool or urine offers direct evidence of recent gluten exposure, but cost and availability are limiting factors[40]. A repeat small bowel biopsy remains the gold standard for assessment of mucosal recovery, typically considered in patients with persistent symptoms, positive serology despite claimed adherence or high risk features[2]. Figure 3 illustrates various methods for assessing GFD adherence. Since no single non-invasive test reliably confirms mucosal healing, an integrated approach combining clinical, dietary, laboratory, and sometimes histological assessment is recommended.

Figure 3 Gluten-free diet adherence monitoring tools. Illustration comparing various methods for assessing gluten-free diet adherence, arranged from least accurate to most accurate (inner to outer rings). GIP: Gluten immunogenic peptide.

GIPs

GIPs are partially digested gluten fragments, excreted in stool and urine, that allow direct, quantitative assessment of recent gluten exposure. Detection in urine reflects gluten ingestion within 6-48 hours, while stool detection reflects intake over 2-7 days, depending on colonic transit[41]. It is more sensitive than dietary questionnaires or anti-tTG antibodies[42] and is a strong predictor of persistent villous atrophy on follow-up biopsy[43]. In a multicentre study of 188 CeD patients on a GFD and 73 healthy controls on a gluten-containing diet, 30% of patients had detectable stool GIP, while nearly all controls (98.5%) showed quantifiable GIP[44]. Ruiz-Carnicer et al[45] found urinary GIP positivity in 58% of GFD-treated patients, with higher rates on weekends. GIP testing showed 94% sensitivity and 97% NPV compared with duodenal biopsy, and identified Marsh II-III lesions in 25% of patients that would have been missed by serology, symptoms, or questionnaires alone[45]. Despite its high sensitivity, GIP detection can be influenced by intermittent gluten intake, timing of sample collection, and individual variations in digestion and intestinal transit[40]. Moreover, GIP detects only recent gluten exposure, not cumulative intake, and so multiple samples may be needed; cost and availability can also be limiting.

EMERGING BIOMARKERS IN CED

The biomarker landscape in CeD is rapidly advancing, with novel candidates emerging for both diagnosis and longitudinal monitoring. Among novel diagnostic tools, antibodies against tTG-gliadin neo-epitopes have demonstrated superior accuracy (sensitivity 98%-100%, specificity 93%-96%) compared with conventional anti-tTG assays[46-48]. Anderson et al[49] demonstrated that CeD patients in remission, after a 3-day gluten challenge (8-9 g/day), exhibited a transient rise (days 3-6) in circulating IFN-γ-producing gluten-specific T cells, serving as a plausible surrogate for the Th1-driven CeD response[49]. Similarly, HLA-DQ2 gliadin tetramers increase in peripheral blood after short-term gluten exposure and even allow diagnosis in patients already on a GFD[50,51]. A rapid rise in serum IL-2, peaking 4 hours post-gluten challenge, has been shown to correlate with acute gastrointestinal symptoms[46,52,53] while ex vivo whole blood assays measuring gluten-induced IL-2 release have shown concordance with in vivo findings[54]. With refined IL-2 detection techniques, signals may be identified even without formal gluten challenge, underscoring its potential as a practical monitoring tool[55]. Finally, circulating microRNAs and transcriptomic profiles are being explored as non-invasive signatures of mucosal inflammation, adding another dimension to monitoring tools[56,57].

Table 1 provides a comparative summary of emerging biomarkers, highlighting their biological mechanisms, clinical applications, and available diagnostic performance metrics[41-48,51-54,58]. Taken together, these emerging biomarkers, ranging from next-generation serology to T-cell and cytokine assays, along with molecular signatures, offer the potential to transform CeD care by reducing reliance on duodenal biopsy, improving detection of dietary lapses, and enabling more precise assessment of therapeutic interventions in clinical trials.

Table 1 Emerging biomarkers in celiac disease.

Biomarker	Biological basis	Clinical application	Diagnostic performance	Ref.
Faecal/urinary GIP	Partially digested gluten fragments in urine/faeces	Objective assessment of GFD adherence; detects recent gluten ingestion	No fixed sensitivity/specificity for gluten exposure (depends on timing of collection; short detection window (24-48 hours)	[41-45]
			Repeated GIP testing correlates with mucosal status but does not independently predict healing
tTG-neo antibodies	Antibodies to neo-epitopes formed by tTG-gliadin complexes	Diagnosis of active CeD	Sensitivity 98%-100%, specificity 93%-96% [vs anti tTG antibodies (sensitivity 74%-100%, specificity 78%-100%)]	[46-48,58]
			Accuracy for detecting villous atrophy in GFD patients: 90%, higher than other serologic tests
HLA DQ2 gliadin tetramer assay	Identifies circulating gluten-specific CD4+ T cells	Diagnosis of CeD even if patients are on GFD	On GFD, sensitivity 97%, specificity 95%	[51]
			On gluten diet, sensitivity 100%, specificity 90%
Serum IL-2 rise post gluten challenge	Rapid cytokine surge reflecting acute gluten-specific T-cell activation	Detects acute gluten exposure	No validated sensitivity/specificity reported yet; consistent IL-2 peak at about 4 hours after gluten ingestion	[52-54]
Circulating microRNAs	Altered expression patterns reflect mucosal injury	Exploratory diagnostic biomarker	No validated sensitivity/specificity	[56,57]

CeD: Celiac disease; GFD: Gluten-free diet; GIP: Gluten immunogenic peptides; tTG: Tissue transglutaminase inhibitor; IL: Interleukin; HLA-DQ2: Human leucocyte antigen-DQ2.

THERAPEUTIC STRATEGIES AND NOVEL DRUGS IN CED

Figure 4 illustrates the sequential pathophysiological events leading to gluten-induced intestinal injury and maps the therapeutic strategies targeting each step in this cascade.

Figure 4 Treatment targets and strategies in celiac disease. This schematic figure illustrates the pathophysiological steps of gluten-induced intestinal injury and highlights corresponding therapeutic intervention points. Strategies include: (1) removal of toxic gluten peptides; (2) enhancement of epithelial barrier integrity through permeability inhibitors; (3) inhibition of tissue transglutaminase 2-mediated deamination; (4) blockade of HLA-DQ2/DQ8 antigen presentation; (5) immune-modulating therapies targeting both innate and adaptive pathways; (6) microbiome-directed approaches; and (7) miscellaneous emerging modalities. Together, these targeted strategies aim to prevent gluten peptide entry, modify immune activation, restore epithelial integrity, and ultimately reduce enterocyte damage in celiac disease. FN-γ: Interferon-γ; IL-21: Interleukin-21; TNF-α: Tumor necrosis factor-α; tTG: Tissue transglutaminase; HLA-DQ: Human leukocyte antigen-DQ.

Strategy 1 removal or reduction of toxic gluten peptides

Genetic modification of gluten-containing cereals: Genetic modification of gluten-containing cereals to reduce immunogenicity has been explored using RNA interference[59] and CRISPR/Cas9 gene editing[60,61]. Gluten comprises of gliadins and glutenins in wheat, and related proteins (secalin, hordein and avenin) in rye, barley and oats[62]. Gliadins, especially the α- and γ-fractions, contain most immunogenic T-cell epitopes, including the highly resistant 33-mer α-gliadin peptide that binds strongly to HLA-DQ2/DQ8 and drives CeD[63]. Modern hexaploid wheat (Triticum aestivum; AABBDD) arose through natural hybridization[34,64]; the added D-genome improved baking quality but introduced highly immunogenic peptides, explaining why ancient diploid (AA) and tetraploid (AABB) wheats are less immunogenic[34,65]. RNA interference can suppress α- and γ-gliadins[59,66], and CRISPR/Cas9 can precisely edit gliadin genes, achieving up to 85%-97% reduction in immunoreactivity and even replacing toxic epitopes with non-toxic forms[60,61,66]. However, gluten proteins are encoded by a large multigene family across three genomes (A, B, and D) with > 50 T-cell-stimulatory epitopes, making complete detoxification difficult[34]. Extensive gliadin reduction may also impair dough viscoelasticity, and regulatory and consumer acceptance issues remain unresolved[34]. Currently, these strategies are confined to preclinical research, with no genetically engineered “celiac-safe” wheat yet tested in human trials.

Oral glutenases: Humans lack the enzyme necessary to cleave proline-glutamine bonds in gluten, resulting in incomplete digestion and formation of immunotoxic gluten peptides. Oral glutenases from bacterial, fungal or cereal sources have been used to degrade these peptides in the stomach and proximal small intestine[66]. In a randomized placebo-controlled trial, aspergillus niger prolyl endopeptidase (AN-PEP) detoxified up to 8 g of gluten contained in a commercial food product when tested in patients with CeD in remission[67]. However, its effectiveness was limited by variable release from enteric-coated capsules depending on food composition and intestinal pH, meaning partially digested gluten could still trigger symptoms; thus, it may protect against inadvertent gluten exposure but is not sufficient for digestion of normal dietary gluten intake. A more recent trial in patients on a GFD showed reduced symptoms with AN-PEP but no significant change in stool gliadin immunogenic peptide levels, likely due to low baseline peptide levels during the run-in period[68]. Latiglutenase (ALV003) is a combination of two glutenases, endoprotease B, isoform-2 and sphingomonas capsulata prolyl endopeptidase. Endoprotease B, isoform-2 acts at low pH, cleaving QXP sequences abundant in immunogenic gliadin peptides such as the 33-mer, while sphingomonas capsulata prolyl endopeptidase digests proline-glutamine bonds, enabling complementary action[66,69]. Early phase 2 gluten challenge studies showed reduced mucosal injury and symptom severity[70], but a large phase 2b trial found no significant benefit on histology or secondary endpoints[71], though post hoc analysis suggested symptomatic benefit in seropositive patients at higher doses[72]. A meta-analysis of five RCTs (1003 participants) confirmed no significant histologic benefit, suggesting limited overall efficacy with possible symptom relief in select subgroups[73]. TAK-062 (also known as zamaglutenase or Kuma062) is a computationally engineered protease derived from bacterial kumamolisin-alicyclobacillus sendaiensis, optimized for high activity against gluten under gastric pH[66]. In vitro and Phase 1 studies showed that TAK-062 could degrade more than 99% of dietary gluten in mixed meals, confirmed by gastric aspirate analysis under physiological conditions[74]. However, in the phase 2 ILLUMINATE-062 trial (NCT05353985), it did not improve symptoms compared with placebo during controlled gluten exposure[75]. STAN-1 is another endopeptidase of interest, comprising a cocktail of microbial enzymes designed to degrade gluten before absorption in the gastrointestinal tract[76]. In a randomized, double-blind, placebo-controlled trial involving 35 patients with CeD on a GFD, no significant differences in tTG-IgA titers were observed between the STAN-1 and placebo groups[77]. A separate phase I/II trial evaluated changes in tTG-IgA antibodies, symptoms, and intestinal biopsy findings; however, the results from this study have not yet been published (NCT00962182).

Gluten sequestering polymers: Gluten sequestering polymers sequester intraluminal gliadin in stomach and small intestinal lumen, preventing its breakdown into immunogenic peptides[66]. Preclinical studies in animal models demonstrated that poly (hydroxyethyl methacrylate co-styrene sulfonate) [P (HEMA-co-SS)] or BL-7010 can sequester gliadin, prevent its proteolysis into immunotoxic peptides, and protect against gluten-induced intestinal damage with no systemic absorption, thereby limiting toxicity[66,78]. BL-7010 was evaluated in the phase 1/2 trial (NCT01990885), a randomized, double-blind study in patients with well-controlled CeD. The study results, disclosed by BioLineRx, showed that BL-7010 was safe and well-tolerated at single escalating and repeated doses, with no serious or dose-limiting adverse events[79]. Pharmacokinetic analyses confirmed no systemic absorption, supporting its role as a non-absorbable gluten-sequestering polymer[79]. However, while proof of concept in binding gliadin has been established, robust clinical efficacy data such as improvement in symptoms or mucosal healing are still lacking.

Strategy 2 prevention of passage of immunogenic peptides through the TJs

TJs regulate paracellular transport and prevent the passage of harmful bacteria and dietary antigens. Zonulin, a regulator of epithelial permeability at apical TJs, is highly expressed in CeD[80]. Gluten peptides attach to the C-X-C motif chemokine receptor 3 , increasing zonulin formation that activates TJ relaxation leading to increased intestinal permeability and influx of gliadin[81]. Larazotide acetate is a synthetic octapeptide that blocks zonulin-mediated TJ disassembly, thereby reducing paracellular passage of gluten peptides. In a phase 2b trial (NCT00492960) of 184 CeD patients on a GFD, participants received larazotide acetate (1 mg, 4 mg, or 8 mg three times daily) or placebo together with 2.7 g of gluten for 6 weeks. Though larazotide acetate could not demonstrate a statistically significant efficacy in the reduction of intestinal permeability, a favorable trend was seen[82]. Hoilat et al[83] conducted a meta-analysis of trials to study the efficacy and safety of larazotide acetate (AT-1001) in CD. Larazotide treatment was significantly correlated with symptomatic improvement after gluten challenge[83]. Encouraged by phase 2 data, larazotide advanced into a phase 3 trial (NCT03569007; CedLara) designed to evaluate its safety and efficacy in symptom reduction among GFD-treated patients. However, interim statistical review revealed that the trial would require a substantially larger sample size to achieve adequate power. Given the impracticality of enrolling such numbers, the sponsoring company decided to discontinue the trial[84].

Strategy 3 tTG inhibitors

tTG2 deamidates gluten peptides in the lamina propria, increases their negative charge and enhances binding affinity to HLA-DQ2/DQ8 molecules, thereby amplifying T-cell activation in CeD. In addition, tTG2 forms stable complexes with gliadin peptides, further driving autoimmunity[34]. Hence, inhibition of tTG2 has been explored as a therapeutic approach to prevent the generation of highly immunogenic gluten epitopes and to interrupt the autoimmune cascade. tTG2 inhibitors can be classified into three main types: Irreversible inhibitors (e.g., iodoacetamide and 3halo4,5dihydroisoxazoles), reversible inhibitors (e.g., Zn²⁺), and competitive amine inhibitors (e.g., putrescine and monodansylcadaverine)[66,85]. The most advanced agent in this category is ZED1227 (a selective intestinal tTG2 inhibitor), evaluated by Schuppan et al[86] in a phase 2, double-blind, placebo-controlled trial. In this study, 163 patients were randomized to receive 10 mg, 50 mg, or 100 mg of ZED1227, or placebo, during a 6-week gluten challenge with 3 g of daily gluten. The primary endpoint was the villous height-to-crypt depth (Vh:Cd) ratio, while secondary endpoints included IELs density, Marsh-Oberhuber grading, and patient-reported outcomes (Celiac Symptom Index and CeD Questionnaire). ZED1227 treatment led to a significant, dose-dependent improvement of the Vh:Cd ratio and a reduction in IEL density, alongside symptomatic improvement irrespective of dose. Given the ubiquitous expression of transglutaminase, drug localization was further investigated. Analysis of biopsy samples from treated patients demonstrated that approximately 80% of ZED1227 was retained in the epithelium and 20% in the lamina propria, suggesting that its protective effect is mediated primarily through epithelial-level inhibition[87].

Strategy 4 HLA inhibitors

CeD is a genetic disease, with nearly all patients carrying HLA-DQ2 or HLA-DQ8 haplotypes[88]. Gluten peptides that cross the epithelial barrier are deamidated by tTG2, gaining a negative charge that enhances binding affinity to the antigen-presenting grooves of HLA-DQ2/DQ8. This peptide-HLA interaction drives pathogenic T-cell activation and the downstream adaptive immune response. Blocking these binding grooves with gliadin antagonist peptides offers a potential strategy to interrupt antigen presentation and prevent T-cell stimulation[34]. Structural studies of HLA-DQ2 bound to deamidated gluten peptides have enabled the design of such antagonists. For example, alanine substitutions in key residues of α2-gliadin abolished T-cell reactivity[89], while a naturally derived durum wheat decapeptide demonstrated antagonistic effects in vitro[90]. Kapoerchan et al[91] noted that it is the proline-rich gluten peptides that interact with HLA molecules and replacing proline with azidoproline residues made them less immunogenic. Despite its promise, HLA-targeted therapy faces major obstacles, including limited access of antagonists to the peptide-binding groove, peptide instability during delivery, and the potential risk of interfering with broader HLA class II immune functions beyond the gut[34].

Strategy 5 immunotherapy

The immune-mediated pathogenesis of CeD has spurred the development of therapies aimed at suppressing aberrant inflammation or inducing antigen-specific tolerance. These agents broadly fall into two categories: (1) Immunosuppressives that blunt general or pathway-specific immune responses; and (2) Immunomodulators that aim to retrain the immune system towards tolerance against gluten.

Glucocorticoids and budesonide: Systemic glucocorticoids such as prednisone have historically been used in celiac crisis and RCD[34]. Wall et al[92] reported that adding prednisone to GFD accelerated symptomatic improvement. In another study, prednisolone reduced epithelial apoptosis but paradoxically impaired epithelial regeneration[93]. Budesonide, a locally acting steroid with reduced systemic absorption, has been evaluated in RCD, showing some benefit in symptom control, though not in long-term mucosal healing[94]. Ciacci et al[95], in a randomized study, found that treatment with 6 mg budesonide daily for 4 weeks in addition to GFD showed greater efficacy in relieving symptoms in CeD patients with overt malabsorption.

Anti-IFN-γ and anti-tumor necrosis factor agents: Anti-IFN-γ monoclonal antibody (e.g., fontolizumab) has been shown in preclinical studies to prevent intestinal epithelial damage induced by gliadin-specific T-cell-derived cytokines[96]. By blocking IFN-γ, these agents may also reduce gliadin-induced increases in intestinal permeability, thereby interrupting the cycle of inflammation and mucosal injury. Although no formal clinical trials in CeD have been completed, these findings support the theoretical rationale for IFN-γ blockade in CeD.

Anti-tumor necrosis factor (TNF) therapy, particularly infliximab has been explored mainly in RCD, where mucosal inflammation is severe. Case reports and small series of refractory patients have suggested benefit with infliximab, but controlled trial data are lacking[97,98]. TNF blockade is not recommended outside of selected refractory cases due to variable efficacy and safety concerns.

Lymphocyte trafficking and homing inhibitors: CCX282-B is an oral antagonist of the CC chemokine receptor 9, which is expressed on circulating lymphocytes and plays a key role in guiding these immune cells to the intestinal mucosa[99,100]. Its ligand, C-C chemokine ligand 25, is secreted by intestinal epithelial cells and becomes upregulated during intestinal inflammation[101]. A phase 2, randomized, double-blind, placebo-controlled clinical trial (NCT00540657) investigated whether CCX282-B (Vercirnon) could reduce gluten-induced intestinal damage in patients with CeD[102]. A total of 90 participants were enrolled, with half assigned to receive 250 mg of CCX282-B twice daily over a 13-week period. The primary objective was to determine changes in the Vh:Cd ratio in small bowel biopsies before and after gluten exposure. Secondary endpoints included assessment of mucosal inflammation, serologic markers of CeD, and clinical symptom burden. Although the study was completed in 2008, the results were never published. Another key element for gut-homing is the α4β7 integrin, expressed on over 90% of intestinal lymphocytes. Its principal binding partner is mucosal addressin cell adhesion molecule-1, which is localized to the gastrointestinal tract and gut-associated lymphoid tissue[103]. Based on this biology, a phase 2 clinical trial (NCT02929316) was initiated to assess whether vedolizumab, a monoclonal antibody targeting α4β7 integrin, could prevent gluten-induced small intestinal damage in CeD. The trial, however, was terminated in October 2018 due to insufficient enrollment[104].

IL-15 pathway blockade: IL-15 is a pivotal cytokine driving IEL activation and epithelial destruction[10,12]. A phase 2a, double-blind trial evaluated the role of AMG 714, an anti-IL-15 monoclonal antibody, in patients with CeD subjected to gluten challenge[105]. Sixty-four participants were randomized to receive either AMG 714 (150 mg or 300 mg) or placebo, administered via two subcutaneous injections every two weeks over a 10-week period. The primary endpoint was change in Vh:Cd ratio, assessed by duodenal biopsies at baseline and study completion. Secondary endpoints included IEL counts, improvement in Marsh-Oberhuber score, changes in serological markers (anti-tTG and anti-deamidated gliadin peptide antibodies), and symptom improvement. The study found no significant difference in Vh:Cd ratio among treatment arms; however, reductions in lymphocyte density and symptom burden suggested potential therapeutic benefit, warranting further evaluation[105]. Building on these findings, another trial investigated AMG 714 in type II refractory CeD[106]. In this study, 28 patients were randomized to receive either placebo or AMG 714 (8 mg/kg) intravenously on day 0, day 7, and every two weeks for 10 weeks. The primary objective was reduction of aberrant IELs, measured by flow cytometry on small bowel biopsies. While the primary endpoint was not met, treatment was associated with a reduction in diarrhea frequency. Schumann et al[107] recently published results from a phase 1a/b trial evaluating CALY-002, a humanized anti-IL-15 monoclonal antibody previously known as PRV-015[107]. The study found CALY-002 to be safe and well tolerated, with evidence of attenuation of gluten-induced mucosal damage in well-controlled CeD subjects following gluten challenge. Another phase 2b, randomized, double-blind, placebo-controlled trial (NCT04424927) evaluated three different dose regimens of PRV-015, an anti-IL-15 monoclonal antibody, as an adjunct to a GFD in adults with non-responsive CeD. The study, which enrolled 226 participants, reached completion on July 30, 2024[108]. However, as of now, results have not been published.

Dual cytokine (IL-15 and IL-21) blockade: IL-21 synergizes with IL-15 in IEL activation[109]. BNZ-2, a γ-chain cytokine antagonist, blocks IL-15 and IL-21 signalling. Preclinical data supports its efficacy. In a study by Ciszewski et al[110], duodenal tissue from untreated celiac patients showed upregulation of IL-15RA and IL-21, and functional studies demonstrated that these cytokines act cooperatively to enhance intraepithelial cytotoxic T-cell activation, proliferation, and cytolytic function[110]. BNZ-2 specifically blocked these effects without interfering with other γ-chain cytokines, suggesting that dual IL-15/IL-21 inhibition may represent a promising strategy to limit T-cell-mediated mucosal injury in CeD.

Janus kinase inhibitors: Because IL-15 and related cytokines signal through the Janus kinase (JAK)/signal transducer and activator of transcription pathway, small-molecule JAK inhibitors have been tested[66]. Tofacitinib, a JAK1/3 inhibitor, showed rapid clinical and histologic benefit in small open-label studies of RCD II[111]. However, sample sizes were very small (n = 6), and efficacy on long-term outcomes remains uncertain. The phase 2 clinical trial NCT05636293 is investigating the safety and efficacy of ritlecitinib, a selective JAK3 inhibitor, in preventing gluten-induced mucosal injury and symptoms in patients with CeD[112]. Participants are randomized to receive either placebo or ritlecitinib 200 mg orally once daily, alongside a controlled gluten challenge (10 g/day for 21 days, reduced to 5 g/day after day 3 if not tolerated). The primary endpoint is change in small intestinal histology, measured by Vh:Cd ratio, while secondary outcomes include patient-reported symptom assessment. The trial is scheduled to complete in 2025 and is currently listed as active, recruiting[112].

Lymphocyte proliferation inhibitor: Teriflunomide works by inhibiting dihydroorotate dehydrogenase, an enzyme critical for de-novo pyrimidine synthesis, resulting in a cytostatic suppression of lymphocyte proliferation. Its potential to mitigate gluten-induced immune activation in CeD was evaluated in a phase 2a randomized clinical trial[113]. In this study, 15 patients with well-controlled CeD underwent a 3-day gluten challenge while receiving either 14 mg/day of teriflunomide or a placebo. The primary objective was to assess the drug's impact on gluten-specific T-cell activation and efflux using HLA-DQ: Gluten tetramers. The trial results demonstrated that teriflunomide did not significantly alter gluten-specific T-cell activity compared with placebo, indicating that it is unlikely to be effective as a non-dietary therapeutic option for CeD.

Targeting B cells and T cells: The use of anti-CD3 antibodies to deplete effector T cells has been proposed as a non-dietary therapeutic approach in CeD[63,114]; however, dedicated preclinical and clinical studies in CeD are currently lacking. Similarly, rituximab, an anti-CD20 monoclonal antibody targeting B cells, has been administered in select cases of RCD II, showing anecdotal benefit[115,116], but no controlled trials have been conducted to confirm its efficacy.

Modulating antigen presentation to T cells: Cathepsin S is a cysteine protease expressed in APCs, which cleaves p10, a 10-kDa fragment of the major histocompatibility complex-II bound invariant chain, during the assembly of major histocompatibility complex-II antigen-peptide complexes. By blocking this, cathepsin S inhibitors reduce the presentation of antigens (including gluten peptides) to CD4+ T cells, thereby blunting T-cell activation[117]. In a single centre phase 1 randomized trial (NCT02679014) Cathepsin S inhibitor RO5459072 was evaluated in 19 celiac patients during a 13-day gluten challenge. Although the study was designed to assess whether RO5459072 could prevent the gluten-induced increase in gliadin-specific IFNγ-secreting T cells, most participants showed only a weak response to gluten, and the primary endpoint was not met, indicating limited efficacy of Cathepsin S inhibition in CeD[117].

Immunomodulators and antigen-specific tolerance induction: Peptide based desensitization therapy or tolerance induction has long been used to treat allergic disorders. Immune tolerance strategies in CeD aim to reprogram the adaptive immune system to recognize gluten as a harmless antigen, thereby preventing pathogenic T-cell activation and downstream inflammation[34]. Various strategies have been employed.

Peptide-based therapeutic vaccine (NexVax2): NexVax2 is a gluten peptide-based antigen-specific immunotherapy comprising three synthetic peptides that include six HLA-DQ2.5-restricted, immunodominant T-cell epitopes[118]. An early phase 1 study (NCT00879749) demonstrated the biological activity of NexVax2, confirming its ability to desensitize gluten-reactive T cells[119]. However, in a subsequent phase 2 trial (NCT03644069) designed to evaluate clinical efficacy and patient-reported outcomes, the study was terminated early after interim analyses showed no meaningful benefit in reducing acute gluten-induced symptoms[120]. Consequently, further development of NexVax2 was discontinued.

Nanoparticle-based tolerance therapies: KAN-101 (glycopolymer-gliadin conjugate) is a liver-targeting antigen-specific therapy designed to induce tolerance to gluten peptides in HLA-DQ2.5 positive patients[121]. The rationale for liver targeting is based on the liver’s natural tolerogenic properties. As the first immune organ exposed to dietary and microbial antigens from the gut, the liver favors deletion or anergy of antigen-specific T cells and supports the expansion of regulatory T cells. By directing gluten peptides to this environment, KAN-101 aims to reprogram pathogenic T cells into a tolerant state, thereby preventing the inflammatory cascade in CeD. A first-in-human phase 1 study demonstrated that KAN-101 was safe across escalating doses with no dose-limiting toxicities and had rapid clearance, supporting potential for long-term use[122]. More recently, data from the ongoing ACeD-it phase 1b/2 trial showed that KAN-101 not only modulates gluten-induced immune responses (attenuating T-cell and cytokine activation) but also leads to meaningful reductions in gluten-triggered symptoms and improved patient-reported outcomes[123]. The SynCeD phase 2a trial (KAN-101-03) (NCT06001177) is underway to assess the efficacy of KAN-101 in protecting the intestinal mucosa from gluten-induced damage in celiac patients on a GFD[124]. This multi-centre, double-blind, placebo-controlled study aims to evaluate histological protection in the duodenum, alongside continued safety and tolerability assessments.

TAK-101 is another antigen-specific tolerance therapy consisting of gliadin encapsulated in negatively charged poly (DL-lactide-co-glycolic acid) nanoparticles. Administered intravenously, these particles are taken up by APCs in the liver and spleen, where presentation of gliadin promotes T-cell anergy and regulatory T-cell induction[121]. A phase 1 dose-escalation trial (NCT03486990) confirmed safety and tolerability with no serious adverse events[125]. In the pivotal phase 2a trial (NCT03738475), 33 CeD patients on GFD underwent a 14-day gluten challenge: TAK-101 reduced circulating gliadin-specific IFN-γ-producing T cells by 88% vs placebo (P = 0.006), with trend towards preserved Vh:Cd ratio and modulation of effector memory T-cell subsets[125]. A larger phase 2 study (NCT04530123) is ongoing to further assess efficacy in controlling gluten-induced symptoms and immune activation in CeD patients subjected to gluten challenge[126].

TPM502 comprises of three peptides, each encoding two overlapping T-cell epitopes that capture the major gluten epitopes for HLA-DQ2.5. Recently reported results from a phase 2a, multi-centre, double-blind, randomized, placebo-controlled trial (NCT05660109) showed that TPM502 was safe and well tolerated across all doses, with mostly mild side effects and only a single patient experiencing multiple Grade 3 adverse events[127,128]. Importantly, TPM502 demonstrated a dose-dependent, statistically significant reduction in IL-2 and IFN-γ release by gluten-specific T cells, indicating effective antigen-specific tolerance. This immune reprogramming was supported by phenotypic changes in gluten-specific CD4+ T cells (consistent with anergy/exhaustion) and an increase in regulatory T cells, suggesting durable tolerance. Clinically, patients also reported a dose-dependent reduction in gastrointestinal symptoms following gluten challenge, captured using a validated celiac-specific patient-reported outcomes tool. These findings demonstrate successful antigen-specific tolerance induction in patients with CeD, supporting TPM502 as a promising disease-modifying therapy[128].

siRNA-based therapies: Nanoparticles delivering siRNA against TG2 or IL-15 have shown potential in vitro CeD models, reducing gliadin-induced immune activation[129].

Helminth therapy: Deliberate inoculation with Necator americanus (hookworm) has been investigated as a means to suppress gluten-driven immunopathology and potentially restore tolerance in CeD. The rationale stems from the ability of helminths to induce a Th2-skewed and regulatory immune environment (IL-4, IL-10, transforming growth factor-β, and expansion of Tregs), which can counterbalance the pathogenic Th1 responses in CeD[12]. The first prospective, randomized, double-blind, placebo-controlled phase 2 study (NCT00671138) enrolled 20 patients with CeD in remission on a GFD. Participants were randomized to hookworm inoculation or placebo. Duodenal as well as rectal biopsies and blood samples were collected before and after gluten challenge. Outcomes, including mucosal injury, systemic inflammation, and clinical response, showed no significant differences between groups, indicating that hookworm inoculation, although safe, did not prevent gluten-induced mucosal damage[130]. Another randomized, placebo-controlled phase 1 trial (NCT02754609) involving 54 CeD patients demonstrated that while hookworm infection failed to restore tolerance to sustained moderate gluten intake, it was associated with improved symptom scores after intermittent, very low-dose gluten exposure[131]. These studies indicate that N. americanus inoculation, although safe, does not prevent gluten-induced mucosal injury. Given the invasive nature of therapy, variable efficacy, and potential safety concerns, routine clinical application of hookworm infection in CD remains unlikely.

Strategy 6 microbiome modulation

Alteration in the gut microbiome (increased abundance of Bacteroides spp. and a decrease in Bifidobacterium spp.) has been linked to CeD pathogenesis[132], and several microbiota-directed strategies have therefore been explored as adjunctive treatments. Probiotics (mainly Bifidobacterium and Lactobacillus strains, and multi-strain mixes such as VSL#3) may reduce symptoms in patients after staring a GFD[66,133]. Figure 5 enumerates the potential benefits of probiotics in the treatment of CeD[134,135]. Lindfors et al[10] evaluated Lactobacillus fermentum and Bifidobacterium lactis (B. lactis) in Caco-2 cell cultures and found that B. lactis prevented gliadin-induced epithelial barrier dysfunction, suggesting a protective effect against toxic gliadin peptides[136]. In a small RCT of 22 patients with active CeD on a gluten-containing diet, Bifidobacterium infantis improved gastrointestinal symptoms but did not alter cytokines, serology, or gut permeability[137]. In newly diagnosed children, Bifidobacterium longum CECT 7347 given with a GFD improved growth parameters, reduced CD3⁺ T cells, lowered TNF-α, and favourably modified the microbiota, although without symptom improvement[138]. In another RCT, VSL#3 showed no benefit in microbiota composition or symptoms after two weeks in symptomatic patients on a GFD[139]. A recent crossover RCT of B. infantis in persistently symptomatic adults on a long-term GFD reported improvement in specific symptoms among the most symptomatic patients (P = 0.046), along with distinct shifts in stool microbiota composition, but no changes in GIP or adverse events[140]. In conclusion, probiotic therapy in CeD shows modest and strain-specific effects, with some evidence for symptom improvement and microbiota modulation, but no consistent impact on serology, mucosal healing, or gluten handling. Current data remain preliminary, and larger, well-controlled trials are required before probiotics can be recommended as adjunctive therapy in CeD.

Figure 5  Potential benefits of probiotics in celiac disease.

Strategy 7 miscellaneous

Mesenchymal stem cells: Mesenchymal stem cells (MSCs) possess potent immunomodulatory and regenerative properties and have been used experimentally in severe/refractory cases[66]. Ciccocioppo et al[141] described a 51-year-old woman with type II RCD who experienced symptomatic improvement following multiple infusions of autologous bone marrow-derived MSCs[141]. While MSCs represent a theoretically promising approach for refractory or complicated CeD, their use remains experimental and far from routine clinical application.

SIRT 6 modulator: IMU-856 is an oral small molecule modulator of sirtuin 6, a protein that serves as a transcriptional regulator of bowel epithelium regeneration. A first-in-human, double-blind, randomized, placebo-controlled trial of IMU-856 in healthy volunteers and patients with CeD showed that the drug was generally safe and well tolerated, with mostly mild adverse events[142]. In the gluten-challenge arm, patients receiving IMU-856 had markedly less villous height reduction compared with placebo, suggesting a potential protective effect on intestinal mucosa.

OX40 L blockade: Amlitelimab (SAR445229) is a fully human, non-depleting monoclonal antibody targeting the OX40 ligand, a co-stimulatory molecule expressed on APCs. By binding to OX40 ligand, amlitelimab inhibits its interaction with the OX40 receptor on activated T cells, thereby modulating T-cell activation and reducing inflammation without depleting T cells[143]. This mechanism offers a novel approach to controlling immune responses in autoimmune diseases. In CeD, it is being evaluated in a phase 2a/b trial (NCT06557772) for adults with non-responsive CeD, aiming to improve gluten-induced intestinal mucosal changes (as measured by the villous height to crypt depth ratio) and symptoms. The trial is actively recruiting participants[144].

CRITICAL APPRAISAL OF EMERGING THERAPIES IN CED

Table 2 summarizes key published trials on CeD drugs[68,71,75,79,83-86,95,104-107,111,113,117,120,122-125,127,128,131,137-139,141,142,145,146]. Despite remarkable expansion of therapeutic research in CeD, most emerging therapies have demonstrated only partial or inconsistent efficacy due to major trial-level constraints. Many studies suffer small sample sizes and short follow-up, producing low statistical power to detect clinically important changes in mucosal histology or rare safety signals. Heterogeneity in trial design, including variable gluten doses, differing challenge durations, inconsistent primary endpoints (symptoms, serology, Vh:Cd ratio, or IEL counts) and diverse patient selection criteria, creates difficulty in cross-trial comparison and risks selective reporting. Glutenases such as AN-PEP, latiglutenase, and TAK-062 show biochemical degradation of gluten in vitro or during controlled gluten challenges, but large trials consistently fail to demonstrate meaningful mucosal protection, limiting their role to mitigation of accidental exposure. TJ modulators (larazotide) improve symptoms modestly but have not shown robust histologic benefit, and phase 3 development was halted because the modest effect size required an impractically large sample to demonstrate efficacy. tTG2 inhibition (ZED1227) remains the most promising enzymatic approach, with clear dose-dependent histologic protection, but concerns about long-term safety and systemic spillover require clarification. Immunomodulatory approaches are biologically rational but have yielded variable results, often improving symptoms or IEL counts without reversing villous injury, and also raise important safety concerns, including infection risk, cytopenias, thromboembolic events, and potential long term malignancy risk, which are unacceptable for many patients with otherwise well-controlled disease on a GFD. Antigen-specific tolerance therapies represent a major conceptual advance, showing consistent suppression of gluten-specific T-cell responses, though long-term durability and real-world mucosal protection remain unproven. Nanoparticle-based delivery systems appear safe and mechanistically potent but require large, multi-dose trials. Microbiome-directed therapies and stem-cell-based strategies remain experimental with limited clinical applicability. Overall, current data suggest that most agents are likely to function as adjuncts to GFD rather than replacements, and robust, longer-duration phase 3 trials with standardized endpoints and comprehensive safety monitoring are needed before widespread clinical adoption.

Table 2 Summary of key published trials on celiac disease drugs.

Drug	Mechanism	Trial design	Result	Ref.
AN-PEP	Gastric active enzyme; degrades gluten peptides	RCT in a complex meal setting (containing 0.5 g gluten); measured gastric/duodenal gluten levels	Significantly degraded most gluten in stomach	[145]
AN-PEP	Oral glutenase	RCT, CeD on GFD; 650 mg × 3/day × 4 weeks	No significant reduction in stool GIP vs placebo	[68]
Latiglutenase (ALV003/IMGX003)	Combination oral glutenase	Phase 2 RCT (multicentre); 494 symptomatic CeD; multiple doses tested (100-900 mg); 12-24 weeks	No overall improvement in histology or symptoms vs placebo	[71]
			Post-hoc analysis showed symptom benefit in seropositive subgroup
Latiglutenase (ALV003/IMGX003)	Combination oral glutenase	Phase 2 gluten challenge RCT; 1200 mg latiglutenase; 2 g/day gluten × 6 weeks	Reduced mucosal damage and symptom severity vs placebo	[146]
TAK 062 (kuma 062/zamaglutenase	Engineered protease, active at gastric pH	RCT phase 2 (ILLUMINATE-062 trial) (NCT05353985) in 153 CeD patients, used SIGE-gluten bar	Well tolerated; no significant benefit over placebo	[75]
BL 7010	Non-absorbable gluten sequestering polymer	Phase 1/2 RCT; well-controlled CeD; single and repeated doses	Safe, limited systemic absorption; full results unpublished	[79]
Larazotide acetate (AT 1001)	Zonulin pathway blocker, stabilizes tight junctions	Meta-analysis of 4 RCTs	Well tolerated; improved GI symptoms vs placebo	[83]
Larazotide acetate	Zonulin pathway blocker, stabilizes tight junctions	Phase 3 RCT (CedLara)	Terminated due to sample size	[84]
ZED 1227	Oral selective intestinal tTG2 inhibitor	Phase 2 gluten challenge RCT; 6 weeks ZED 1227 at 3 different doses	Dose dependent mucosal protection; improved symptoms	[86]
Budesonide	Locally acting steroid; reduced systemic absorption	RCT, 20 CeD patients with malabsorption, budesonide 6 mg × 4 weeks plus GFD	Greater efficacy in relieving symptoms vs GFD alone	[95]
AMG 714 (PRV 015)	Anti-IL15 mAb (blocks IL15)	Phase 2a gluten challenge RCT; AMG 150 mg or 300 mg given as 2 subcutaneous injections every 2 weeks × 10 weeks	Failed primary endpoint (Vh:Cd) change (baseline and week 12) but improved symptoms and IEL density	[105]
AMG 714	Anti-IL15 mAb	Phase 2a RCT; 28 patients [refractory CeD type II; 2 IV doses of AMG 714 (8 mg/kg)] over 10 weeks vs placebo	No change in aberrant IELs but symptomatic benefit	[106]
CALY 002 (PRV-015)	Anti-IL15 mAb	Phase 1 a/b gluten challenge RCT	Good tolerability; attenuated mucosal injury	[107]
Anti-α4β7 integrin (vedolizumab)	Blocks gut-homing lymphocytes	Phase 2 gluten challenge RCT	Terminated due to insufficient enrollment	[104]
Tofacitinib	Small molecule JAK 1/3 inhibitor	Open label study; refractory type II CeD; 6 patients	Clinical and histologic benefit, but no change in the amount of aberrant IELs	[111]
Teriflunomide	Lymphocyte proliferation inhibitor (suppresses de novo pyrimidine synthesis)	Gluten challenge phase 2a RCT; 15 CeD patients; assessed gluten specific T cell activation and efflux using HLA DQ gluten tetramers	Teriflunomide was not effective in reducing gluten specific T cell activity vs placebo	[113]
RO5459072 (cathepsin S inhibitor)	Antigen presentation blocker	Single centre, gluten challenge RCT; 19 CeD patients; 100 mg × 2/day	Primary endpoint (↑ gliadin-specific IFN-γ secreting T cells) not met	[117]
NexVax2	Peptide vaccine (3 synthetic gliadin peptides	Phase 2 RCT; multicentre	Stopped early (no benefit)	[120]
KAN 101	Liver targeted glycopolymer gluten conjugate	Phase 1 RCT; HLA DQ2.5 CeD	Safe; rapid clearance	[122-124]
		ACeD-it phase 1b/2 RCT	Reduced T-cell/cytokine activation, improved PROs
		SynCeD phase 2a trial ongoing
TAK 101	Gliadin coated nanoparticles (IV, liver targeting)	Phase 1/2 gluten challenge RCT; 33 patients	Well tolerated; prevented mucosal injury	[125]
		Phase 2a RCT; 33 CeD, 14 day gluten challenge	↓ Gluten-specific IFN-γ+ T cells, mucosal protection vs placebo
TPM502	Nanoparticles carrying 3 gluten peptides	Phase 2a RCT	Safe; induced tolerance, ↓ IL-2/IFN-γ release, improved symptoms	[127,128]
Necator americanus (hookworm)	Immune deviation	RCT phase 1; 54 CeD; escalating gluten consumption	Improved symptoms at low gluten exposure; no sustained tolerance	[131]
Oligofructose enriched inulin	Prebiotic	RCT; 34 paediatric CeD; 12 weeks supplementation of oligofructose enriched inulin (10 g/day)	In patients with increased intestinal permeability, supplementation improved calprotectin and SAT	[147]
Oligofructose enriched inulin (synergy 1)	Prebiotic	34 paediatric CeD given synergy 1 (10 g/day) vs placebo (maltodextrin 7 g/day)	Synergy 1 modestly altered fecal microbiota quality and increased bacterial metabolite production	[148]
Probiotics (Bifidobacterium, VSL3)	Modulate microbiota; prevent barrier dysfunction	Small RCTs	Some symptom benefit; inconsistent mucosal/serology effect	[137,139]
IMV 856 (SIRT 6 modulator)	Enhances epithelial regeneration	Phase 1 RCT; 10-160 mg	Safe, less villous height reduction	[142]
MSCs	Immunomodulatory, regenerative	Case reports in RCD II	Symptomatic benefit; experimental	[141]

AN-PEP: Aspergillus niger prolyl-endopeptidase; CeD: Celiac disease; GFD: Gluten-free diet; RCT: Randomized controlled trial; SIGE: Simulated inadvertent gluten exposure; tTG: Tissue transglutaminase inhibitor; RCD: Refractory celiac disease; HLA: Human leucocyte antigen; IL: Interleukin; IFN: Interferon: Vh:Cd: Villous height-to-crypt depth; GIP: Gluten immunogenic peptide; IELs: Intraepithelial lymphocytes; JAK: Janus kinase; SAT: Sugar absorption test.

EMERGING MOLECULAR TARGETS IN CED

Recent insights from genome-wide association studies highlight several novel molecular targets beyond the classical HLA-DQ2/DQ8 predisposition that may shape future therapies for CeD. Candidate genes such as THEMIS (involved in thymocyte selection), PTPRK (linked to intestinal barrier integrity), FUT2 (modulating gut microbiota composition), BACH2 (a regulator of T- and B-cell differentiation and immune homeostasis), and RGS1 (regulating gut T-cell trafficking and inflammation) have emerged as promising targets[12]. These genetic pathways, largely related to T-cell maturation, barrier regulation, and microbiome interactions, provide opportunities to move beyond gluten exclusion toward precision therapies that reprogram immune tolerance, restore barrier function, or reshape host-microbial interactions in CeD.

CONCLUSION

CeD, once considered a condition managed solely by lifelong gluten avoidance, is now at the forefront of therapeutic innovation with a diverse range of investigational strategies in development. From gluten detoxification approaches (genetically modified wheat, glutenases, and sequestering polymers) to barrier stabilizers (larazotide), enzyme inhibitors (tTG2 blockers), HLA-DQ antagonists, immune-modulating biologics (anti-IL-15, JAK inhibitors, B-cell therapies), and cutting-edge tolerance-inducing strategies (nanoparticle-based immunotherapy), the therapeutic pipeline reflects a paradigm shift towards targeted and adjunctive treatments.

Yet, translation into routine practice remains challenging, as many agents demonstrate only surrogate efficacy without consistent mucosal healing, and most are likely to serve as adjuncts rather than replacements for the GFD. Small sample sizes, short study durations, and persistent safety concerns, particularly with immune-modulating therapies, further limit generalizability.

Looking ahead, advances in biomarkers, genomics, and microbiome research are expected to enable patient stratification and usher in a personalized, multimodal treatment approach that integrates dietary management with adjunctive pharmacological strategies tailored to individual disease phenotype and risk. While no agent has yet supplanted the GFD, the breadth of current research provides optimism that the next decade may finally deliver safe and effective adjuncts, and potentially transformative therapies, for patients living with CeD.