Review
This review examines the role of intestinal barrier dysfunction in coeliac disease (CD), a condition in which genetically predisposed individuals mount an immune-mediated response to dietary gluten that damages the small intestine. The authors explore the evidence that increased intestinal permeability is a central feature of CD pathophysiology, detailing the contributing mechanisms: dysregulation of the protein zonulin, pro-inflammatory cytokines, alterations in gut microbiota, and immune responses to gliadin peptides. The review then comprehensively surveys therapeutic strategies aimed at restoring barrier integrity, including dietary interventions, nutritional supplements, and investigational pharmacological agents such as larazotide acetate (a tight-junction regulator) and IMU-856 (a SIRT6 activator targeting mucosal regeneration). The authors also highlight a key limitation in the field: the absence of validated, reliable biomarkers for accurately measuring intestinal permeability in CD. They advocate for further research into barrier-restoring therapies, particularly as adjuncts to a gluten-free diet for maintaining disease remission. As a narrative review, the paper synthesises existing literature but does not generate new primary data, and conclusions are subject to the quality and heterogeneity of the underlying studies.
Review
This narrative review examines complementary biological strategies for managing celiac disease (CeD) beyond a strict gluten-free diet (GFD). The authors synthesize evidence on several therapeutic approaches: (1) enzymatic degradation of immunogenic gluten peptides using bacterial and fungal prolyl endopeptidases (PEPs) and engineered enzyme combinations such as latiglutenase; (2) restoration of intestinal barrier integrity via the zonulin antagonist larazotide acetate; (3) gut microbiota modulation using probiotic strains including Lactobacillus and Bifidobacterium to reduce inflammation and support gliadin breakdown; and (4) plant-derived cysteine proteases from sprouting cereals as gluten detoxification agents. The review also considers enzymatic processing in food production to improve safety and accessibility of gluten-free products. The authors frame these strategies as a multidimensional complement to the GFD, particularly for patients with persistent symptoms or incomplete mucosal recovery following accidental gluten exposure. Limitations inherent to this study type include the absence of a systematic search protocol, potential selection bias in source inclusion, and the inability to draw causal conclusions. Primary clinical trial data across the reviewed interventions vary considerably in quality and scale.
Review
This review examines the current and emerging therapeutic landscape for celiac disease (CeD), an autoimmune enteropathy triggered by dietary gluten. The authors note that while a strict gluten-free diet (GFD) remains the only established treatment, its burdensome nature and incomplete efficacy in some patients have driven significant research into alternatives. The review systematically covers multiple therapeutic categories: gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), intestinal permeability modulators (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), immune tolerization strategies (e.g., TAK-101, KAN-101, Nexvax2), probiotics, nutraceuticals, and food modification technologies. The authors conclude that despite encouraging preclinical and early clinical results across these approaches, no therapy has yet been conclusively proven as an effective GFD alternative. Key limitations of the review include its narrative rather than systematic design, potential selection bias in literature cited, and the absence of head-to-head comparisons between strategies. The authors emphasize the urgent need for further research to validate efficacy, optimize dosing, and establish safety in broader patient populations.
Nutrients · Sep 2025DOI ↗ Review
This narrative review examines emerging therapeutic strategies for four major pediatric gastroenterological conditions: celiac disease (CeD), eosinophilic esophagitis (EoE), inflammatory bowel disease (IBD), and autoimmune hepatitis (AIH). For CeD, the authors discuss gluten-degrading enzymes (latiglutenase, Kuma030), the zonulin inhibitor larazotide acetate, transglutaminase 2 inhibitors (ZED-1227), and monoclonal antibodies such as AMG 714, noting inconsistent clinical outcomes and limited pediatric data. For EoE, biologics including dupilumab, cendakimab, dectrekumab (IL-13 inhibitors), mepolizumab, reslizumab, benralizumab (IL-5/IL-5R inhibitors), and the TSLP inhibitor tezepelumab are reviewed with varying reported efficacy. IBD coverage includes biologics (vedolizumab, ustekinumab, risankizumab) and small molecules (tofacitinib, etrasimod, upadacitinib), alongside personalized approaches integrating therapeutic drug monitoring. Emerging AIH therapies for refractory or steroid-dependent cases are also explored. The authors highlight proteomics and precision medicine as growing tools to individualize care. A key limitation is the narrative design, which is subject to selection bias, and the scarcity of pediatric-specific trial data across all discussed treatments.
Healthcare (Basel, Switzerland) · Apr 2025DOI ↗ Review
This review paper examines the role of zonulin — a protein that regulates intestinal tight junctions (TJs) — in the pathogenesis of Chronic Inflammatory Disorders (CIDs). The authors explore how dysregulation of zonulin contributes to increased intestinal permeability ("leaky gut"), which may facilitate the translocation of harmful substances from the gut into the bloodstream, potentially driving or worsening conditions such as Inflammatory Bowel Disease (IBD), celiac disease, and Multiple Sclerosis (MS). The paper synthesizes preclinical and clinical research on larazotide acetate, a zonulin antagonist, highlighting its potential to improve gut barrier integrity and reduce inflammation in CID patients. The authors also discuss zonulin's promise as a biomarker for intestinal permeability. Key limitations acknowledged by the review include the need for further mechanistic clarification of zonulin antagonists and robust clinical trials to establish their efficacy and safety. As a narrative review, this paper does not generate new primary data, and its conclusions are dependent on the quality and consistency of the underlying studies it synthesizes. The authors call for continued research to inform personalized therapeutic strategies for CIDs.
Current medicinal chemistry · Jan 2025DOI ↗ Review
This review examines the role of zonulin — a protein regulator of tight junctions in intestinal epithelial cells — in the context of the microbiota-gut-brain axis. The authors synthesize evidence from the past decade linking gut dysbiosis to increased intestinal permeability, whereby bacterial fragments and toxins enter systemic circulation, trigger local and systemic inflammation, and ultimately affect the brain. The review discusses how zonulin may also influence blood-brain barrier integrity, suggesting a dual role in both gut and neurological health. The authors survey potential pharmaceutical strategies targeting zonulin-associated pathways, including larazotide acetate and various zonulin receptor agonists and antagonists. Notably, the review also raises important methodological concerns, including inconsistent and potentially misleading nomenclature surrounding "zonulin" in the literature, as well as unresolved questions about the protein's exact molecular sequence. As a narrative review, it does not present new experimental data and is subject to selection bias. Its strength lies in synthesizing emerging findings and clearly identifying open scientific questions, making it a useful conceptual reference but not a source of direct clinical evidence.
International journal of molecular sciences · Apr 2023DOI ↗ Review
This systematic review examines the role of the zonulin pathway in regulating tight junction integrity and its contribution to increased epithelial and endothelial permeability across a range of chronic and acute inflammatory conditions. The authors searched PubMed and Google Scholar using terms related to Larazotide (also known as AT-1001, FZI/0, and INN-202), retrieving 209 publications, which were then filtered for relevance and English language. Findings were organized by disease area, including celiac disease, type 1 diabetes, other autoimmune diseases, inflammatory bowel disease, Kawasaki disease, respiratory diseases (both infectious and non-infectious), and miscellaneous conditions. The review concludes that evidence from both in vivo and in vitro studies supports a substantial role for zonulin dysregulation in these diseases, and suggests Larazotide — a zonulin antagonist — as a potentially viable therapeutic strategy. The authors also highlight newly identified molecular targets for Larazotide. Key limitations include the heterogeneity of the underlying studies (spanning animal models, in vitro work, and human trials of varying quality), and the review's broad scope may obscure differences in evidence quality across disease indications.
Current medicinal chemistry · Jan 2021DOI ↗