Published Research
Potassium-Competitive Acid Blocker Increases Ileal Permeability and Exacerbates Ileal Inflammation under Stress Conditions in a Mouse Model of Eosinophilic Enteritis.
Yamamoto K, Tanaka F, Nishida Y, Maruyama H, Ominami M, et al. — 2026
INTRODUCTION: Potassium-competitive acid blockers (P-CABs) have been empirically administered to treat non-esophageal eosinophilic gastrointestinal diseases, although their efficacy remains unproven. Our previous findings demonstrated that psychological stress impairs the intestinal barrier and exacerbates eosinophilic enteritis (EoN) in a mouse model. Moreover, we demonstrated that P-CAB increased intestinal permeability under psychological stress. The aim of this study is to clarify the hypothesis that P-CAB exacerbate EoN by increasing intestinal permeability under stressful conditions. METHODS: An EoN model was established in BALB/c mice using ovalbumin (OVA) sensitization and challenge. Mice were subjected to water avoidance stress (WAS) or sham stress (SS) and were administered P-CAB or saline as a vehicle. The ileum was collected for the analysis of ileal microscopic inflammation, mRNA and protein expression levels of T helper type 2 (Th2) cytokines, and ex vivo ileal permeability using a Ussing chamber. RESULTS: Compared with the WAS + Vehicle group, WAS + P-CAB significantly exacerbated the incidence of diarrhea, villus/crypt ratio, eosinophil and mast cell counts, mRNA and protein levels of Th2 cytokines, OVA-specific immunoglobulin E protein levels, and ileal permeability. Larazotide acetate, a zonulin inhibitor, significantly improved ileal inflammation and decreased ileal permeability in the WAS + P-CAB-treated EoN mice. CONCLUSIONS: P-CAB increased ileal permeability and exacerbated EoN under stressful conditions. Furthermore, a zonulin inhibitor demonstrated therapeutic effects in EoN with P-CAB under stressful conditions.
Integrated Role of Microbial, Fungal, and Plant-Derived Interventions in the Management of Celiac Disease: A Narrative Review.
Kubala K, Pietrucha T, Goldyn M, Grabinska M, Halik P, et al. — 2026
Celiac disease (CeD) is a chronic autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals carrying human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes. While a strict gluten-free diet (GFD) remains the primary treatment, many patients experience persistent symptoms and incomplete mucosal recovery, often due to accidental exposure. This narrative review evaluates complementary biological strategies that enhance gluten management beyond dietary avoidance. We discuss enzymatic approaches using bacterial and fungal prolyl endopeptidases (PEPs) and engineered enzyme combinations, such as latiglutenase, to degrade immunogenic peptides in the gastrointestinal tract. Furthermore, we examine the restoration of intestinal barrier integrity through zonulin antagonists such as larazotide acetate. The role of gut microbiota modulation with probiotics, such as Lactobacillus and Bifidobacterium strains, is analyzed for its potential to reduce inflammation and support gliadin degradation. Additionally, plant-derived cysteine proteases from sprouting cereals are presented as promising agents for gluten detoxification. Finally, the application of enzymatic degradation in food processing is considered to improve the safety and affordability of gluten-free products. Together, these strategies offer a multidimensional framework for enhancing clinical outcomes and quality of life for individuals with CeD.
Larazotide Acetate Protects the Intestinal Mucosal Barrier from Anoxia/Reoxygenation Injury via Various Cellular Mechanisms.
Kim J, Madan JP, Laumas S, Krishnan BR, Jin Y — 2025
: Larazotide acetate (LA) is a synthetic octapeptide under development as a therapeutic candidate for celiac disease, acting to reduce intestinal permeability and regulate tight junctions (TJs). Although several studies have shown barrier-protective effects, the cellular mechanisms underlying LA's actions in the intestinal epithelium remain unclear. This study aimed to elucidate the mechanistic roles of LA in maintaining intestinal epithelial integrity during cellular injury. C2BBe1 and leaky IPEC-J2 cell monolayers were pretreated with 10 mM LA and subjected to anoxia/reoxygenation (A/R) injury. Transepithelial electrical resistance (TEER), TJ protein localization, and phosphorylation of myosin light chain-2 (MLC-2) were analyzed. In addition, RNA sequencing was conducted to identify differentially expressed genes and signaling pathways affected by LA treatment. LA pretreatment significantly increased TEER and preserved TJ protein organization during A/R injury. Transcriptomic analysis revealed enrichment of genes related to barrier regulation, small GTPase signaling, protein phosphorylation, proliferation, and migration. LA pretreatment markedly reduced MLC-2 phosphorylation, likely through modulation of the ROCK pathway, consistent with RNA-seq findings. Moreover, LA enhanced cellular proliferation, validating transcriptomic predictions. LA exerts a protective effect on intestinal epithelial integrity by stabilizing tight junctions, reducing MLC-2 phosphorylation, and promoting epithelial proliferation. These findings highlight a novel mechanism for LA and support its therapeutic potential in treating gastrointestinal disorders associated with "leaky gut" and mucosal injury.
Is There a Future Without Gluten Restrictions for Celiac Patients? Update on Current Treatments.
Girbal-González M, Pérez-Cano FJ — 2025
Celiac disease (CeD) is a chronic autoimmune enteropathy triggered by dietary gluten in genetically predisposed individuals. Along with other disorders such as non-celiac gluten/wheat sensitivity and gluten allergy, adherence to a strict gluten-free diet (GFD) is required as the only effective treatment for CeD. To this end, and partially due to the burdensome nature and limited efficacy in some patients of a GFD, significant research into alternative therapies has been catalyzed. This review gives a perspective on current and emerging treatment strategies targeting different aspects of CeD pathogenesis. These include gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), modulators of intestinal permeability (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), and strategies for immune tolerization (e.g., TAK-101, KAN-101, Nexvax2). Newer approaches are also targeting probiotics to modulate the gut microbiota (e.g., VSL#3, HEAL9), nutraceuticals (e.g., polyphenols, vitamins), or food modifications to remove the gluten from naturally gluten-containing foodstuffs (e.g., gluten transamidation, Gluten Friendly™ technology). Despite encouraging results in preclinical and clinical trials, no treatment has yet been conclusively proven to serve as an effective alternative to the GFD. Continued research is essential to validate efficacy, optimize dosing, and ensure safety in broader patient populations. Here, we provide a comprehensive overview of the therapeutic landscape for CeD, analyze the main strengths and limitations of each treatment and highlight promising directions for future management of CeD, altogether evidencing the urgent need to develop effective alternatives for these patients.
Antibacterial hyaluronic acid hydrogel with sustained release of larazotide as effective colitis treatment.
Yu F, Chen Y, Ouyang S, Tong B, Jiang Z, et al. — 2025
Gut barrier loss exacerbated gut microbiota dysbiosis by permitting pathogenic blooms, while gut microbiota dysbiosis caused the development of gut mucosal wounds by reducing mucus and breaking down epithelial tight junction. Current therapies combating colitis often fail to address both gut barrier dysfunction and microbial imbalance. Herein, inspired by natural gut mucus, a dual-crosslinked hydrogel (HSMP-LA) composed of thiol/maleimide-modified hyaluronic acid together with co-loading of antimicrobial ε-polylysine (ε-PL) and larazotide acetate (LA) had been developed as an injectable artificial gut mucus to simultaneously restore barrier integrity and modulate gut microbiota. HSMP-LA exhibited robust muco-adhesion, the prolonged retention, and sustained-release profile of LA, effectively shielding the epithelium from luminal pathogens and toxins. Besides, HSMP-LA showed the broad-spectrum antimicrobial activity, while its sustained-release LA selectively inhibited zonulin-mediated tight junction disruption via combating MLCK/p-MLC signals, restoring epithelial integrity in LPS-injured Caco-2 cells. In DSS-induced colitis mice, HSMP-LA significantly reduced disease activity, suppressed pro-inflammatory cytokines and upregulated anti-inflammatory IL-10. It repaired tight junctions (ZO-1, occluding and claudin-5), restored mucus production (MUC2), and rebalanced gut microbiota. HSMP-LA hydrogel might offer a synergistic strategy to combat colitis via halting the vicious dysbiosis-mucus-epithelial barrier disorders cycle.