Larazotide acetate

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

Purpose:The standard of care for treatment of celiac disease (CD) is a stringent lifetime gluten-free diet (GFD). Larazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of CD. We endeavored to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) which studied the efficacy and safety of AT-1001 in patients with CD.Methods:We examined four databases from inception to 20-August-2020. We pooled continuous outcomes as mean difference and dichotomous outcomes as risk ratio with 95% confidence interval under the fixed-effects meta-analysis model.Results:Four RCTs met our eligibility criteria, comprising 626 patients (AT-1001, n=465, placebo, n=161). Three and two RCTs reported outcomes of patients undergoing gluten challenge (intake of 2.4-2.7 grams of gluten/day) and GFD, respectively. For change in lactulose-to-mannitol ratio, the endpoint did not significantly differ between AT-1001 and placebo groups, irrespective of the gluten status. Subgroup analysis of patients undergoing gluten challenge showed AT-1001 treatment (compared with placebo) significantly correlated with better symptomatic improvement in the two endpoints of change in total gastrointestinal symptom rating scale (total GSRS) and CD-specific GSRS (CD-GSRS). However, no significant difference was noted among patients undergoing GFD for the abovementioned two efficacy endpoints. Compared with placebo, AT-1001 favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge. Other AEs were comparable between both AT-1001 and placebo groups.Conclusions:AT-1001 is largely well-endured and seems somehow superior to placebo in alleviating gastrointestinal symptoms among CD patients undergoing gluten challenge. Nevertheless, additional RCTs are warranted to validate these findings.

Background and aim:The epithelial cells are the strongest determinants of the physical intestinal barrier. Tight junctions (TJs) hold the epithelial cells together and allow for selective paracellular permeability. Larazotide acetate (LA) is a synthetic octapeptide that reduces TJ permeability by blocking zonulin receptors. In this study, we aimed to investigate the effects of LA, a TJ regulator, on the liver and intestinal histology in the model of acute liver failure (ALF) in rats.Materials and methods:The thioacetamide (TAA) group received intraperitoneal (ip) injections of 300 mg/kg TAA for 3 days. The TAA+LA(dw) (drinking water) group received prophylactic 0.01 mg/mL LA orally for 7 days before the first dose of TAA. The LA(dw) group received 0.01 mg/mL LA orally. The TAA + LA(g) (gavage) group received prophylactic 0.01 mg/mL LA via oral gavage for 7 days before the first dose of TAA. The LA(g) group received 0.01 mg/mL LA via oral gavage. While liver tissue was evaluated only with light microscopy, intestinal samples were examined with light and electron microscopy.Results:Serum ammonia, AST, and ALT levels in the TAA group were significantly higher than in control groups (allp< 0.01). Serum ALT levels in the TAA + LA(dw) group were significantly lower than in the TAA group (p< 0.05). However, serum ammonia and ALT levels did not differ between the TAA and other groups. Serious liver damage in the TAA group was accompanied by marked intestinal damage. There was no significant difference between the TAA and TAA + LA(dw) groups and TAA and TAA + LA(g) groups for liver damage scores. However, intestinal damage scores significantly decreased in the TAA + LA(dw) group compared to the TAA group. In the TAA + LA(dw) group, fusion occurred between the surface epithelial cells of neighboring villi and connecting regions formed as epithelial bridges between the villi.Conclusion:Our findings suggest that LA reduced intestinal damage by acting on TJs in the TAA-induced ALF model in rats.