Larazotide Acetate: A Pharmacological Peptide Approach to Tight Junction Regulation

2021 ◽  
Author(s):  
Zachary M Slifer ◽  
B Radha Krishnan ◽  
Jay Madan ◽  
Anthony T Blikslager
Keyword(s):  
Celiac Disease ◽  
Tight Junction ◽  
Barrier Function ◽  
Actin Filaments ◽  
Animal Studies ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Small Rodent ◽  
Immune Reactivity ◽  
Single Chain

Larazotide acetate (LA) is a single-chain peptide of eight amino acids that acts as a tight junction regulator to restore intestinal barrier function. LA is currently being studied in phase 3 clinical trials and is orally administered to adult patients with celiac disease as an adjunct therapeutic to enhance intestinal barrier function that has been disrupted by gliadin-induced immune reactivity. Mechanistically, LA is thought to act as a zonulin antagonist to reduce zonulin-induced increases in barrier permeability and has been associated with the redistribution and rearrangement of tight junction proteins and actin filaments to restore intestinal barrier function. More recently, LA has been linked to inhibition of myosin light chain kinase, which likely reduces tension on actin filaments, thereby facilitating tight junction closure. Small (rodent) and large (porcine) animal studies have been conducted that demonstrate the importance of LA as a tight junction regulatory peptide in conditions other than celiac disease, including collagen-induced arthritis in mice and intestinal ischemic injury in pigs.

scholarly journals The Punicalagin Metabolites Ellagic Acid and Urolithin A Exert Different Strengthening and Anti-Inflammatory Effects on Tight Junction-Mediated Intestinal Barrier Function In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Nina A. Hering ◽  
Julia Luettig ◽  
Britta Jebautzke ◽  
Jörg D. Schulzke ◽  
Rita Rosenthal
Keyword(s):  
Protein Expression ◽  
Tight Junction ◽  
Ellagic Acid ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Bioactive Metabolites ◽  
Cell Models ◽  
Urolithin A ◽  
Ht 29

Scope: Ellagitannins are polyphenols found in numerous fruits, nuts and seeds. The elagitannin punicalagin and its bioactive metabolites ellagic acid and urolithins are discussed to comprise a high potential for therapeutically or preventive medical application such as in intestinal diseases. The present study characterizes effects of punicalagin, ellagic acid and urolithin A on intestinal barrier function in the absence or presence of the proinflammatory cytokine tumor necrosis factor-α (TNFα).Methods and Results: Transepithelial resistance (TER), fluorescein and ion permeability, tight junction protein expression and signalling pathways were examined in Caco-2 and HT-29/B6 intestinal epithelial cell models. Punicalagin had less or no effects on barrier function in both cell models. Ellagic acid was most effective in ileum-like Caco-2 cells, where it increased TER and reduced fluorescein and sodium permeabilities. This was paralleled by myosin light chain kinase two mediated expression down-regulation of claudin-4, -7 and -15. Urolithin A impeded the TNFα-induced barrier loss by inhibition of claudin-1 and -2 protein expression upregulation and claudin-1 delocalization in HT-29/B6.Conclusion: Ellagic acid and urolithin A affect intestinal barrier function in distinct ways. Ellagic acid acts preventive by strengthening the barrier per se, while urolithin A protects against inflammation-induced barrier dysfunction.

scholarly journals Maternal Dietary Linoleic Acid Altered Intestinal Barrier Function in Domestic Pigeons (Columba Livia)

2020 ◽  
Author(s):  
Qianqian Xu ◽  
Xiaoting Zou ◽  
Xinyang Dong
Keyword(s):  
Gene Expression ◽  
Linoleic Acid ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Morphology ◽  
Adverse Impact ◽  
Intestinal Barrier Function ◽  
Intestinal Health ◽  
Inflammation Cytokines

Abstract BackgroundLinoleic acid (LA) is predominantly essential for poultry. Deficiency of LA in poultry were manifested in various aspects such as retarded growth and reduced resistance to disease. The effects of LA on intestinal health in vitro and in mammals has been studied, whereas research related to the effects of LA on intestine health in poultry was scanty. Intestinal health and immune function play an important role in pigeon squab growth. Considering squabs are fed by their parents, the purpose of this study was to explore the effects of maternal dietary LA on intestinal barrier function in squabs by determining intestinal morphology, gene expression of tight junction protein, immune cytokines, and microbial flora.ResultsA completely randomized design with a control group, 1% dietary LA supplementation group, 2% dietary LA supplementation group, and 4% dietary LA supplementation group was used. Six squabs from each treatment were randomly sampled at 21 posthatch. Results indicated that LA supplementation improved intestinal morphology as reflected by increased villus height, villus area and the ratio of villus to crypt, and the promotion at dosage of 1% was most significant. Besides, 1% LA supplementation elevated distribution density of goblet cell in intestine, and strengthened tight junction between enterocytes by up-regulating claudin3 and occludin gene expression, but down-regulating claudin2 gene expression. Moreover, 1% LA supplementation reduced secretion of pro-inflammation cytokines and increased anti-inflammation cytokines partly. The diversity index Chao1 of intestinal microbiota in 1% LA supplementation group was higher than other groups. And Butyrivibrio as beneficial bacteria was the biomarker of LA1%. However, excessive (4%) LA supplementation led to adverse impact on intestinal immunity and microbiota.ConclusionsMaternal dietary LA in three levels all could improve intestinal morphology in squabs. Therein, appropriate dosage (1%) supplementation might enhance mucosal protection and epithelium barrieer in squabs, and furthermore consolidated intestine immunity and luminal microbial environment. However, excessive (4%) LA supplementation might lead to adverse impact on immunity and microbiota. Maternal dietary LA might alter intestinal barrier function in pigeon squabs in a dose-dependent manner.

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