The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate

Abstract

Celiac disease (CD) is a common chronic immune disease triggered by gluten. Gliadin peptides pass through the epithelial layers, either paracellularly or transcellularly, to launch a potent adaptive immune response in the lamina propria. This aberrant immune response leads to diverse gastrointestinal and extra-gastrointestinal symptoms. Currently, the only treatment for CD is a strict lifelong adherence to a gluten-free diet (GFD), which can be challenging. An early effect of gluten in CD is an increase in gut permeability. Larazotide acetate, also known as AT-1001, is a synthetic peptide developed as a permeability regulator primarily targeting CD. In vitro studies indicate that larazotide acetate is capable of inhibiting the actin rearrangement caused by gliadin and clinical studies have been conducted using this peptide as a therapy for CD.

Keywords: Caco-2 cells; gliadin; gluten-free diet; intestinal integrity; paracellular permeability; zonulin.

Figure 1.

Gliadin peptides pass through the epithelial barrier paracellularly or transcellularly. In the transcellular pathway, the gliadin peptides bind to the secretory IgA at the apical membrane of intestine. Then transferrin receptor CD71 facilitates the delivery of the gliadin peptides to the lamina propria. In the paracellular pathway, the gliadin peptides bind to CXCR3. At the same time, zonulin is released and subsequent transactivation of EGFR by PAR₂ leads to disorganization of the tight junction and entrance of gliadin peptides to the lamina propria. APC, antigen presenting cells; CXCR3, chemokine CXC motif receptor 3; EGFR, epidermal growth factor receptor; HLA, human leukocyte antigen; IgA, immunoglobulin A; IFN-γ, interferon-γ; MYD88, myeloid differentiation factor 88; PAR₂, protease activated receptor 2; TCR, T-cell receptor; TG2, transglutaminase 2; TJ, tight junction; TNF-α, tumour necrosis factor-α.

Figure 2.

Molecular structure of larazotide acetate.