From celiac disease to coccidia infection and vice‐versa: The polyQ peptide CXCR3‐interaction axis

Abstract

Zonulin is a physiological modulator of intercellular tight junctions, which upregulation is involved in several diseases like celiac disease (CeD). The polyQ gliadin fragment binds to the CXCR3 chemokine receptor that activates zonulin upregulation, leading to increased intestinal permeability in humans. Here, we report a general hypothesis based on the structural connection between the polyQ sequence of the immunogenic CeD protein, gliadin, and enteric coccidian parasites proteins. Firstly, a novel interaction pathway between the parasites and the host is described based on the structural similarities between polyQ gliadin fragments and the parasite proteins. Secondly, a potential connection between coccidial infections as a novel environmental trigger of CeD is hypothesized. Therefore, this report represents a promising breakthrough for coccidian research and points out the potential role of coccidian parasites as a novel trigger of CeD that might define a preventive strategy for gluten-related disorders in general. Also see the video abstract here: https://youtu.be/oMaQasStcFI

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

“…Zhang et al proved on CXCR3 knock-out mice that LPS-induced intestinal dysfunction and barrier damage is a CXCR3-dependent mechanism related to the NF-κB signalling pathway [ 55 ]. Lauxmann et al drew attention to the structural similarity between gliadin fragments and certain parasite proteins and showed that the polyQ sequences of coccidian proteins can bind to the intestinal CXCR3 receptor, leading to an increase in intestinal permeability, thereby promoting parasite invasion into the lamina propria [ 56 ]. Indeed, the possible connection between zonulin and parasitic infections, such as malaria, was suggested by genetic studies, demonstrating an increased allele frequency in disease population [ 57 ].…”

Cyclospora cayetanensis: A Perspective (2020–2023) with Emphasis on Epidemiology and Detection Methods

“…In a recent study, a large percentage of patients (46.7%, 50/107) with unexplained rheumatic pain had a parasitic infection; cyclosporiasis was observed in 32% of those patients [ 115 ]. It has also been hypothesized that coccidia infections, including cyclosporiasis, could be environmental triggers for celiac disease [ 116 ]. Most reported clinical cases of cyclosporiasis in the past three years involved immunocompromised persons, such as HIV-positive, transplant recipients, or cancer patients [ 15 , 114 , 117 , 118 , 119 , 120 ].…”

Bromelain-loaded nanocomposites decrease inflammatory and cytotoxicity effects of gliadin on Caco-2 cells and peripheral blood mononuclear cells of celiac patients

“…Glutamine-rich sequences of gliadin, especially 19-mer, bind to the highly expressed CXCR3 receptors, thus leading to increased intestinal epithelial permeability due to the increased release of zonulin. This increased permeability leads to the entrance of gliadin-derived toxic and immunogenic peptides into the lamina propria, which are deamidated by tissue transglutaminase (tTG2), resulting in a stronger binding affinity for HLA-DQ2 and DQ8 on antigen-presenting cells (APCs) 3 . In the following, innate and adaptive immunity mechanisms activate, causing chronic inflammation and tissue damage in the small intestine 4 .…”