Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments

Abstract

For decades, the pathogenesis of a variety of human diseases has been attributed to increased intestinal paracellular permeability even though scientific evidence supporting this hypothesis has been tenuous. Nevertheless, during the past decade, there have been a growing number of publications focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately causing chronic inflammation, including autoimmunity, in genetically predisposed individuals. The gut mucosa works as a semipermeable barrier in that it permits nutrient absorption and also regulates immune surveillance while retaining potentially harmful microbes and environmental antigens within the intestinal lumen. Celiac disease (CD), a systemic, immune-mediated disorder triggered by gluten in genetically susceptible individuals, is associated with altered gut permeability. Pre-clinical and clinical studies have shown that gliadin, a prolamine component of gluten that is implicated in CD pathogenesis, is capable to disassembling intercellular junctional proteins by upregulating the zonulin pathway, which can be inhibited by the zonulin antagonist larazotide acetate. In this review, we will focus on CD as a paradigm of chronic inflammatory diseases in order to outline the contribution of gut paracellular permeability toward disease pathogenesis; moreover, we will summarize current evidence derived from available clinical trials of larazotide acetate in CD.

Keywords: Antigen trafficking; Autoimmunity; Gut permeability; Inflammation; Tight junctions; Zonulin.

Figure 1.

The modern system-biology pathogenic theory of chronic inflammatory diseases. The fragile balance between health and disease is determined by several factors such as genetic background, exposure to environmental factors, loss of gut barrier function, inappropriate mucosal immunity, and microbiome imbalance. The onset and the natural history of several diseases are the outcome of changes of these tightly interlaced and mutually influencing elements. Predicting models of health according to these factors are the ultimate goals of primary prevention in the boosting field of “personalized – precision” medicine.

Figure 2.

Proposed involvement of barrier dyfunction in the pathogenesis of non-infective chronic inflammatory diseases. (1) Under physiological circumstances, there is a tightly control of antigen trafficking from the gut lumen into the intestinal lamina propria (antigen sampling) that leads to mucosal tolerance, homeostasis and anergy mediated by the involvement of a variety immune cells and anti-inflammatory cytokines. (2) Following a variety of environmental stimuli, including gut microbiome imbalance (dysbiosis), paracellular permeability is increased secondary to the upregulation of specific pathways, including the zonulin pathway. (3) As a consequence of prolonged and uncontrolled antigen trafficking, innate immune response or immunoregulatory defects leads to the onset of inflammation with secondary production of pro-inflammatory cutokines, including TNF-aloha and IFN-gamma that, by themselves, are causing further increase in gut permeability by activating the myosin light chain kinake (MLCK) pathway. (4) This mechanism starts a vicious cycle of further increase in gut permeability and subsequent antigen trafficking that ultimately lead to break of tolerance and onset of chronci inflammatory diseases whose nature depends on the genetic host predisposition

Figure 3.

Proposed involvement of the innate and adaptive immune system in the gut mucosal events leading to break of gluten tolerance and onset of celiac disease. Undigested gliading fragment binds to the CXCR3 receptor leading to zonulin release, increased paracellular permeability, access to gliadin fragments into the lamina propria, activation of the innate immune system that in tunr causes activation of the adaptive immune system that ultimately leads to the autoimmune insult of the gut mucosa typical of the celiac enteropathy