Zonulin

 I wanted to discuss “leaky gut”, its connection to autoimmune disease (AD) and the significance of the messenger molecule, zonulin. I have a very personal connection to this research and I was inspired to see it changing the landscape of AD. Fasano states that genetics, environment, intestinal permeability (related to dysbiosis), a hyperactive immune system controlling the immune tolerance response balance, the composition of gut microbiome and its epigenetic influence on genomic expression have been linked to AD (Fasano, 2020).

This review looked at the role of impaired intestinal barrier function on autoimmune pathogenesis (Fasano, 2012a). ADs are damaged tissue and loss of function due to an overactive immune response that turns on the body’s own organs. That biological self-tolerance and immunity to non-self antigens is controlled by gut-associated lymphoid tissue, the neuroendocrine network, the intestinal epithelial barrier, and intercellular tight junctions (Fasano, 2012a). A key function of the intestine is to control environmental antigens moving through the intestinal mucosal barrier (Fasano, 2012b). Intestinal tight junctions (TJ) create gradients for absorption and transport of nutrients and control the balance between tolerance and immunity to non-self antigens (Fasano, 2012b). 

Zonulin modifies intercellular TJs and thus is very involved in passage of macromolecules and in tolerance of the immune response (Fasano, 2012b). The intestinal epithelial TJ must be controlled quickly and in coordination by systems that facilitate the assembly of a TJ multi-protein network (Fasano, 2012b). When zonulin pathways are deregulated in susceptible individuals it can result in AD because zonulin's up-regulation in genetically susceptible individuals (Fasano, 2012b). These processes of dysregulation can be stopped if the combination of genes and environmental triggers are prevented by restoring the zonulin-dependent intestinal barrier function (Fasano, 2012a). Novel clinical evidence supports this new model and the reasoning for new approaches to prevent and treat the gut to indirectly treat AD. 

I find this work to be fascinating. I have known for a long time about the connection the gut has to AD but it has been difficult to understand and, even less clear is how to fix the problem. Studies like these I feel are on the cutting edge of AD and it’s eventual resolution.

References

Fasano, A. (2012a). Leaky gut and autoimmune diseases. Clinical Reviews in Allergy & Immunology, 42(1), 71–78. https://doi.org/10.1007/s12016-011-8291-x 

Fasano, A. (2012b). Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences, 1258(1), 25–33. https://doi.org/10.1111/j.1749-6632.2012.06538.x

Fasano, A. (2020). All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research, 9. https://doi.org/10.12688/f1000research.20510.1