Autoimmune disease (AID) is a condition in which a person’s immune system produces an inappropriate response against its own cells, tissues and/or organs, resulting in inflammation and damage. There are about 80 recognised AIDs affecting as many as 1 in 20 Australians.
Currently, the treatment of AID is focused on relieving symptoms as there is no known curative therapy. While the cause of AID is largely unknown, it is generally accepted that interplay between environmental factors and genetic susceptibility underlies the autoimmune response. However, this paradigm does not fully explain the development and progress of disease.
In recent years, evidence has emerged that intestinal integrity, and specifically that of the intestinal tight junctions (TJs), may play a significant role. Not all that long ago, it was thought that the functions of the gastrointestinal tract (GIT) were limited to the digestion and absorption of nutrients and water homeostasis. However, it is now well established that another crucial function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a very sophisticated barrier mechanism. Thus, together with the gut-associated lymphoid tissue (GALT) and the neuroendocrine network, the intestinal epithelial barrier has been shown to control the equilibrium between tolerance and immunity to non-self antigens.
This link was unexpectedly stumbled upon by researchers developing a vaccine to fight cholera. What they discovered was that the toxin produced by the disease-causing bacteria, Vibrio cholerae, had the ability to open the complex TJ structures that had previously been thought to be inert. So, while the cholera vaccine failed, it led to the discovery that a single molecule, which they named Zot (zonula occludens toxin; zonula occludens is latin for tight junction), had the ability to destabilise the complex structure of the TJs in a rapid, reversible and reproducible fashion.
What they also realised was that this process was far too complex to have evolved simply to harm the host and hypothesised that V. cholerae must cause diarrhoea by exploiting a pre-existing pathway that regulates intestinal permeability, which was later elucidated as the zonulin pathway.
Zonulin is an endogenous protein that to date is the only know physiological modulator of TJ integrity and, while the physiological roles of the zonulin pathway are yet to be fully established, it appears to be involved in TJ regulation responsible for the movement of fluid, macromolecules, and leukocytes between the intestinal lumen and the blood stream and vice versa.
The zonulin-driven disassembly of the TJs may also represent a defensive mechanism which flushes out microorganisms, so contributing to the innate immune response against bacterial colonisation of the small intestine as described with Zot.
Nowadays, a fast-growing number of diseases are recognised to involve zonulin-mediated alterations in intestinal permeability related to changes in TJ competency, including AID, cancer development, infections and allergies.
A good example of this paradigm is coeliac disease (CD), which is a unique model of AID because, unlike most other AIDs, its genetic link (HLA genotypes DQ2 and DQ8), the specific autoimmune response against tissue transglutaminase and the triggering environmental factor (gliadin fraction of wheat gluten) are all known.
Gliadin initiates intestinal permeability through the release of zonulin, which in turn initiates the detrimental cascade of events seen in patients with CD. However, once gluten-containing foods are removed from the diet, serum zonulin levels decrease, intestinal barrier function is restored, the autoimmune processes shut down and the intestinal damage is healed.
This model of AID subverts the traditional theories underlying the development of these diseases – molecular mimicry and the bystander effect – and suggests that the autoimmune process can be modulated by preventing the continuous interplay between the genes and environmental triggers.[5,6]
Since zonulin-dependent TJ dysfunction allows such interactions, it makes sense that new therapies aimed at re-establishing intestinal barrier integrity by down-regulating the zonulin pathway would offer innovative and unexplored approaches for the management for AID. While the search is underway to find suitable zonulin inhibitors, research suggests that several probiotic species act to restore TJ integrity.
In addition to gliadin, enteric infections and changes in the gut microbiota composition have been shown to affect the intestinal barrier function by triggering intestinal zonulin release. This may explain why some people who are born with a genetic susceptibility to AID, such as CD, may not show symptoms of the disease until later in life.
It is understood that the microbiome differs from person to person, even varying in the same individual at different stages of life, thus influencing which genes are active at any given time. Hence, a person who has been able to tolerate gluten for many years, may suddenly lose tolerance if there are changes to their microbiota in a way that causes formerly quiet susceptibility genes to become active. If this hypothesis is correct, conditions such as CD may be prevented or managed by ingestion of selected probiotics.
Probiotics play a major role in maintaining the homeostasis of the gut flora through adhering to and colonising the intestinal mucosa on which they compete with pathogenic bacteria. Certain species, particularly members of the lactobacillus genus, also enhance and protect barrier function via modulation of TJs.
For example, in vitro research has demonstrated that L. rhamnosus can ameliorate the negative effects of gliadin on zonulin-induced intestinal paracellular permeability and its co-administration may restore barrier function. L. plantarum enhances the function of the intestinal barrier by increasing the expression levels of no less than 19 genes involved in TJ formation.
Based on these findings, it can be concluded that commensal bacteria can influence gut permeability by supporting TJ integrity and may therefore play a significant role in the clinical management of AID and other disorders in which intestinal barrier function is compromised.
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- Anderson RC, Cookson AL, McNabb WC, et al. Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiol 2010;10:316. [Full Text]