Coeliac disease: From pathogenesis to novel therapies

Our advanced understanding and knowledge about the development of coeliac disease opens the possibility of a treatment, which may provide less dietary restriction for people with coeliac disease. A recent review paper looks at the pathogenesis of coeliac disease and critically discusses the possibilities of other therapies.

Novel Therapies

Some new therapies that look at possible treatments for people with coeliac disease have been tested in cultures and animal models. These advances in therapies are promising and exciting however, there is still a long way to go before being able to apply these potential treatment options. Here we take a look at some of the therapies from the review paper.

Intraluminal therapies

These therapies look at reducing the effect of gluten on the immune system or preventing the uptake of gluten across the intestinal epithelium.

Wheat variants and genetic modification

Wheat strains with lower immune response can be created by genetic modification or found in existing varieties. Different wheat varieties including tetraploid and hexaploid, have been shown to have different effects on gut damage.

• Hexaploid wheat is widely used in the food industry.
• Tetraploid is another form of wheat, originating from the wild. Tetraploid has been shown to be less toxic in comparison to hexaploid wheat, when looking at duodenal biopsy samples from people with coeliac disease.

Pretreatment of flours

Sourdough bread with 30% fermented wheat flour, oats, millet and buckwheat has a similar texture to regular wheat sourdough bread. Certain lactobacilli added to sourdough for fermentation can break down the protein of proline/glutamine rich gluten peptides and reduce their immune response. Pilot studies have shown that this sourdough bread did not result in symptoms. Further research is needed to draw firm conclusions.

Oral enzyme therapy

Oral enzyme therapy could be a useful treatment to enable people to follow a less strict gluten-free diet or as a possible safety net protecting against cross-contamination. Proteins reaching the intestine are digested by gastric pepsin and pancreatic proteases. They are then further broken down by brush border enzymes to amino acids, dipeptides or tripeptides and are transported across the epithelial layer. Current research is looking at using propyl endopeptidases found in different microorganisms to stop the peptides reaching the lamina propria (connective tissue beneath the epithelium of the small intestine).

It is likely that, oral enzyme therapy will not be able to break down gluten found in a normal diet that contains more than 13g of gluten a day. However, it may help to stop the ill effects of a few hundred milligrams of gluten for people who are highly sensitive or have refractory coeliac disease.

Inhibition of Intestinal permeability

Increased intestinal permeability can result in more gluten peptides passing through the subepithelial lamina propria and can contribute to gut damage. The damaged epithelium of people with coeliac disease releases a paracrine protein product (zonulin) that can increase the permeability of the intestine.

An octapeptide has been developed that blocks the zonulin receptor and stops the effect this has on intestinal permeability. In trials, people treated with this had improved symptom scores and a reduced autoantibody response. Its use is likely to have a similar effect to oral enzyme therapy and not be suitable for treating an unrestricted amount of gluten in the diet.

Inhibitors to block the development of coeliac disease

Coeliac disease is strongly associated with the genes HLA-DQ2 and HLA-DQ8.  The HLA genes and the antibodies IgA tissue transglutaminase are markers of coeliac disease and are key in the development of the disease. 

Transglutaminase inhibitors

The use of transglutaminase inhibitors could result a reduction in their binding to HLA-DQ2 and HLA-DQ8. This would mean a reduced immune response and less villous atrophy. Transglutaminase inhibitors have been developed and tested, mainly in vitro. Transglutaminase has many important functions in tissue homeostasis. This means that they have to be tested to ensure they are taken up by the intestine and do not reach the systemic circulation.

HLA-DQ2 inhibitors

Blocking HLA-DQ2 is a possible target for preventing the immune response seen in coeliac disease. Similar approaches have been investigated in other autoimmune diseases including Type 1 diabetes, rheumatoid arthritis and multiple sclerosis. Currently no benefit has been found, mainly due to inefficient drug delivery. This should be easier in coeliac disease since the small intestine can be accessed via an oral route.

Peptides with high affinity to coeliac disease have been designed. However, there are concerns that this treatment could cause side effects such as immunosupression or hypersensitivity. Further research is needed to develop a treatment that would not have these side effects and would be effective in blocking the access of gliadin peptides binding to DQ2.

Changing the immune response to gluten

The most attractive treatment would be to restore the tolerance to ingested gluten. This may be possible, as only 1 of the 30 carriers of the HLA-DQ2 and HLA-DQ8 genes will develop coeliac disease in their life time. Research is currently being carried out in Australia into a ‘gluten vaccination’. This vaccination would aim to suppress the immune response to gluten in the diet and therefore prevent gut damage.  

Other research is looking at the use of bifidobacterium (often used as a probiotic) to reduce the inflammation seen in the small intestine in people with coeliac disease. Clinical studies have not yet been performed to know if this would be effective treatment.

Therapies targeted at immune cells

Therapies that target the immune cells have been used in other autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease). These treatments can have significant side effects and in view of a usually effective gluten-free diet have not been used to treat people with coeliac disease. They may potentially be beneficial for people with refractory coeliac disease and EATL (enteropathy-associated T-cell lymphoma).

Further possible treatments that show promise for refractory coeliac disease include:

• antagonists that block the inflammatory process
• bone marrow transplantation
• mesenchymal stem cell therapy.

Conclusion

With further advances in the development of coeliac disease, clinical validation of many of these therapies is expected in the future. These developments could also be beneficial in the treatment of other autoimmune conditions.  

Schuppan D, Junker et al (2009) Celiac Disease: From Pathogenesis to Novel Therapies. Gastroenterology. 137: 1912-1933