Conclusions and Proposals for Future Work

Given that the disease is mechanistically so well defined, I think future work should focus primarily on discovering novel treatments and attempting to build a more algorithmic approach to determining susceptibility. In terms of discovering novel treatments, there is a lot of talk in the field about inhibiting a variety of enzymes, modulating tight junctions, etc., but there is not as much discourse regarding the inhibition of zonulin production. As the mechanism by which gliadin induces the production of zonulin, and that the overexpression of zonulin in Celiac disease patients directly correlates with increased permeability of the small intestine and therefore all of the autoimmune effects. I think that devising small molecules designed to attack either the zonulin receptor or the CXCR3 receptor that gliadin binds to offer a unique opportunity with a relatively easy delivery system (given its potential to be oratory) as a therapy for Celiac disease.

Another figure demonstrating the many potential avenues by which to treat Celiac disease, emphasizing in particular, the importance of zonulin in the pathogenesis of the disease Source: Vanga, 2014
Another figure demonstrating the many potential avenues by which to treat Celiac disease, emphasizing in particular, the importance of zonulin in the pathogenesis of the disease Source: Vanga, 2014

There has also been some discourse in the literature regarding microbes in the oral cavity that are capable of digesting the gluten peptides resistant to human peptidases (Vanga, 2014). There has also been discourse about the implementation of oral peptidases to help digest gliadin further (Khosla, 2011). I think further characterizing these microbes and peptidases, and if they have any adverse effects on human health could possibly offer a unique avenue to treat Celiac disease. If either don’t have any adverse oral effects, and they are capable of efficiently degrading gliadin proteins, these microbes could have significant clinical impact. Possibly similar to fluoride supplementation, either could potentially be harnessed in something as trivial as toothpaste, so that daily application could help to further degrade gliadin peptides and reduce the amount of circulating epitopes in Celiac disease individuals, which could hopefully reduce symptoms.

Just some toothpaste. Source Google Images
Just some toothpaste. Source Google Images

I think ultimately, though, further genetic characterization of the disease and a more comprehensive understanding of the degree to which varying loci are involved in disease susceptibility is the next frontier in Celiac research. Currently, the amount of ambiguity circulating disease susceptibility in given individuals makes diagnosis, particularly in asymptomatic individuals, difficult, and delayed diagnosis can cause complications in the individual. I would argue more extensive genetic mapping data combined with in depth pedigree familial inheritance analysis needs to be continued to more rigorously define which genes in what percentage confer susceptibility to the disease. I also think better defining the parameters of the trigger event would be incredibly useful in diagnosis. Given the supposed breadth and variation of possible events, however, experiments to accurately determine this would most likely be difficult to do in humans. They would most likely need to be performed in a mouse model, where environmental conditions could be strictly controlled. The only problem with this is that mouse models do not always translate well to human systems.

Despite all this, in a matter of just ten to 15 years, Celiac disease has progressed from a life manipulating illness, to a more than manageable disease given the increase in awareness and the great expansion of the gluten free options available. I can only imagine that with the current popularity of the disease and the amount of research dedicated to finding therapies for it that in the next five to ten years, Celiac disease could evolve into a minor inconvenience at most.

 

Jump to other pages of Celiac disease:

Title Page

History and Metabolic Context

Molecular Basis of the Disease State

Treatment and Disease Management

Annotated Bibliography

6 Replies to “Conclusions and Proposals for Future Work”

  1. Great ideas for future work! I like your shout-out to the use of bacteria to help digest what the body cannot. The microbiology of the gut is one area of medicine that we do not know much about, but as I’m sure you came across during your research there is already a lot of hope being placed on what we can do with it. One example that is already being used in some clinical centers is the “fecal transplant” for patients with resistant C. difficile infection. As you note it may be beneficial for some Celiac patients to ingest designer bacteria to help with their digestion.
    I’m not sure how applicable it is to Celiac, but with many autoimmune diseases people have been discussing the “hygiene theory”, which is the idea that as our standard of living has been getting better and “cleaner”, our immune systems are exposed to less threats to fight, which may or may not increase the chance the the immune system accidentally targets the body. You showed that there are specific alleles that tend to cause Celiac, so this theory might not be as applicable here, but its worth a thought. Great job!

    1. Hey Mazen,

      Thanks for the comment! The hygiene theory is certainly an interesting one and exposure or lack there of to bacteria at a young age could very well be one of the environmental factors that influence the development of Celiac disease. There is some speculation that some micrflora actually aid in the digestion of gliadins, so it’d be very interesting if we were able to characterize the microflora of normal individuals versus Celiac individuals. It is very possible that the absence of a specific microorganism designed to digest gliadin is significant in developing the disease.

      Links I referenced:

      http://www.sciencedirect.com/science/article/pii/B9780124017160000131

  2. Thomas, You are a gentleman and a scholar.

    Now question time: Is there a need to consume gluten? That is, are celiacs missing out on much? Although gluten seems to be in a wide variety of products and these must be avoided, do gluten alternatives provide sufficient nutrition? Maintaining a gluten-free diet seems like an annoyance, but is that the only real consideration of why we might want to develop a method for celiacs to consume gluten? If that’s the case, I could how an individual would opt to maintain a gluten-free diet over an unrestricted diet at the price of a costly treatment.

    In the same vain, I also want to call out your genetic mapping/familial pedigree idea. I agree that it would be nice to know how likely an individual is to develop celiac, but is this approach worth our time? It seems as though the symptoms of gluten intolerance are fairly distinct and you’ll know when something is wrong. Further, with such highly accurate diagnostic tests and no long-term side effects after discontinuation from previous gluten consumption, I can’t see how it would be cost effective to trace the likelihood of onset. After all, genetic predisposition does not mean that occurrence is set-in-stone. I don’t mean to put you on the spot, but I don’t see that project being a first priority any time soon.

    Nice job on the project! We’re almost finished, keep up the good work!

    1. Ryan,

      To be called a gentleman and a scholar by the legend himself… I am most honored.

      In all seriousness though, there is no need to consume gluten in one’s diet, as gluten is essentially just a group of carbohydrates. I would say clinically, the main reason to develop a treatment is that in about 30% of cases, a gluten free diet does not remove all symptoms. Other than that, the food is relatively expensive, which is an issue for individuals of certain demographics.

      I would argue the biggest need for characterization of the disease is to provide a model for other diseases that are less well understood. So far, Celiac is one of the most understood inflammatory conditions, and even further characterization of it, especially from a genetic standpoint, I think could open doors to future research on more elusive diseases.

      Links I referenced:

      http://www.ncbi.nlm.nih.gov/pubmed/24285451

  3. Hi Tommy- I’m really impressed with your ideas for future work! I am particularly intrigued by your proposal regarding harnessing microbes that can break down gluten resistant to human peptidases- maybe because I’m a little bit of a bacteria nerd. I know you mentioned that adverse health effects of administering these bacteria would have to be investigated. Out of curiosity, did you come across any literature that delved into what these effects may be? I think the idea of a toothpaste that could help those with Celiac’s is brilliant- I just wonder what the consequences of altering the flora environment in the mouth would be. I wonder if they would out-compete other helpful bacteria in the mouth and cause other adverse side effects. Perhaps they would not, however, since a toothpaste would only be altering the flora in the mouth for a brief time- but would this amount of time be enough for the bacteria to get to work and start breaking down some gluten? I feel like the logistics are challenging, but good idea!

    1. Hey Gabby,

      When I was thinking about this idea I kind of chuckled to myself, because while it is pretty cool to consider, it is most likely not that feasible. It is easy to imagine that the introduction of any microbe, unless it was ridiculously tinkered with, could easily disrupt the fragile environment of our mouth. I did, however, come across a different paper that discussed the use of oral peptidases to help digest the gliadin. These, I could see being much more feasible and much less problematic than the oral microbes. There are actually already specific drugs and drug cocktails that are undergoing clinical trials to be ready for distribution! As far as the toothpaste goes, anything introduced to break down gliadin would have to have a half life of at least 12 hours in the mouth to be effective in that kind of delivery system.

      Links I referenced.

      http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02376.x/abstract

Comments are closed.