A few decades ago, you wouldn’t see any. Today, however, you won’t leave the supermarket without finding gluten-free labels on all sorts of foods, ranging from the usual suspects (grains, cereals, bread) to the lesser-known ones (beer, candies, French fries, gravy, processed meats, salad dressings and sauces, seasoned snack foods, and others).
Don’t get me wrong; we’ve come a long way! A gluten-free diet (GFD) remains the only treatment for coeliac disease. Still, I wonder whether most people are actually aware of this? A GFD is quickly becoming one of the trendiest alimentary diets. If you search the Internet, you will find claims of how GFD can increase your health and life span, and help you lose weight or rejuvenate your skin (ok, I didn’t actually find the last one!). My point is, a GFD has a point. In fact, a GFD may occasionally lead to vitamin and mineral deficiencies if not properly monitored by a physician or a nutritionist. Nonetheless, with reports of non-coeliac gluten sensitivity (NCGS) increasing,1 the long-term effects of a GFD on non-coeliac individuals do deserve further exploration. In addition, a significant number of patients with coeliac disease are nonresponsive to gluten withdrawal (nonresponsive celiac disease; NRCD), with unintentional gluten intake accounting for >50% of these cases.2 Alternatively, patients may develop refractory coeliac disease (RCD) despite strict adherence to a GFD for at least 6–12 months, in the absence of other causes of NRCD and overt malignancy. Both of these patient populations exhibit persistent or recurrent malabsorptive symptoms and intestinal injury. As such, the development of novel nondietary therapies for coeliac disease is of utmost importance.
In recent years, a large number of targets likely to halt the process of immunological injury in coeliac disease have been explored. These include prolylendopeptidases to assist intraluminal digestion of gluten, zonulin antagonists to prevent the passage of immunogenic peptides through tight junctions (TJs) and blocking of HLA-DQ2 to prevent binding of immunogenic peptides.3 Of note, some of the targets have already reached phase II clinical trials.4 At the moment, however, they will probably not be able to fully replace a GFD regime, but rather be used as adjunctive therapies. Indeed, this might be the case for larazotide acetate, for which the phase IIb clinical trial results have just been published.5
Larazotide acetate is an 8-mer peptide that regulates intestinal TJs. In turn, TJs control the paracellular permeability and apical–basolateral polarity of intestinal cells, and deregulated permeability of intestinal cells is associated with coeliac disease. Proof-of-concept studies have shown that larazotide acetate inhibits gliadin translocation across cells, as well as gliadin-induced macrophage recruitment to the small intestine, both of which are events critical to the development of coeliac disease.6,7 By further promoting actin rearrangement, larazotide acetate stabilizes and preserves TJ structure, thus preventing gluten from reaching the intestinal submucosa and triggering an inflammatory response. Prior phase II clinical trials suggested larazotide acetate to be safe, well tolerated and effective in reducing gastrointestinal symptoms after a gluten challenge.8,9 Still, these studies were somewhat criticized for not meeting one of their primary endpoints, namely the lactulose-to-mannitol ratio, which is an experimental biomarker of intestinal permeability. In this most recent phase IIb trial,5 the primary endpoint was set as the difference, on average, in the on-treatment ‘Celiac Disease Gastrointestinal Symptom Rating Scale’ (CeD-GSRS) score. Larazotide acetate was shown to improve both gastrointestinal and nongastrointestinal symptoms of coeliac disease, resulting in fewer gastrointestinal symptomatic days in patients who have persistent symptoms despite a GFD. Not without its limitations, as acknowledged by the study authors, larazotide acetate may embody a future therapeutic option for coeliac disease patients who have persistent symptoms. Perhaps equally important, this study illustrates how the design of clinical trials for coeliac disease should be constantly improved, with surrogate endpoints specifically tailored to the drug, disease and target patient population.
It may be some years before a GFD replacement is available. Thankfully, however, in parallel with all the current clinical research into coeliac disease, the food industry also has their brightest minds working in the laboratory to develop new gluten-free products. It shouldn’t be long before you go to the supermarket and find that guilty pleasure you’ve been craving for years … now gluten-free!
When it comes to separating the wheat from the chaff, there were three specific sessions at UEG Week 2014 on the lingering challenges for distinguishing and managing coeliac disease, NCGS, RCD and NRCD, as well as establishing the need for diagnostic biopsies and novel therapeutics (see Further UEG Resources below). Simply sign in to myUEG to watch the recorded sessions! You can also expect a full update on coeliac disease at UEG Week 2015 and, as always, don’t forget to browse through the UEG Education Library for more resources.
- Fasano A, Sapone A, Zevallos V, et al. Non-celiac gluten sensitivity. Gastroenterology Epub ahead of print 14 March 2015. DOI: http://dx.doi.org/10.1053/j.gastro.2014.12.049
- Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007; 5: 445-450.
- Makharia GK. Current and emerging therapy for celiac disease. Front Med 2014; 1: 6.
- Gottlieb K, Dawson J, Hussain F, et al. Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials. Gastroenterol Rep Epub ahead of print 26 February 2015. DOI: 10.1093/gastro/gov006
- Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology Epub ahead of print 12 February 2015. DOI: http://dx.doi.org/10.1053/j.gastro.2015.02.008
- Gopalakrishnan S, Durai M, Kitchens K, et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 2012; 35: 86–94.
- Gopalakrishnan S, Tripathi A, Tamiz AP, et al. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides 2012; 35: 95–101.
- Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 2012; 107: 1554–1562.
- Kelly CP, Green PH, Murray JA, et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment Pharmacol Ther 2013; 37: 252-262.
Further UEG Resources
“Coeliac disease, wheat allergy and wheat sensitivity: Still the tip of the iceberg” Session at UEG Week 2014.
“New challenges in gluten sensitivity: From bench to bedside” Session at UEG Week 2014.
"Challenges in coeliac disease and gluten-related disorders” Session at UEG Week 2014.