The Science Behind Enzyme Therapy

Sharyn Reinhold, M.S.

Enzymes play a key role in the complex digestive system. Produced endogenously by the gastrointestinal tract, digestive enzymes help to break down proteins, fats, and carbohydrates for proper digestion and absorption of nutrients.1 However, certain dietary proteins resist digestion in the human gastrointestinal tract. Glutenins and gliadins found in wheat, barley, and rye are primary examples. Gluten is a storage protein with high proline content (12-17%).2 Gliadin which is a prominent peptide in gluten is particularly proline rich. Proteases (protein-digesting enzymes) that can break down proline bonds are essentially non-existent in the human gastrointestinal tract. This was further validated in vivo by Salden et al (2015) when pepsin, a major digestive enzyme produced in the stomach, had very little effect on the degradation of ingested gluten among healthy volunteers.3

Roughly one out of one hundred people are affected by celiac disease and many more are eliminating gluten from their diets for health reasons. It is suspected that many individuals on a gluten-free diet are still frequently exposed to gluten, as evidenced by the 50% of celiac patients who continue to experience symptoms as well as elevated autoantibodies and/or damage to the villi of the small intestine. The exact cause or causes of exposure may be hard to pinpoint, but most likely includes a combination of inadequate education on gluten-containing foods, cross-contamination (particularly in restaurants), and lack of compliance due to the nearly-ubiquitous presence of gluten in the food supply along with social pressure.

Since the 1950s, researchers have been studying various enzymes for gluten-digesting potential. Most of these have been in the prolyl endopeptidase (PEP) family. These enzymes can break down internal proline-containing peptide bonds. Microbial prolyl oligopeptidases were the focus of much of the early research on the topic. However, they were shown to be inadequate because they could not survive contact with pepsin or the low pH of the stomach. Stepniak and colleagues (2006) were among the first to study a more recently identified Aspergillus niger-derived prolyl endopeptidase (AN-PEP). Their results showed that not only did AN-PEP break down gluten peptides 60 times faster than typical prolyl oligopeptidases, it also remained stable at a gastric pH as low as two, with optimal function at a pH of four - five.*2

In 2009, Ehren et al found that more complete clearance of gluten epitopes could be achieved by combining aspergillopepsin with dipeptidyl peptidase IV (DPP-IV) from Aspergillus oryzae.* Dipeptidyl peptidase IV is another candidate used to support resolving gluten digestion.* DPP-IV is part of the exopeptidase family and often used in foods and supplements as a debittering agent. This study looked at more complex meals and found that in the presence of competing proteins such as casein, aspergillopepsin was less effective than when it was introduced to gluten alone. Aspergillopepsin first breaks down larger proteins into short peptides which can subsequently be cleared by DPP-IV, as it is more specific to these potentially immuno-toxic peptides. The combination resulted in the complete hydrolyzation of approximately one gram of gluten before it reached the small intestine.4

At least two human trials have demonstrated the safety of AN-PEP as an oral supplement.3,5 One of these, a double-blind, placebo-controlled crossover study was published in 2015 in the Journal of Alimentary Pharmacology & Therapeutics. Healthy subjects ingested four grams of gluten in the context of a low or high caloric meal with the addition of AN-PEP. Based on the results of gastric and duodenal aspirate samples, which tested for the presence of alpha-gliadins, it was found that virtually all gluten peptides were degraded in the stomach within 1 hour (before reaching the small intestines), regardless of the caloric value of the meal.3

Although these advancements regarding commercially available gluten enzyme(s) supplements are exciting for individuals who experience adverse reactions to gluten, it is still recommended that those who need to follow a gluten-free diet continue to do so to the best of their ability. As little as 10-100 mg of gluten can cause a problem for those with celiac disease, which is about the amount of exposure from cross-contamination or hidden sources of gluten in processed foods.4 Oral AN-PEP containing supplements are not a substitute for a gluten-free diet and are not intended to allow voluntary deviation from the recommended diet. However, endo- and exopeptidases may mitigate the damaging effects of accidental gluten exposure.


  1. Ianiro, G, et al.. Curr Drug Metab. 2016 Feb; 17(2):187-93.
  2. Stepniak, D, et al. Am J PhysiolGastrointest Liver Physiol. Sept 2006; 291 (4): G621-9
  3. Sadlen, BN et al.. Aliment PharmacolTher. 2015 Aug; 42(3): 273-85.
  4. Ehren, J, et al. PLoS One. 2009; 4(7): e6313.
  5. Tack, GJ, et al. World J Gastroenterol. Sept. 2013; 19(35): 5837-47.

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