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Anp3.5
AN-PEP Research
Mostly mechanism / observational
11 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most AN-PEP studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality randomised trials published 2006–2025 with a typical study size of 18 participants.
Based on 11 studies · 4 RCTs · 114 total participants
Confidence
Moderate confidence
By outcome
Gluten breakdown
Mostly mechanism / observational11 studies
Coeliac disease & gluten sensitivity
Too few graded studies5 studies
Digestive health
Too few graded studies1 study
Safety profile
Too few graded studies1 study
Steady research
3 studies in the last 5 years
200620152025
1RCTCited 23×n=40 · small study2024
In plain English: The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.
Stefanolo JP et al. · World J Gastroenterol (2024)
Exploratory double-blind, randomised, placebo-controlled trial in 40 adults with coeliac disease on a long-term gluten-free diet: two enzyme capsules with each of three meals a day, or placebo, for 4 weeks after a 4-week run-in
Gluten immunogenic peptides were undetectable in 65.6% of stool samples, and no difference between the enzyme and placebo arms was detected. The enzyme did not significantly reduce overall stool GIP concentration
Median GIP in the enzyme arm was 44.7% lower than during its own run-in, a comparison within the arm, not against placebo
In plain English: Thus even in a physiological meal setting, AN-PEP significantly degraded most gluten in the stomach before it entered the duodenum.
König J et al. · Sci Rep (2017)
Randomised, placebo-controlled crossover study in 18 self-reported gluten-sensitive adults who ate a porridge containing 0.5 g gluten with two tablets of high-dose enzyme, low-dose enzyme or placebo
The primary outcome, at least 50% gluten degradation in the duodenum with the high dose compared with placebo, was met in 10 of 13 comparisons
Stomach gluten exposure fell from a median 176.9 with placebo to 22.0 (high dose) and 25.4 μg × min/ml (low dose), both p = 0.001
In plain English: AN-PEP significantly enhanced gluten digestion in the stomach of healthy volunteers.
Salden BN et al. · Aliment Pharmacol Ther (2015)
Randomised, double-blind, placebo-controlled crossover study in 12 healthy volunteers. A liquid low- or high-calorie meal containing 4 g gluten, with enzyme or placebo, was given directly into the stomach through a catheter
The enzyme lowered α-gliadin exposure in the stomach compared with placebo (low-calorie meal 35 vs 389, high-calorie meal 53 vs 386 μg × min/mL, P < 0.001)
It also lowered α-gliadin exposure in the duodenum (low-calorie 7 vs 168, high-calorie 4 vs 32 μg × min/mL, P < 0.001)
In plain English: However, when compared with the control bread for inducing GI symptoms, no treatment effects were apparent.
Rees D et al. · Br J Nutr (2018)
Double-blind, randomised crossover trial in 16 adults who self-reported benefit from a gluten-free or low-gluten diet and 12 controls, eating normal bread, bread treated with the enzyme during baking, or low-protein bread
Here the enzyme was used to pre-treat the flour, not taken as a supplement. It lowered immunogenic gluten in the bread by about 40%
Normal wheat bread increased gastrointestinal symptoms in the gluten-sensitive group, but the enzyme-treated bread produced no symptom benefit compared with the control bread
In plain English: However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN-PEP.
Tack GJ et al. · World J Gastroenterol (2013)
Randomised, double-blind, placebo-controlled pilot study in 16 adults with treated coeliac disease who ate toast containing about 7 g gluten a day with the enzyme for 2 weeks, then 14 were randomised to gluten with enzyme or placebo for 2 weeks
The primary endpoint, change in duodenal histology, was not met because the placebo group did not deteriorate, so no protective effect could be shown
Two patients were excluded before the randomised phase because their duodenal mucosa worsened by two Marsh steps while eating gluten with the enzyme
In plain English: AN-PEP accelerated the degradation of gluten in the stomach compartment to such an extent that hardly any gluten reached the duodenum compartment.
Mitea C et al. · Gut (2008)
Laboratory study in a dynamic model that mimics human digestion, using a slice of bread and a standard fast-food meal with and without the enzyme
With the enzyme, gluten was degraded in the stomach compartment to the point that hardly any reached the duodenum compartment
A digestion model, not people. Whether this protects a person with coeliac disease was not tested
In plain English: In contrast, the pure enzyme AN-PEP effectively degraded all nine epitopes in the pH range of the stomach at much lower dose.
Janssen G et al. · PLoS One (2015)
Laboratory comparison of five general digestive enzyme supplements with the purified Aspergillus niger enzyme
The general digestive enzyme supplements left the nine immunogenic epitopes of the 26-mer and 33-mer gliadin fragments largely intact
The purified Aspergillus niger enzyme degraded all nine epitopes at stomach pH at a much lower dose. A general digestive enzyme blend is not a substitute
In plain English: Despite encouraging results in preclinical and clinical trials, no treatment has yet been conclusively proven to serve as an effective alternative to the GFD.
Girbal-González M et al. · Nutrients (2025)
Narrative review of current and emerging treatments for coeliac disease, including gluten-degrading enzymes such as Aspergillus niger prolyl endopeptidase
Concludes that a strict gluten-free diet remains the only effective treatment and that no alternative, enzymes included, has been proven to replace it
In plain English: Nevertheless, none of the supplements was able to abolish iTCLs response, particularly at the end of gastric phase, thus allowing to conclude that they work to different, but potentially limited extent.
Camarca A et al. · Food Res Int (2025)
Laboratory digestion of pizza with three over-the-counter gluten enzyme supplements, one of which contained the Aspergillus niger prolyl endopeptidase
The supplement containing the prolyl endopeptidase degraded immunotoxic gluten epitopes most rapidly and reduced the response of intestinal T cell lines from coeliac patients
None of the supplements abolished the coeliac T cell response, especially at the end of the gastric phase, so their effect in a real meal may be limited
In plain English: Therefore, AN-PEP should not be used to replace a gluten free diet, but rather to support digestion of occasional and/or inadvertent gluten consumption.
Montserrat V et al. · Food Chem (2015)
Laboratory model of stomach conditions testing how meal composition affects the enzyme
Other food proteins slowed gluten breakdown, baked gluten was degraded less efficiently than raw gluten, fat had no effect and an acidic carbonated drink increased activity
The authors conclude the enzyme should support digestion of occasional or inadvertent gluten, not replace a gluten-free diet