DPP IV protease and gluten-degrading enzyme supplements

What it is

These are enzyme products sold or developed to break down gluten. Many over-the-counter digestive supplements contain dipeptidyl peptidase IV (DPP-IV), an enzyme from the mould Aspergillus oryzae that clips proline-containing pieces off the end of protein chains and works best at intestinal, not stomach, pH. A different enzyme, prolyl endopeptidase from Aspergillus niger (AN-PEP), cuts inside gluten chains and works at stomach pH; latiglutenase is an investigational drug mixture.

What the research says

Common DPP-IV-type digestive enzyme supplements do not protect people with coeliac disease: laboratory testing found they leave the immune-triggering parts of gluten largely intact. AN-PEP breaks down gluten in the stomach in controlled feeding studies, but a trial in coeliac patients on a gluten-free diet found no reduction in gluten peptides in stool. The investigational drug latiglutenase did no better than placebo on intestinal damage in a large trial. Coeliac organisations and experts state these enzymes are not a substitute for a strict gluten-free diet, and there is no evidence of benefit for non-coeliac gluten sensitivity.

Evidence grade: Not supported by the research.

What goes wrong

Joseph A. Murray, MD, a Mayo Clinic coeliac specialist quoted by Beyond Celiac in 2015, warned coeliac patients not to use gluten-reducing enzyme preparations, saying they have no proven benefit; this is his view, reported by the organisation. (Source 1)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: People with coeliac disease.
• How long: not applicable.
• Result: Expert opinion (2015): risk of relying on unproven products.
• Funding: not applicable.

It is vitally important that patients with celiac disease do not use any of these preparations that are being touted for reducing gluten.

The National Celiac Association, quoting Thompson, Dennis and Emerson (Journal of the Academy of Nutrition and Dietetics, 2017), advised that where a product has not been tested for residual gluten by competitive ELISA, avoiding products with ingredients grown on gluten-containing growth media may be best. (Source 2)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: People with coeliac disease.
• How long: not applicable.
• Result: Position (2022, quoting a 2017 journal article): possible residual gluten from growth media in untested products.
• Funding: not applicable.

until more is known about residual gluten from growth media, erring on the side of caution and avoiding products containing ingredients grown on gluten-containing growth media may be best if the product is not tested for residual gluten using a competitive ELISA.

What the evidence supports

In a randomised placebo-controlled crossover study in 18 gluten-sensitive people, AN-PEP taken with a gluten-containing porridge reduced gluten reaching the stomach and duodenum. (Source 3)

• Randomized trial, Low certainty.
• Size: 18 participants.
• Who: Gluten-sensitive subjects (not coeliac patients)
• How long: 180 minutes per test meal.
• Result: Stomach gluten AUC 176.9 (placebo) to 22.0 high dose (p = 0.001); duodenum 14.1 to 6.3 (p = 0.019)
• Funding: industry-funded (DSM provided enzymes and part funding; one author employed by DSM)

Thus even in a physiological meal setting, AN-PEP significantly degraded most gluten in the stomach before it entered the duodenum.

What the evidence does not support

In laboratory tests, five commercially available digestive enzyme supplements showed only modest gluten detoxification and left the nine immunogenic epitopes of the key gliadin fragments largely intact, while pure AN-PEP degraded them. (Source 4)

• Lab study in cells, Low certainty.
• Size: 5 commercial supplements.
• Who: Laboratory assays (ELISA, mass spectrometry, T cell proliferation)
• How long: not applicable.
• Result: Supplements showed only modest gluten detoxification by ELISA; epitopes largely intact.
• Funding: partly industry-funded (DSM Food Specialties, developer of AN-PEP) plus Dutch government grant.

The enzyme supplements leave the nine immunogenic epitopes of the 26-mer and 33-mer gliadin fragments largely intact. In contrast, the pure enzyme AN-PEP effectively degraded all nine epitopes in the pH range of the stomach at much lower dose.

In the paper's discussion (not a clinical trial), the authors concluded from their laboratory results that these supplements cannot be used to counteract gluten in gluten-intolerant people, and that preparations of similar composition would also fail to degrade gluten. (Source 5)

• Lab study in cells, Low certainty.
• Size: 5 commercial supplements.
• Who: Laboratory assays.
• How long: not applicable.
• Result: Qualitative conclusion.
• Funding: partly industry-funded (DSM Food Specialties)

Thus, the currently available enzyme supplements cannot be used to counteract the effect of gluten consumption in gluten intolerant individuals.

In a 494-patient phase 2 trial in symptomatic coeliac disease, latiglutenase did not differ from placebo in change in villous height to crypt depth ratio, intraepithelial lymphocyte counts or coeliac blood markers; all groups, including placebo, improved. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 494 patients.
• Who: Adults with coeliac disease on a gluten-free diet for at least one year with moderate-to-severe symptoms and villous atrophy, North America and Europe.
• How long: 12 or 24 weeks.
• Result: No difference between groups in histology or symptoms; both groups improved.
• Funding: not stated in fetched text (investigational drug trial)

there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease

In laboratory tests of nine commercial gluten supplements, DPP-IV was described as inactive at stomach pH, and several supplements showed minimal epitope-digesting activity. (Source 7)

• Lab study in cells, Low certainty.
• Size: 9 commercial supplements.
• Who: Laboratory ELISA assays.
• How long: not applicable.
• Result: Supplements 4-9 minimal activity at pH 3.5 by either ELISA.
• Funding: industry-funded (Glutagen Pty Ltd, maker of GluteGuard)

Supplements 4–9 demonstrated minimal activity at pH 3.5 with either ELISA.

In its 2015 lay summary of the Janssen et al. laboratory study, the Celiac Disease Foundation stated that commercial enzyme supplements will not properly protect against gluten exposure. (Source 8)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: People with coeliac disease.
• How long: not applicable.
• Result: Position statement (2015)
• Funding: not applicable.

Limit of this finding: This is the Foundation's own summary. Its wording that the enzymes 'cannot even survive the pH of the stomach' is not what the underlying study reported: the study found the supplements had near-neutral pH optima and modest gluten detoxification, but left the immune-triggering parts of gluten largely intact.

This means that the commercialized enzymes will not properly protect against gluten exposure to improve celiac disease symptoms.

Where the evidence is mixed

In a 4-week exploratory trial in 40 coeliac patients on a gluten-free diet, AN-PEP (GliadinX) did not significantly reduce overall gluten immunogenic peptides in stool (the primary measure), but median stool GIP in the AN-PEP arm was 44.7% lower than during run-in and fewer AN-PEP patients were symptomatic than during run-in (P < 0.03); the authors called for further research. (Source 9)

• Randomized trial, Low certainty.
• Size: 40 randomised.
• Who: Adults with coeliac disease on a long-term gluten-free diet, Argentina.
• How long: 4 weeks after 4-week run-in.
• Result: No significant reduction in overall stool GIP and no difference between arms; median GIP 44.7% lower than run-in in AN-PEP arm; proportion symptomatic (CSI > 38) significantly lower than run-in in AN-PEP arm (P < 0.03); no serology change.
• Funding: independent (coeliac association of Madrid; Argentine Society of Gastroenterology)

Limit of this finding: The positive results compare the AN-PEP arm with its own run-in period, not with placebo, in a small exploratory trial; they suggest a possible symptom effect worth testing, not a proven benefit.

The AN-PEP treatment did not significantly reduce the overall GIP stool concentration. However, given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm, further clinical research is warranted.

Where the research disagrees

Whether AN-PEP has meaningful benefit for people with coeliac disease

• König et al. (2017, DSM-supported), crossover RCT in 18 gluten-sensitive people, measuring gluten in gut contents: "Thus even in a physiological meal setting, AN-PEP significantly degraded most gluten in the stomach before it entered the duodenum." (Source 3)
• Stefanolo et al. (2024), exploratory RCT in 40 coeliac patients: "The AN-PEP treatment did not significantly reduce the overall GIP stool concentration. However, given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm, further clinical research is warranted." (Source 9)

How much

• Reference intake: No reference intake exists; these are not nutrients. The National Celiac Association states the lifelong gluten-free diet remains the only accepted treatment for coeliac disease. (Source 10)
• Upper limit: No upper limit has been set by any body for DPP-IV or gluten-degrading enzymes. (Source 7)
• Studied: Coeliac trial: two AN-PEP capsules (GliadinX) at each of three meals per day for 4 weeks, versus placebo. (Source 11)
• Studied: Latiglutenase 100-900 mg daily or placebo for 12 or 24 weeks in 494 coeliac patients. (Source 6)

A common belief, and what the research shows

The belief: A gluten-digesting enzyme pill lets people with coeliac disease or gluten sensitivity eat gluten safely.

What the research shows: Laboratory testing found "Currently available digestive enzyme supplements are ineffective in degrading immunogenic gluten epitopes." Joseph A. Murray, MD (Mayo Clinic), quoted by Beyond Celiac, said "there is no data to support the use of those enzymes for non-celiac gluten sensitivity either."

Questions and answers

What is it?

DPP-IV is a protein-cutting enzyme, usually made from the mould Aspergillus oryzae, that is added to many digestive supplements. It trims proline-containing pairs of amino acids off the end of protein chains and works at intestinal pH but not stomach pH. (Source 7)

What does it do in the body?

Gluten is rich in proline, so human digestive enzymes leave large fragments intact, and these fragments trigger the immune reaction in coeliac disease. Supplements claim to break those fragments down, but tested products left the immune-triggering parts largely intact. (Source 4)

Is it good or bad for you?

The evidence does not show these supplements protect people with coeliac disease. The main risk is false reassurance: Mayo Clinic coeliac specialist Joseph A. Murray, quoted by Beyond Celiac, warned patients not to use them to reduce gluten. (Source 1)

How do you get more of it?

These enzymes come only from supplements or investigational drugs; the body does not need them from food. Trials have given AN-PEP capsules with meals, and latiglutenase as an investigational drug. (Source 11)

If it is harmful, what reduces it?

Does not apply: the enzyme is not something that builds up in the body. What coeliac organisations focus on reducing is gluten exposure itself, through a strict gluten-free diet. (Source 10)

Why might someone be low in it or missing it?

Does not apply to the supplement enzyme. The reason gluten is hard to digest is its structure: its high proline content resists human digestive proteases, leaving large fragments in everyone. (Source 12)

Which whole foods contain it or feed it?

No whole food is a studied source of these gluten-degrading enzymes. The enzymes in supplements are produced from moulds such as Aspergillus oryzae and Aspergillus niger. (Source 12)

What happens if you do not have it?

Nothing is known to happen without the supplement. A strict gluten-free diet remains the only available treatment for gluten intolerance. (Source 12)

How can you test for it?

There is no test for 'having' these enzymes. Researchers judge whether an enzyme works by measuring gluten immunogenic peptides in stool or gluten in gut contents; in the coeliac AN-PEP trial, stool peptides were usually undetectable and did not differ between groups. (Source 13)

References

1. Beyond Celiac. Are Enzymes Safe for the Celiac Disease Community? Researchers Set the Record Straight. 2015. Read the source
2. National Celiac Association. What is GliadinX product (digestive enzyme supplement)?. 2022. Read the source
3. Scientific Reports. Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. 2017. DOI 10.1038/s41598-017-13587-7. Read the source
4. PLOS One. Ineffective Degradation of Immunogenic Gluten Epitopes by Currently Available Digestive Enzyme Supplements. 2015. PMID 26030273, DOI 10.1371/journal.pone.0128065. Read the source
5. PLOS One. Ineffective Degradation of Immunogenic Gluten Epitopes by Currently Available Digestive Enzyme Supplements. 2015. PMID 26030273, DOI 10.1371/journal.pone.0128065. Read the source
6. Gastroenterology. No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease. 2017. PMID 27864127, DOI 10.1053/j.gastro.2016.11.004. Read the source
7. Frontiers in Nutrition. Relative Rates of Gluten Digestion by Nine Commercial Dietary Digestive Supplements. 2021. DOI 10.3389/fnut.2021.784850. Read the source
8. Celiac Disease Foundation. Study Demonstrates Current Enzyme Supplements for Celiac Disease Ineffective. 2015. Read the source
9. World Journal of Gastroenterology. Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet. 2024. PMID 38617446, DOI 10.3748/wjg.v30.i11.1545. Read the source
10. National Celiac Association. What is GliadinX product (digestive enzyme supplement)?. 2022. Read the source
11. World Journal of Gastroenterology. Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet. 2024. PMID 38617446, DOI 10.3748/wjg.v30.i11.1545. Read the source
12. PLOS One. Ineffective Degradation of Immunogenic Gluten Epitopes by Currently Available Digestive Enzyme Supplements. 2015. PMID 26030273, DOI 10.1371/journal.pone.0128065. Read the source
13. World Journal of Gastroenterology. Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet. 2024. PMID 38617446, DOI 10.3748/wjg.v30.i11.1545. Read the source