Digestive enzyme blends

What it is

Digestive enzyme blends are mixtures of enzymes that break down proteins (proteases), carbohydrates (amylases) and fats (lipases). Prescription pancrelipase is an extract of pig pancreas; supplement blends are often made by fungal or microbial fermentation. Products differ in enzyme type, source and dose.

What the research says

For people whose pancreas does not make enough enzymes (exocrine pancreatic insufficiency, for example in cystic fibrosis), prescription enzyme replacement is the standard treatment, though a Cochrane review found the evidence comparing formulations mostly very low quality. For over-the-counter blends in people without that condition, evidence is thin: one 120-person trial in functional dyspepsia reported benefit, while a trial in children with autism found no clinically significant effect. High-dose prescription enzymes are linked to fibrosing colonopathy in children, and allergic reactions and raised uric acid are reported.

Evidence grade: Limited evidence.

What goes wrong

High-dose pancreatic enzyme products are associated with fibrosing colonopathy and colonic stricture, mainly in children with cystic fibrosis; the FDA label sets dose ceilings. (Source 1)

• Official position, Low certainty.
• Size: Post-marketing reports.
• Who: Mostly children with cystic fibrosis.
• How long: Usually prolonged use.
• Result: Colonic stricture associated with doses above 6,000 lipase units/kg/meal in children under 12.
• Funding: industry label (FDA-approved)

Pancreatic enzyme products exceeding 6,000 lipase units/kg/meal have been associated with colonic stricture, a complication of fibrosing colonopathy

Pancreatic enzyme products can cause severe hypersensitivity reactions including anaphylaxis, and their purine content can raise uric acid at high doses. (Source 1)

• Official position, Low certainty.
• Size: Post-marketing reports.
• Who: Patients using pancreatic enzyme products.
• How long: Not stated.
• Result: No rates given.
• Funding: industry label (FDA-approved)

Severe hypersensitivity reactions including anaphylaxis, asthma, hives, and pruritus have been reported with pancreatic enzyme products.

The same label notes the purines in pancreatic enzyme products may raise blood uric acid, with hyperuricemia at high doses. (Source 1)

• Official position, Low certainty.
• Size: Not stated.
• Who: Patients using pancreatic enzyme products.
• How long: Not stated.
• Result: No rates given.
• Funding: industry label (FDA-approved)

Pancreatic enzyme products contain purines that may increase blood uric acid levels.

What the evidence supports

In a randomised double-blind placebo-controlled trial in functional dyspepsia, a fungal multi-enzyme blend was reported to improve quality of life, pain and sleep scores without side effects. (Source 2)

• Randomized trial, Low certainty.
• Size: 120 adults.
• Who: Adults aged 18 to 59 with functional dyspepsia.
• How long: 2 months.
• Result: Improvement in NDI-SF, VAS pain and PSQI sleep scores in the enzyme group (between-group numbers not given in the abstract)
• Funding: no external funding reported.

The results showed an improvement in NDI-SF1, NDI-SF2–5, VAS, and PSQI scores in subjects treated with the multi-enzyme blend

In cystic fibrosis, a Cochrane review found delayed-release microspheres gave less fat in stool and less abdominal pain than tablets in two small trials. (Source 3)

• Systematic review, Very low certainty.
• Size: 41 participants in two trials (review: 14 trials, 641 people)
• Who: Children and adults with cystic fibrosis.
• How long: Mostly 4 weeks per treatment period.
• Result: Less faecal fat and abdominal pain with microspheres.
• Funding: not stated in the summary.

those taking delayed-release microspheres (miniature drug capsules) had less fat in their poo than those taking delayed-release tablets

What the evidence does not support

The same Cochrane review could not show any formulation was better for weight, height or BMI, and rated the evidence moderate at best but mostly very low. (Source 3)

• Systematic review, Very low certainty.
• Size: 14 trials, 641 participants.
• Who: Children and adults with cystic fibrosis.
• How long: Mostly 4 weeks.
• Result: No difference between formulations for most outcomes.
• Funding: not stated.

We found the quality of the evidence for the different outcomes to be moderate at best, but mostly very low.

In a double-blind crossover trial in children with autism, a digestive enzyme supplement produced no clinically significant improvement in behaviour, gastrointestinal symptoms or sleep versus placebo. (Source 4)

• Randomized trial, Low certainty.
• Size: 43 children.
• Who: Children aged 3 to 8 with autism spectrum disorder.
• How long: 6 months (crossover)
• Result: No clinically significant differences; small statistically significant improvement in food variety only.
• Funding: not stated.

treatment with enzyme was not associated with clinically significant improvement in behaviour, food variety, gastrointestinal symptoms, sleep quality

How much

• Reference intake: No RDA exists; digestive enzymes are made by the body and are not essential dietary nutrients. (Source 5)
• Upper limit: No dietary upper limit exists. For prescription pancrelipase (CREON label, FDA, revised 2/2024), dosing above 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day or 4,000 lipase units/g fat/day should not be exceeded without further investigation. (Source 1)
• Studied: Functional dyspepsia trial: 2 capsules a day, each with 200 mg of a fungal multi-enzyme blend, for 2 months (Ullah 2023). (Source 2)

A common belief, and what the research shows

The belief: Everyone with bloating needs digestive enzymes because they are enzyme-deficient.

What the research shows: True enzyme deficiency (exocrine pancreatic insufficiency) is a diagnosed condition with causes such as chronic pancreatitis and cystic fibrosis; the Mayo Clinic test page notes a fecal elastase result 'Normal concentrations of fecal pancreatic elastase (PE) do not exclude the possibility' of mild disease, and evidence for over-the-counter blends in people without it is thin.

Questions and answers

What is it?

Mixtures of enzymes that digest protein, starch and fat. They can come from pig pancreas, plants or microbes, and products vary widely. (Source 5)

What does it do in the body?

In the gut they break food into smaller parts that can be absorbed. When the pancreas makes too little, food is poorly digested and absorbed. (Source 6)

Is it good or bad for you?

Clearly useful as prescription therapy for diagnosed pancreatic insufficiency. For over-the-counter use the evidence is limited and mixed, and high doses of prescription products carry rare but serious risks. (Source 1)

How do you get more of it?

The body makes its own digestive enzymes, mainly in the pancreas. Studied supplements include prescription pancrelipase and fungal enzyme blends. Nothing here is a recommendation. (Source 6)

If it is harmful, what reduces it?

Does not apply; these enzymes are not harmful at normal levels. The harms reported relate to high supplemental doses. (Source 1)

Why might someone be low in it or missing it?

Low enzyme output happens in exocrine pancreatic insufficiency, most often from chronic pancreatitis, and also with cystic fibrosis, pancreatic cancer or surgery, diabetes, gastric surgery and some bowel conditions. (Source 7)

Which whole foods contain it or feed it?

The sources we read did not identify whole foods that meaningfully replace pancreatic enzymes. Pineapple (bromelain) and papaya (papain) contain protein-digesting enzymes, covered in their own entries. (Source 5)

We searched: Ianiro 2016 review of digestive enzyme supplementation; WebSearch on OTC enzyme supplements

What happens if you do not have it?

Without enough pancreatic enzymes, people can develop fatty stools, bloating, weight loss and nutrient deficiencies. (Source 6)

How can you test for it?

Fecal elastase in stool is a common first test for pancreatic insufficiency. In a meta-analysis it detected about 77% of cases with 88% specificity, gives false positives when the chance of disease is low, and can miss mild disease. (Source 6)

References

1. US Food and Drug Administration (accessdata.fda.gov). CREON (pancrelipase) delayed-release capsules - US Prescribing Information (revised 2/2024). 2024. Read the source
2. Biomedicine & Pharmacotherapy. Efficacy of digestive enzyme supplementation in functional dyspepsia: A monocentric, randomized, double-blind, placebo-controlled, clinical trial. 2023. PMID 37976892, DOI 10.1016/j.biopha.2023.115858. Read the source
3. Cochrane Database of Systematic Reviews 2020, Issue 8 (CD008227.pub4). Pancreatic enzyme replacement therapy for people with cystic fibrosis (Cochrane Review, plain language summary). 2020. DOI 10.1002/14651858.CD008227.pub4. Read the source
4. Journal of Autism and Developmental Disorders. Digestive Enzyme Supplementation for Autism Spectrum Disorders: A Double-Blind Randomized Controlled Trial. 2010. DOI 10.1007/s10803-010-0974-2. Read the source
5. Current Drug Metabolism 17(2):187-193. Digestive Enzyme Supplementation in Gastrointestinal Diseases. 2016. PMID 26806042, DOI 10.2174/138920021702160114150137. Read the source
6. Mayo Clinic Laboratories. ELASF - Pancreatic Elastase, Feces: Clinical Information. Read the source
7. Mayo Clinic Laboratories. ELASF - Pancreatic Elastase, Feces: Clinical Information (causes of EPI). Read the source