November/December 2021 Issue

CPE Monthly: Digestive Enzymes and Nutrition
By Sara Chatfield, MPH, RDN, LDN
Today’s Dietitian
Vol. 23, No. 9, P. 50

Suggested CDR Performance Indicators: 8.1.3, 8.1.4, 10.4.4, 10.4.6
CPE Level 2

Take this course and earn 2 CEUs on our Continuing Education Learning Library

The human digestive system contains digestive enzymes that perform vital actions in the body’s process of breaking down food into simple nutrients that can be absorbed and utilized. Digestive enzymes also are found in a variety of foods and in prescription and over-the-counter (OTC) supplements.

Consumer demand for dietary supplements is high; sales are estimated to have reached $5.5 billion in 2020.1 Digestive enzyme supplements especially have become increasingly popular with consumers, with a $522.2 million market in 2018 that’s expected to more than double to $1.2 billion by 2026.2

According to market research, a rise in awareness of gastrointestinal (GI) disorders, along with increased disposable income and changing lifestyles internationally, is fueling the increase in popularity of digestive enzymes. In 2018, tablet forms of enzymes were the most popular, comprising 21% of the market, and amylase was the best-selling enzyme category.2

Despite the large market for and the popularity of digestive enzyme supplements for a wide variety of conditions and ailments, there’s a limited body of research on the effects of OTC digestive enzymes for many of these conditions.

This continuing education course reviews the role of digestive enzymes, describes food and supplement sources of digestive enzymes, and discusses their potential benefits and risks for a variety of health conditions.

Digestive Enzymes in the Body
Digestive enzymes in the human GI tract, which can be grouped into the following categories, are essential to the processing of macronutrients for absorption:

Amylases in saliva and pancreatic juices break down complex carbohydrates into di-, tri-, and oligosaccharides, which are then further broken down to monosaccharides on the brush border membrane of the small intestine by the disaccharidases maltase, isomaltase, sucrase, and lactase.3

Proteases, including pepsin in the stomach and pancreatic proteases, break down polypeptides into oligopeptides and amino acids. A variety of peptidases on the brush border membrane of the small intestine break down remaining oligopeptides into amino acids.3

Lipases in the tongue glands, stomach, and pancreas break down fats into free fatty acids and monoglycerides; the majority of fat digestion occurs in the small intestine with the help of pancreatic enzymes. Short-chain fatty acids are produced by the bacterial breakdown of undigested fats in the colon.3

Food Sources of Digestive Enzymes
Many foods contain naturally occurring digestive enzymes. There’s little research, however, regarding the health effects of consuming the enzymes in these foods. Some in vitro studies have found that kiwifruit extract containing the protease actinidin helped with digestion of a variety of common protein sources.4 There’s also a theoretical basis for an intestinal anti-inflammatory effect of the cysteine proteases found in kiwi, figs, pineapple, and papaya, but more research is needed.5

The National Institutes of Health note that medicinal use of papaya may have safety concerns, especially during pregnancy or breast-feeding, or in individuals with thyroid conditions or conditions affecting blood sugar. Those with latex allergies may be allergic to papaya.6

Click to enlarge

OTC Supplements
A wide variety of OTC enzymes is available in various combinations, including different amylases, proteases, and lipases. Many of these enzymes, such as chymotrypsin, are from animal—generally bovine or porcine—sources.7 However, there are many plant-based options available, such as papain (from papaya) and bromelain (from pineapple), and enzymes derived from microbial or fungal sources, including lipase from the fungus Aspergillus oryzae—which has shown activity similar to animal-based lipase—and lactase produced from the yeast Kluyveromyces lactis.8

Potency of OTC enzymes varies depending on the brand, and units may be listed as US Pharmacopeia (USP) for animal-sourced enzymes, or Food Chemicals Codex (FCC) for plant-sourced enzymes, both of which are determined by enzyme activity assays; however, other measures may be used, especially if assays for a particular enzyme aren’t available through these sources.9,10 Dose recommendations generally are listed on manufacturer labels and, for digestive enzymes, often advise taking the supplement with food.

Prescription Enzyme Therapy in Pancreatic Disorders
Exocrine pancreatic insufficiency is associated with several diseases, including acute and chronic pancreatitis, pancreatic cancer, cystic fibrosis, and pancreatic or other GI surgeries.11 Chronic pancreatitis is the most common cause of pancreatic insufficiency in adults, while cystic fibrosis is the most common cause in children. Pancreatic enzymes generally are prescribed when pancreatic lipase secretion is reduced by 90% or more, causing fat malabsorption, which can lead to malnutrition and impaired absorption of fat-soluble vitamins.12,13

There currently are six FDA-approved pancreatic enzymes, available by prescription only: Creon, Pancreaze, Zenpep, Ultresa, Viokace, and Pertzye. Each contains different ratios of lipase, protease, and amylase.14 The medication dosages are between 3,000 to 36,000 USP units of lipase per capsule.

A typical patient dosage is between 500 and 2,500 USP units of lipase/kg/meal and one-half of that for snacks, taken before meals or with the first bite of food; generally, the enzymes are effective for about one hour.14 The most common side effects reported from the enzymes are headache, dizziness, abdominal pain, and flatulence.13

These products are from porcine or sometimes bovine sources.8 This may be problematic for patients with allergies to pork products, or who have religious, cultural, or ethical concerns with their use.13 There’s interest in developing lipases from plant-based (fungal or bacterial) sources due to their increased range of pH activity.7,11

The goal of normalizing fat absorption can be elusive, and patients may need individualized therapy due to challenges of enzyme inactivation or timing with food intake. Antacids are sometimes added to keep patients’ gastric pH above 4 to protect the lipase from degradation. Enteric-coated microbead preparations also are available for patients who may need additional treatment options, with the general goal of restoring fat absorption to at least 85%. In one study, cystic fibrosis patients’ persistent steatorrhea improved with increased doses of enteric-coated pancreatic enzymes and the addition of omeprazole. Enteric-coated enzymes can be opened and sprinkled onto soft foods for patients unable to swallow them whole.12

Supplemental Digestive Enzyme Use in Common Health Conditions

Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) affects about 12% of people in the United States.15 For some patients, this functional disorder can be debilitating, with its symptoms of abdominal pain, bloating, and constipation and/or diarrhea. Patients consistently report a lower health-related quality of life.16 The etiology of IBS still isn’t entirely understood, but symptoms may be linked to food intolerances, including those to lactose and other FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), fatty foods, and caffeine.17

There’s a limited number of studies looking at digestive enzyme use in IBS. In a double-blinded crossover study, 255 adult patients, mean age 52, with diarrhea- predominant IBS and self-identified food triggers took either prescription Viokase capsules or a placebo with a varied number of—but at least six—trigger meals. The digestive enzyme treatment was linked to a significant reduction (about 60%) in reported diarrhea-predominant IBS symptoms from patients’ baseline, compared with a 34% reduction with placebo. A large patient dropout rate was noted in this study.18

In a study of 50 patients, mean age 51, treated with a mixture of beta-glucan and inositol (both thought to have potential effects on the GI system) with unspecified digestive enzymes at lunch and dinner for four weeks, compared with 40 patients who received placebos, a significant improvement was noted in bloating, flatulence, and abdominal pain three to four weeks after the treatment was started. Limitations included a short study period and the small number of subjects. In addition, researchers didn’t determine the effects of individual supplements.16

In another study, researchers gave beta-glucan, inositol, and digestive enzymes for four weeks, in addition to the pharmacological treatment mesalamine, to inflammatory bowel disease patients in clinical remission who also had IBS symptoms. The 23 adult patients (mean age 49) who received the treatment reported significant improvements in abdominal pain, bloating, flatulence, and general well-being, compared with only a mild change in the mesalamine-only group. Again, the effects of individual supplements are unknown.19

Lactose Intolerance
Lactose intolerance occurs when lactose malabsorption leads to GI symptoms, the main cause of lactose malabsorption being lactase deficiency.11,20 The presence of lactase on the intestine’s brush border is necessary to break down lactose into the monosaccharides glucose and galactose. Lactase peaks at birth in humans and begins to decrease after the first few months of life, and in the majority of humans reaches undetectable levels, known as primary lactase deficiency. The exceptions are descendants of populations that traditionally practice cattle domestication; this lactase persistence trait is highest in northern European populations. Secondary lactase deficiency can be caused by GI infection, inflammatory bowel disease, abdominal surgery, and other health issues.21

Worldwide, up to 50% of those with lactose malabsorption have symptoms, such as abdominal pain, bloating, borborygmi, and diarrhea.20,22 While most people can tolerate small amounts (less than 12 g) of lactose, IBS patients have a high rate of self-reported dairy intolerance and symptoms after the consumption of even low to moderate doses of lactose and other FODMAPs.21

Supplemental lactase may help individuals with lactose intolerance to continue consuming preferred quantities of dairy products. These include prehydrolyzed (lactose-free) milk products, or OTC lactase supplements, most commonly tablets or capsules. Some studies have shown that lactase derived from the yeast K lactis is superior to that from the fungus Aspergillus niger. Yogurt with probiotics also may be tolerated by those with lactose intolerance, as the beneficial microbes help hydrolyze the lactose, decreasing it by 25% to 50%.11

Studies using hydrogen breath testing have demonstrated that the amount of both lactose and lactase consumed affects results. Fermentation of unabsorbed carbohydrates in the colon, including lactose, produces hydrogen (H2) along with other gases, which is then absorbed and exhaled, allowing for measurement of elevated breath H2 levels as a test for malabsorption.17 Some studies, however, suggest that H2 levels and GI symptoms aren’t directly correlated in subjects with lactose intolerance.20

In one study, 6,000 IU and 3,000 IU of lactase were shown to reduce breath H2 excretion significantly in lactose-intolerant subjects, with 6,000 IU demonstrating a larger reduction. Both doses reduced GI symptoms significantly when given with 20 g lactose; however, neither dose was effective when subjects consumed 50 g lactose.11

In a double-blinded, placebo-controlled crossover study, two varying doses of lactase were added to milk given to 28 adults (mean age 43) with a positive H2 breath test for lactose intolerance. With both lactase treatments—milk prehydrolyzed with 3,000 units 10 hours before consumption and milk prehydrolyzed with 6,000 units five minutes before consumption—breath H2 excretion and clinical symptoms were significantly reduced, and the 10 hours before treatment significantly improved symptoms more than the just before treatment.22 Prehydrolyzed products may improve tolerance to dairy more than OTC lactase supplements; however, the convenience of shelf-stable supplements may also impact this choice.

Gluten Intolerance
In celiac disease, consumption of gluten peptides rich in the amino acids proline and glutamine causes an immune reaction in individuals with a genetic predisposition.11 In recent years, several gluten-degrading protease enzymes, some of which target proline specifically, have been studied as potential therapies for gluten intolerance.11,13

Some of these enzymes have been shown to enhance degradation of gluten peptides in the stomach during in vitro and in vivo studies; however, they haven’t demonstrated an effect on patients’ clinical markers. In addition, various challenges to the efficacy of these enzymes have been identified, including an inability to break down all gluten fragments, lack of activity at the low pH levels found in the acidic gastric environment, and possible interaction with various food components.11,23,24

There currently are commercially available enzyme products marketed as helping with gluten digestion. Many of these contain the enzyme dipeptidyl peptidase IV, but some don’t specify the protease. Many also contain amylases, lipases, and other substances such as probiotics.25 Although they may claim to break down gluten or help with the GI symptoms associated with eating gluten, these products haven’t been proven to be effective in the acidic stomach environment at breaking down the gluten peptides toxic to those with celiac disease.11

The potential of enzymes with glutenase activity needs further study before they can be recommended to those with celiac disease or gluten sensitivities.23

Autism Spectrum Disorders
Autism spectrum disorders (ASDs), characterized by social and communication difficulties and sensory challenges, are theorized to have a gut-brain connection.26,27 Diets restricted in gluten and casein anecdotally have improved symptoms in some children with autism, and it’s been hypothesized that these proteins release exorphins with opioidlike effects. Digestive enzymes are theorized to break exorphins into smaller peptides without these effects.28

In a double-blinded, randomized, placebo-controlled crossover trial, 43 children with ASD between the ages of 3 and 8 were given a plant-derived combination of protease enzymes (peptidase, protease 4.5, and papain) for three months during their treatment period. Overall, no significant differences were found in children’s’ behavior, language, sleep quality, or GI symptoms while taking the enzymes vs placebo. Only the food variety measure (representing the range of foods eaten) improved during one month of the study.28

In a double-blinded, randomized clinical trial with 101 children aged 3 to 9 with ASD, a mixture of papain and pepsin or placebo was given for three months. Significant improvements were noted in the digestive enzyme group in general behavior and GI symptoms, mainly in repetitive and stereotypic behaviors. No crossover was included in this study. Researchers noted rashes, skin itching, and abdominal pain as possible side effects of the treatment.26

The mixed results from these two compared studies show the need for further research to assess the use of digestive enzymes in ASDs.

Common Digestive Problems
Though many digestive enzyme supplements purport to help with common digestive problems, such as gas, bloating, and indigestion, or with maintaining or enhancing normal digestion, there isn’t much research to support these claims.

In one study, 62 volunteers with common digestive complaints, such as nausea, heartburn, abdominal pain, and bloating, were randomly assigned to receive either prescription domperidone or a plant-derived digestive enzyme complex. There was significant improvement in all subjects’ symptoms with both treatments, and a significant reduction in abdominal pain with the digestive enzyme treatment compared with the prescription medicine; subjects’ other symptom responses didn’t indicate significant difference between the two treatments.29

In a double-blinded, placebo-controlled trial of 52 healthy children aged 4 to 17 with gas-related GI complaints, researchers used the enzyme alpha-galactosidase (derived from A niger) as the treatment. This enzyme is designed to break down nonabsorbable oligosaccharides, which can result in an overproduction of gas when metabolized by intestinal bacteria.30

The children who received the alpha-galactosidase supplement had significantly decreased scores for severity of abdominal bloating and flatulence compared with placebo. Meanwhile, their other GI complaints showed nonsignificant improvement with the enzyme. The treatment was noted as well tolerated.30

One study found that a prescription enzyme given to healthy adults before and after a high-fat meal reduced GI symptoms.7

These studies provide some evidence that certain digestive enzymes may help with common digestive problems; however, the general lack of research makes it difficult to determine their efficacy.

Osteoarthritis (OA) affects nearly 34% of adults older than 65 and 14% of adults aged 25 to 65, causing gradual loss of joint cartilage with inflammation and pain.31 Lab studies suggest that enzyme supplements have anti-inflammatory properties that could theoretically help with OA. One small trial of an OTC enzyme preparation with bromelain, trypsin, and rutin (a flavonoid) found that it significantly improved pain compared with the prescription NSAID diclofenac, with fewer adverse events.7

In another study with 295 adults aged 40 to 80 with OA of the knee, the treatment of bromelain, trypsin, and rutin led to significant improvement in patients’ joint pain and function, which was comparable to diclofenac and greater than placebo. This study had a large patient dropout rate. It also was noted that companies associated with the enzyme being studied had employed two of the investigators.31

Though these studies highlight a possible benefit of digestive enzymes in treating OA, there are limited studies to support this.

Exercise-Induced Inflammation
The potential anti-inflammatory effects of enzyme supplementation also have been investigated for postexercise muscle soreness. In a small double-blinded study of 20 men aged 18 to 29, researchers gave one-half of the participants an enzyme complex (containing multiple protease sources and also amylase and lipase) four times daily for four days, starting one day before a downhill running session, while giving matched controls a placebo. The enzyme group showed greater improvements in recovery of contractile function and less subjective pain from leg muscle damage induced by the running exercise, compared with the control group. Other measures of muscle recovery, such as pressure pain threshold and agility, didn’t differ significantly between the groups.32

In a randomized, double-blinded, placebo-controlled crossover trial, 28 adults aged 20 to 50 were given four tablets of an enzyme complex containing trypsin, bromelain, and rutin three times per day, from 72 hours before to 72 hours after an exhaustive (muscle fatigue–inducing) unaccustomed exercise. Researchers noted significant improvements in subjects’ metabolic, immune, and inflammatory biomarkers with the enzyme therapy compared with placebo.33

Although these studies suggest that enzymes may be helpful for exercise-induced muscle soreness, both studies were small, and other studies have noted no difference when treating delayed-onset muscle soreness with enzymes.7

Safety of Digestive Enzyme Supplements
Dietary supplements are regulated by the FDA Center for Food Safety and Applied Nutrition. The Dietary Supplement Health and Education Act of 1994 set safety and labeling requirements for dietary supplements. Dietary supplement labels can display certain health claims, most commonly related to “structure and function” (the supplement’s effect on body structure or function), “general well-being,” or benefits related to nutrient deficiencies. Structure and function claims are required to have the disclaimer, “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” Claims also are required to be “truthful, not misleading, and substantiated by credible scientific evidence.”34

Despite this, the labels of some digestive enzyme products have been noted to have misleading claims. Claims and labels for dietary supplements don’t require the rigor of the testing and approval processes for prescription medications.25

Supplement companies are responsible for meeting Good Manufacturing Practices to ensure their products are free of contaminants and are accurately labeled. The FDA monitors safety mainly through adverse event reports that consumers, health professionals, and manufacturers submit to its MedWatch Safety Information and Adverse Event Reporting Program. Some organizations, such as, NSF International, and US Pharmacopeial Convention, offer evaluations of supplement quality in exchange for use of their seal of approval on labels.34

Despite limited regulation, the risks of taking supplemental digestive enzymes generally are low. The most commonly reported side effects are mild digestive complaints, although other risks, including allergic reactions, are possible. The presence of various contaminants also is possible in these OTC products. Pregnant or lactating women should consult their health care provider before taking enzymes, as some may be unsafe.7

In the general population, excessive intake of papain may cause esophageal perforation.7 Fibrosing colonopathy, a rare but severe reaction associated with high-dose (prescription) enzyme therapy in children with cystic fibrosis, causes collagen deposition and strictures in the colon.13 The interactions between digestive enzyme supplements and other supplements or medications are unclear.7

Research Limitations
Due to the general lack of research on digestive enzymes and health, and concerns associated with the available research—such as evidence in only laboratory studies, small sample sizes in human studies, and lack of clinical data—it’s challenging to determine the efficacy, if any, of digestive enzymes for most of the common health conditions explored in this course.

Putting It Into Practice
Because clients and patients may start taking OTC supplements such as digestive enzymes on their own, or after discussion with other health care providers, nutrition professionals routinely should ask about any supplement use during nutrition assessments. If clients and patients are taking or considering supplemental digestive enzymes, RDs should present up-to-date evidence on their potential benefits and risks.

Although the practice of treating exocrine pancreatic insufficiency with prescription enzyme supplements is well established, there’s less support for use of OTC digestive enzymes for other health conditions, despite their growing popularity. Nutrition professionals should educate patients on the digestive process and dietary or lifestyle strategies that may help with managing their health conditions or digestive complaints. Patients with IBS may benefit from identifying and reducing food triggers, such as FODMAPs. Patients with celiac disease should be encouraged to maintain a gluten-free diet and discouraged from trying products that claim to break down gluten. There’s evidence that individuals with GI symptoms related to lactose intolerance may find lactase supplements or prehydrolyzed dairy products helpful, in conjunction with education about lactase levels in foods.

Nutrition professionals may consider supporting a trial of supplemental digestive enzymes, along with their other nutrition recommendations, for clients without contraindications who have health conditions for which enzymes have shown some evidence of benefit. Patients taking OTC digestive enzymes should be encouraged to check manufacturer recommendations for dosage and timing with meals and monitor for possible side effects. If RDs discuss digestive enzyme supplements with or recommend them to patients, this information should be relayed to the rest of the health care team.

Due to the popularity of dietary supplements, and in particular digestive enzyme supplements, nutrition professionals may encounter clients and patients who are taking digestive enzymes or interested in trying them. In light of the limited research available, RDs can help patients weigh the possible benefits of trying digestive enzymes against potential concerns with safety or side effects.

— Sara Chatfield, MPH, RDN, LDN, is a Chicago-based freelance nutrition writer who has practiced dietetics in clinical and community settings.

Learning Objectives

After completing this continuing education course, nutrition professionals should be better able to:
1. Distinguish three types of digestive enzymes naturally occurring in the body and describe their roles.
2. Identify five foods containing digestive enzymes.
3. Describe the use of prescription digestive enzymes in the treatment of pancreatic insufficiency.
4. Counsel clients on several potential benefits and risks of using supplemental digestive enzymes for gastrointestinal and other health conditions.

CPE Monthly Examination

1. Which type of enzyme begins the body’s process of breaking down carbohydrates?
a. Amylase
b. Glutenase
c. Lipase
d. Protease

2. Which of the following foods contains amylase, protease, and lipase?
a. Avocado
b. Miso
c. Ginger
d. Honey

3. Which health condition is the most common cause of pancreatic insufficiency in adults?
a. Cystic fibrosis
b. Irritable bowel syndrome
c. Acute pancreatitis
d. Chronic pancreatitis

4. Prescription enzyme supplements are dosed based on which enzyme?
a. Amylase
b. Lipase
c. Protease
d. Lactase

5. Patients with irritable bowel syndrome often have trouble digesting even small to moderate amounts of which of the following?
a. Protein
b. Lactose
c. Fiber
d. Gluten

6. Probiotics in yogurt have been shown to decrease its lactose content by what percentage?
a. 5% to 10%
b. 15% to 20%
c. 25% to 50%
d. 50% to 75%

7. Gluten-degrading enzymes, under study for their ability to help break down gluten peptides, are classified as which of the following?
a. Amylases
b. Proteases
c. Amino acids
d. Lipases

8. The enzyme alpha-galactosidase is designed
to break down which of the following?
a. Oligosaccharides
b. Exorphins
c. Peptides
d. Lactose

9. Bromelain, included in supplement formulas found in some studies to help arthritis pain, also is found in which food?
a. Honey
b. Papaya
c. Pineapple
d. Banana

10. The most commonly reported side effect of OTC digestive enzymes is:
a. Allergic reaction.
b. Fibrosing colonopathy.
c. Esophageal perforation.
d. Mild digestive complaints.

1. From vitamin D to collagen: supplements and functional ingredients are in high demand. SPINS website. Updated July 8, 2020. Accessed October 12, 2020.

2. Digestive enzymes market revenue to reach USD 1,210.1 million by 2026. GlobeNewswire website. Published April 8, 2019. Accessed October 12, 2020.

3. Goodman BE. Insights into digestion and absorption of major nutrients in humans. Adv Physiol Educ. 2010;34(2):44-53.

4. Richardson DP, Ansell J, Drummond LN. The nutritional and health attributes of kiwifruit: a review. Eur J Nutr. 2018;57(8):2659-2676.

5. Bayer SB, Gearry RB, Drummond LN. Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. Crit Rev Food Sci Nutr. 2018;58(14):2432-2452.

6. Papaya. MedlinePlus website. Updated September 22, 2020. Accessed February 16, 2021.

7. Varayil JE, Bauer BA, Hurt RT. Over-the-counter enzyme supplements: what a clinician needs to know. Mayo Clinic Proc. 2014;89(9):1307-1312.

8. Roxas M. The role of enzyme supplementation in digestive disorders. Altern Med Rev. 2008;13(4):307-314.

9. Enzyme labels. Enzyme Essentials website. Accessed October 26, 2020.

10. Understanding enzyme testing: tips from the experts. Sora Laboratories website. Published August 19, 2019. Accessed October 26, 2020.

11. Ianiro G, Pecere S, Giorgio V, Gasbarrini A, Cammarota G. Digestive enzyme supplementation in gastrointestinal disease. Curr Drug Metab. 2016;17(2):187-193.

12. Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21(st) century. World J Gastroenterol. 2014;20(33):11467-11485.

13. Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73.

14. What you need to know about pancreatic enzymes. Columbia Surgery website. Accessed February 18, 2021.

15. Definition & facts for irritable bowel syndrome. National Institute of Diabetes and Digestive and Kidney Diseases website. Updated November 2017. Accessed October 12, 2020.

16. Ciacci C, Franceschi F, Purchiaroni F, et al. Effect of beta-glucan, inositol and digestive enzymes in GI symptoms of patients with IBS. Eur Rev Med Pharmacol Sci. 2011;15(6):637-643.

17. Bolin T. IBS or intolerance? Aust Fam Physician. 2009;38(12):962-965.

18. Money ME, Walkowiak J, Virgilio C, Talley NJ. Pilot study: a randomised, double blind, placebo controlled trial of pancrealipase for the treatment of postprandial irritable bowel syndrome-diarrhoea. Frontline Gastroenterol. 2011;2(1):48-56.

19. Spagnuolo R, Cosco C, Mancina RM, et al. Beta-glucan, inositol and digestive enzymes improve quality of life of patients with inflammatory bowel disease and irritable bowel syndrome. Eur Rev Med Pharmacol Sci. 2017;21(2 Suppl):102-107.

20. Ibba I, Gilli A, Boi MF, Usai P. Effects of exogenous lactase administration on hydrogen breath excretion and intestinal symptoms in patients presenting lactose malabsorption and intolerance. Biomed Res Int. 2014;2014:680196.

21. Deng Y, Misselwitz B, Dai N, Fox M. Lactose intolerance in adults: biological mechanism and dietary management. Nutrients. 2015;7(9):8020-8035.

22. Montalto M, Nucera G, Santoro L, et al. Effect of exogenous beta-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study. Eur J Clin Nutr. 2005;59(4):489-493.

23. König J, Brummer RJ. Is an enzyme supplement for celiac disease finally on the cards? Expert Rev Gastroenterol Hepatol. 2018;12(6):531-533.

24. Tack GJ, van de Water JMW, Bruins MJ, et al. Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study. World J Gastroenterol. 2013;19(35):5837-5847.

25. Krishnareddy S, Stier K, Recanati M, Lebwohl B, Green PH. Commercially available glutenases: a potential hazard in coeliac disease. Therap Adv Gastroenterol. 2017;10(6):473-481.

26. Saad K, Eltayeb AA, Mohamad IL, et al. A randomized, placebo-controlled trial of digestive enzymes in children with autism spectrum disorders. Clin Psychopharmacol Neurosci. 2015;13(2):188-193.

27. Sathe N, Andrews J, McPheeters M, Warren Z. Nutritional and dietary interventions for autism spectrum disorder: a systematic review. Pediatrics. 2017;139(6):e20170346.

28. Munasinghe SA, Oliff C, Finn J, Wray JA. Digestive enzyme supplementation for autism spectrum disorders: a double-blind randomized controlled trial. J Autism Dev Disord. 2010;40(9):1131-1138.

29. Quinten T, Philippart JM, De Beer T, Vervarcke S, Van Den Driessche M. Can the supplementation of a digestive enzyme complex offer a solution for common digestive problems? Arch Public Health. 2014;72(Suppl 1):P7.

30. Di Nardo G, Oliva S, Ferrari F, et al. Efficacy and tolerability of α-galactosidase in treating gas-related symptoms in children: a randomized, double-blind, placebo controlled trial. BMC Gastroenterol. 2013;13:142.

31. Bolten WW, Glade MJ, Raum S, Ritz BW. The safety and efficacy of an enzyme combination in managing knee osteoarthritis pain in adults: a randomized, double-blind, placebo-controlled trial. Arthritis. 2015;2015:251521.

32. Miller PC, Bailey SP, Barnes ME, Derr SJ, Hall EE. The effects of protease supplementation on skeletal muscle function and DOMS following downhill running. J Sports Sci. 2004;22(4):365-372.

33. Marzin T, Lorkowski G, Reule C, et al. Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial. BMJ Open Sport Exerc Med. 2017;2(1):e000191.

34. Marra MV, Bailey RL. Position of the Academy of Nutrition and Dietetics: micronutrient supplementation. J Acad Nutr Diet. 2018;118(11):2162-2173.