In the healthy human gut, digestive enzymes are secreted to degrade fats, proteins, and carbohydrates. This enzyme activity facilitates the digestion and absorption of a wide range of macro- and micronutrients. When native digestive enzymes are deficient or absent, gastrointestinal (GI) disorders and poor nutrition often occur. In some individuals, nutritional supplementation with exogenous digestive enzymes may ameliorate the symptoms and effects of enzyme deficiencies, such as lactose or gluten intolerance. Common dietary practices, such as the consumption of processed foods, low-quality carbohydrates, and other diets that are low in plant-based nutrients, can also present challenges for digestion that may be improved with digestive enzyme supplementation.
Endogenous Enzymes in Normal Digestion
Enzymes produced throughout the GI tract support the digestion and absorption of food. For example, saliva contains α-amylase, an enzyme that facilitates digestion of polysaccharides. In the stomach, gastric lipase initiates the digestion of fats; pancreatic enzymes secreted in the duodenum continue the digestion of fats. A variety of proteases act to degrade proteins into peptides and amino acids that can be absorbed in the small intestines. Additional examples include the secretion of lactase by the small intestine, brush border cells, and a variety of enzymes that digest other disaccharides and more complex carbohydrates.
Digestive enzymes also contribute to overall health by increasing the availability of nutrients from whole foods. The health benefits of whole foods, such as fruits and vegetables, have been widely publicized. To obtain optimal benefits, whole foods must be broken down by enzymes and other digestive processes, which release phytonutrients from the food matrix.1 Only when released from the food matrix by enzymatic digestion are these nutrients available for absorption.2,3 Such digestive enzymes are found throughout the gut, including in colonic bacteria.2 However, nutrient absorption from whole foods may be improved by supplementation with digestive enzymes.
Common Digestive Disorders and Enzyme Deficiencies
Examples of digestive disorders involving enzyme deficiencies are numerous (Table 1).
The broad category of adverse food reactions, including food intolerance and food allergies, may affect up to 20 percent of the general population.4 Among patients with irritable bowel syndrome (IBS), the prevalence of food intolerance may reach 60 percent or more.5,6 Many of these common conditions involve enzyme deficiencies.
|Adverse food reactions||Gluten intolerance
Complex carbohydrate intolerance
Carbohydrate intolerance is the most common form of adverse food reaction (Table 2).7 A main cause of symptoms in food intolerance is a deficiency of digestive enzymes, such as lactase. When appropriate enzymes are deficient, these carbohydrates remain undigested and unabsorbed and exert osmotic force, driving fluid into the lumen and causing diarrhea. Some non-absorbed carbohydrates are then fermented by gut bacteria, leading to gas formation, abdominal pain, bloating, and flatulence.5,7 These symptoms are typical of intolerance to specific carbohydrates, such as lactose.
A broader definition of carbohydrate intolerance is the consumption of more carbohydrate than a person can metabolize. Under this definition, many millions of Americans have some degree of intolerance, as excess intake of carbohydrates, and especially low-quality carbohydrates, is common. Analyses of the National Health and Nutrition Examination Survey (NHANES) and other studies have demonstrated that low-quality carbohydrates and other macronutrients in the form of processed foods are widely consumed in the United States and Europe and contribute to obesity and poor nutritional status.11-13
Processed foods typically include low-quality nutrients such as refined carbohydrates, which, in the context of intolerance, contribute to spikes in insulin secretion, increased adipose tissue, and the deposition of fat in the liver. Some evidence links consumption of refined carbohydrates with heart disease, diabetes, and other chronic diseases.14,15 Carbohydrate intolerance itself has been linked to obesity and poor physical conditioning.16
Differences in the expression of digestive enzymes may also contribute to this type of carbohydrate intolerance. For example, several recent studies have identified variations in copy number and expression of amylase genes (salivary and pancreatic); these studies linked lower amylase gene copy number with increased risk for obesity, suggesting a mechanism by which carbohydrate intolerance impacts health status.17-19 These findings also suggest potential benefits to supplementation with digestive enzymes in appropriate individuals.
|Complex carbohydrate intolerance||Multiple|
Specific Carbohydrate Intolerances
In about 70 percent of people worldwide, lactase activity declines between the ages of two and five years, often leading to the most common form of digestive enzyme deficiency – lactose intolerance.20 The prevalence of lactose intolerance varies widely by genetic background, with the highest rates reported in Asia and Africa (up to 90 to 100 percent); in the diverse U.S. population, estimates range from 15 to 80 percent.20 People with significant lactose intolerance must avoid foods containing lactose and/or use lactase supplements to support digestion.
Another common adverse food reaction is complex carbohydrate intolerance, which leads to symptoms of bloating, pain, and flatulence following meals containing starches, beans, or similar foods.8,21 This form of intolerance relates to a deficiency in carbohydrate-degrading enzymes in the gut.8
Protein Enzyme Deficiencies
Pepsin is an enzyme required for protein digestion and is responsible for breaking down proteins into amino acids for absorption in the small intestine. It is secreted in its precursor form as a part of “gastric juice” and is converted to the active form by the action of stomach acid. This activation is most efficient at a pH of 1.5 to 2.0, so any deficiency of stomach acid can inhibit pepsin’s activity. Once pepsin leaves the stomach it is deactivated by the higher pH environment of the small intestine, and pancreatic enzymes take over the function of protein digestion.
Pancreatin is a mix of digestive enzymes secreted by the pancreas. Amylases, proteases and lipases are secreted into the duodenum to continue the breakdown of carbohydrate, protein and fat. Pancreatin supplementation can help support digestion in cases of pancreatic insufficiency.
Lipid Enzyme Deficiencies
Conditions related to enzymes that degrade lipids include exocrine pancreatic insufficiency and, possibly, functional dyspepsia (Table 4).
The pancreas is centrally involved in digestion and secretes enzymes that degrade fats, carbohydrates, and proteins. Pancreatic exocrine insufficiency occurs in multiple disease states, including chronic pancreatitis, pancreatic cancer, cystic fibrosis, pancreatic surgery, and diabetes.26-28 Exocrine pancreatic insufficiency is a potentially life-threatening condition in which a lack of pancreatic enzymes leads to highly attenuated digestion of lipids and the passage of undigested fats in the stool (steatorrhea).10 The consequences of exocrine pancreatic insufficiency include abdominal pain, steatorrhea, weight loss, and malnutrition.
|Exocrine pancreatic insufficiency||Pancreatic enzymes (eg, lipases)|
|Functional dyspepsia||Improved with exogenous lipases|
The Role of Bile Acids
Bile acids are produced from cholesterol in the liver and stored in the gall bladder between meals.31,32 During digestion, the gall bladder contracts and conjugated bile acids flow into the gut, where they contribute to the digestion of cholesterol and phospholipids. Bile acids are also required for the activation of some pancreatic enzymes and contribute to the absorption of cholesterol, lipid-soluble vitamins (eg, A, D, K, and E), and fatty acids.31 Certain bile salts, a combination multiple free bile acids (e.g. ursodeoxycholic acid (UDCA)), are commonly used for the treatment of patients with steatohepatitis, biliary cirrhosis, sclerosing cholangitis, and liver transplant.29 Bile salt supplementation may also be used to reduce risk for lithiasis (gall stone formation) and dyspepsia.
Older Adults and Enzyme Deficiencies
Older adults may also have reduced digestive enzyme production and activity, potentially contributing to malnutrition.33 Malnutrition is common and impactful in older adults. It occurs across sites, although estimates of prevalence vary based on age and location (e.g., community versus long-term facilities; rural versus urban living), from almost non-existent among younger elderly to 90 percent of elderly in hospital or rehabilitation settings.34-37 One study even linked poor nutritional status to mortality risk in older adults.38
Some studies have demonstrated reduced secretion of pepsin and pancreatic enzymes in advanced age.33,39,40 A higher prevalence of exocrine pancreatic insufficiency has been demonstrated in older adults.41 An age-related decrease in digestive enzymes could lead to reduced availability and absorption of food-bound vitamins, such as B12 and fat-soluble vitamins (eg, A, D, and E).33
Digestive Enzymes Used in Supplements
Emerging evidence suggests that enzyme supplementation may improve a wide range of conditions, from food intolerance to joint pain. Enzyme supplementation has been widely used to treat a number of digestive disorders. For example, pancreatic enzyme replacement therapy (PERT) is indicated for the management of exocrine pancreatic insufficiency.
Dietary supplements may contain a mixture of different enzymes to support digestion and nutrition. The substrates of digestive enzymes include protein, carbohydrate, and fats (lipids). Specific enzymes or combinations of enzymes, often in conjunction with other nutrients and dietary supplements, may facilitate digestion for a wide range of patients. Current evidence is strongest in support of pancreatic enzyme replacement for pancreatic exocrine insufficiency, β-galactosidase for lactose intolerance, and α-galactosidase for complex carbohydrate intolerance. However, emerging evidence and ongoing studies suggest potential benefits for patients with gluten intolerance and Celiac disease, functional GI disorders (e.g. IBS, functional dyspepsia), and older individuals, among others.
Table 5. Examples of supplemental enzymes and their substrates.
|Other||Betaine HCl (stomach acidification)|
The Evidence for Enzyme Supplementation
The broad definition of carbohydrate intolerance – consuming more carbohydrate than a person can metabolize – offers an opportunity to improve health status through supplementation with exogenous digestive enzymes. Supplements containing amylase, for example, may improve the digestion and management of even low-quality carbohydrates in people with lower native amylase expression. Other supplements, such as betaine HCL and bile salts, foster improved digestion by acidifying the stomach and breaking down the food matrix.
Lactase deficiency is the main cause of lactose intolerance and represents a clear target for enzyme supplementation. Lactase is normally produced by the intestinal villi and cleaves lactose to form galactose and glucose.42 In most neonates, the intestine produces high levels of lactase. After weaning, lactase production typically decreases. In some adults, primary lactose intolerance results when lactase production is insufficient to digest ingested lactose, leading to lactose malabsorption and GI symptoms such as diarrhea and bloating.7,43 Secondary lactose intolerance may occur following damage to the intestinal lining resulting from infectious or autoimmune conditions.7 A very rare genetic deficiency of lactase has also been reported.
For many patients, supplementation with exogenous lactase (β-galactosidase) can alleviate these symptoms.7,44 Studies of lactose intolerant patients have demonstrated reductions in exhaled hydrogen concentration and GI symptoms with lactase supplementation.45,46 The dose of exogenous lactase may require careful timing and titration in association with lactose-containing meals.
The oligosaccharide-degrading enzyme α-galactosidase is widely used in over-the-counter preparations to aid in the digestion of foods containing high levels of galacto-oligosaccharides, such as legumes. Complex carbohydrate intolerance relates to a deficiency in carbohydrate-degrading enzymes in the gut and can be treated with α-galactosidase supplementation.8 For example, a double-blind randomized study of eight healthy volunteers found that administration of α-galactosidase during a meal containing cooked beans significantly reduced flatulence and hydrogen breath test (a measure of gas production during digestion), compared to placebo.47
In a pilot study, use of a combined α-galactosidase and β-galactosidase supplement reduced gut symptoms following an uncontrolled diet when administered to 16 subjects who were intolerant to lactose and/or complex carbohydrates (e.g. oligosaccharides).21
Because these oligosaccharides have also been associated with exacerbation of IBS, the use of supplemental α-galactosidase has been proposed to reduce GI symptoms in this condition. In one study of 31 patients with IBS, foods high in galacto-oligosaccharides significantly increased symptoms in 21 subjects; among these patients, administration of α-galactosidase significantly reduced overall symptoms (P=0.006) and bloating (P=0.017).48 A second placebo-controlled study evaluated 12 weeks of α-galactosidase administration in 125 subjects.49 Symptom severity scores showed a decreasing trend with α-galactosidase compared to placebo. Overall, these studies suggest that oral supplements containing α-galactosidase may improve symptoms in a subset of patients with IBS who are sensitive to galacto-oligosaccharides.
Gastric and pancreatic lipases are key enzymes in the digestion of triglycerides, and optimal levels of digestive lipases are need for the efficient digestion of fats.50 A key problem with pancreatic exocrine insufficiency is the inability to digest fats, resulting in steatorrhea and malnutrition. Pancreatic enzyme replacement therapy (PERT) typically consists of various combinations of proteolytic enzymes (e.g. chymotrypsin and trypsin), amylolytic enzymes (eg, amylase), and lipolytic enzymes (e.g. lipase).51
PERT has been used to treat exocrine pancreatic insufficiency associated with cystic fibrosis, chronic pancreatitis, and other conditions.51-53 In patients with cystic fibrosis and pancreatic insufficiency, PERT is indicated to prevent malnutrition, although evidence describing the optimal formulation and dose are mixed.52 In chronic pancreatitis and other conditions, studies suggest benefits to PERT in fat absorption and other endpoints. For example, a systematic review found that PERT improved fat absorption in patients with chronic pancreatitis and steatorrhea compared to placebo.54 A recent meta-analysis of 17 studies found that PERT significantly increased fat absorption compared to placebo (P<0.00001), and reduced fecal fat excretion and abdominal pain, without significant adverse events.51
Another organ that aids in fat digestion is the gallbladder. While it is not essential to have a gallbladder, its purpose is to store bile to aid in breaking down fatty foods. In a study completed on relatively healthy adults with a family history of gallbladder conditions or attacks, gallbladder insufficiency was explored. Utilizing a whole food-based health product that contained beets in the intervention group yielded significant improvement of gallbladder function and motility at the end of the 12-week trial. In the intervention group receiving the supplementation, there was a decrease in gallbladder wall thickness indicating increased motility.
Some oral pancreatic enzyme supplements have also been demonstrated to reduce postprandial pancreatic secretion, suggesting that these supplements may also attenuate pancreatic duct pressure and related pain in patients with chronic pancreatitis.55
Numerous enzymes contribute to normal digestive processes, and several of these enzymes have been isolated and evaluated for supplementation.
Dyspepsia, which is characterized by symptoms of abdominal discomfort, fullness, early satiety, and nausea, occurs following meals in 20 to 30 percent of the population.59,60 In the absence of organic causes (e.g. peptic ulcer disease), it is termed functional dyspepsia.
Because meals with high fat content can induce and/or exacerbate functional dyspepsia, investigators have evaluated the use of lipase supplements with high-fat meals.61 For example, a double-blind controlled study in 16 healthy volunteers found that 280 mg of acid-resistant lipase significantly reduced stomach fullness compared to placebo when ingested before a fatty meal (P<0.05).30 Studies of pancreatic enzymes containing pancrelipase have reported similar findings.62
The potential benefits of enzyme supplements extend beyond digestive disorders. Studies have also identified improvements in osteoarthritic pain, faster recovery following exercise, and immune stimulation, among other findings.63-67
Betaine hydrochloride (HCl) is a dietary supplement sometimes used to increase stomach acidity. Once ingested, the compound dissociates to free betaine and hydrochloric acid. Betaine has been studied for multiple health benefits, ranging from diabetes to cardiovascular disease.68,69 The use of betaine HCl for stomach acidification has been evaluated to assist in the absorption of acidophilic drugs.70,71 The lowered stomach pH as a result of HCl supplementation may further assist in the digestion of foods, particularly proteins, many of which denature in acidic environments.
Sources of Supplemental Digestive Enzymes
Digestive enzymes used in supplements may be derived from animal, plant, or microbial sources. Supplemental pancreatic enzyme preparations are generally derived from bovine or porcine sources, although lipases can also be synthesized from microbial sources.29 Animal-derived enzyme preparations used for the treatment of exocrine pancreatic insufficiency may be enteric coated (i.e., pH-protected) to prevent inactivation by stomach acid and maintain activity in the small intestine. Enzymes derived from microbial sources may be used at lower doses and across a wider range of pH than pancreatic enzymes derived from animal sources.43
Other sources include microbes such as Aspergillus oryzae and Aspergillus niger (sources of endoproteases and other enzymes), nuts (defatted almond), and fruit (fig, papaya). Papain is purified from papaya fruit and includes a complex of several enzymes with proteolytic, amylolytic, and lipolytic activity.43 Papain is commonly used to aid protein digestion.
Bromelain proteases are derived from the stems and fruit of pineapple. These enzyme preparations are commonly used to facilitate the digestion of protein.43