Enzyme Market Review

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Enzyme Market Review

November 2012

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ietary supplement market analysts continue to forecast the growth of the digestive supplement category. The latest statistics from the National Institutes of Health state that as many as 70 million people suffer from digestive disorders. Approximately 20% of Americans suffer with symptoms of gastroesophageal reflux disease (GERD) at least once a week. Incidence rates for GERD have risen throughout the world including Belgium (28%), Germany (14%), Mexico (35%), Malaysia (38%), Norway (31%) and Turkey (20-23%).1 Likewise, the incidence of functional dyspepsia (non-ulcer indigestion) affects a large portion of the world’s population: Argentina (43%), Germany (20%), Malaysia (30%), Sweden (25%), Turkey (28%) and the United States (up to 12%). Another common digestive complaint is functional constipation, with high incidence rates throughout the world: Australia (30%), Canada (16%), Colombia (27%), Mexico (19%), Netherlands (22%), Turkey (24%) and the United States (18-27%). Digestive issues affect the lives of millions of people globally.1 Once considered a normal consequence of aging, digestive discomfort is now viewed as amendable by consumers. Probiotic products have led the way in educating consumers that this discomfort can be altered. Part of the benefit of these microorganisms is their ability to produce enzymes that may augment the digestive system. Digestive enzyme supplements and probiotic supplements are complementary products that may and often do work together to support optimal digestive health. In recent years, there has been growing international interest in combining the benefits of probiotics and digestive enzymes. Supplemental enzymes have a long history of use for digestive support. In addition to digestive supplements, different enzymes have applications in a variety of nutritional products. One exciting innovation is in the production of oligosaccharides from ingested

starch. Transglucosidase and levansucrase build non-digestible fibers when consumed with a meal. This enzymatic action has many nutritional benefits, including decreasing the caloric availability and glycemic index from dietary carbohydrates as well as acting as a prebiotic fiber to support the growth of probiotics. Other enzymes act as antioxidants or offer systemic benefits. Enzyme supplementation is a robust market with excellent opportunities for expansion.

Enzyme Supplement History

While the recognized use of enzymes as feed additives, dietary supplements and therapeutic agents is relatively new, consumption of enzymes predates written history. Through trial and error, our ancestors discovered the digestive benefits of enzymes. Meats were hung and allowed to age to produce a tender, more flavorful and nutritious steak. Other foods were allowed or even specifically treated to induce the digestive benefits of fermentation. Enzymes, either inherent in the food or introduced by microbes, essentially predigested the foods and contributed to the health of individuals long before anyone knew what an enzyme was or did. The enzyme industry as it exists today began in the late 19th century. By 1894, Dr. Jokichi Takamine had been granted U.S. Patent No. 525,823, “Process of making diastatic enzyme,” which detailed the process and extraction of amylases from koji. His patented product, Taka-diastase, was marketed by Parke, Davis & Company as a digestive aid beginning at the turn of the century and is still marketed throughout the world. By the 1920s, doctors were observing significant changes in patients’ health and some theorized that the growth of the canning industry and pasteurization was the cause. Dr. Edward Howell recognized these processes altered the intake of digestive

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food enzymes. By 1932, Dr. Howell had formed National Enzyme Company to provide supplemental enzymes to replace those destroyed in cooking, canning and food processing. Research soon began on the benefits of adding enzymes to animal feeds to increase growth and health. At the same time, the food processing industry had begun selectively applying enzymes to produce improved food products. These applications produced a large body of research that included the investigation of the safety and toxicity of various enzyme ferments. Today, the use of enzymes in foods, animal feeds and dietary supplements is common.

The Role of Enzymes

Enzymes are proteins that function as catalysts to initiate and regulate the biochemical processes that are necessary for life. The human body produces thousands of different enzymes to build, repair and maintain itself. In your body, as you read this report there are thousands of enzymes directing the processes of each of the billions of cells that make up your body. They are even directly involved in allowing you to see, read and understand the words on this page. Enzymes are such a critical part of a healthy functioning body that many genetic disorders are the result of inefficient, deficient or absence of one or more enzymes. Other dysfunctions may occur when enzyme systems become imbalanced. The benefits of many vitamins and minerals are due to their ability to affect the activity of various enzymes. These nutrients often act as cofactors and coenzymes that activate or increase the functionality of enzymes. Enzymes are vital for our daily health and wellness. Enzymes exhibit substrate specificity, meaning they will only catalyze a reaction with a specific compound or group

of compounds. For example, proteases will only catalyze the breakdown of proteins and will not react with carbohydrates or fats. The ability of an enzyme to interact with its substrate is attributed to the conformational structure of the enzyme’s active site. Simply stated, the active site of a protease will “fit” with the shape of proteins where it does not “fit” with a carbohydrate or fat. “Enzyme activity expression can be profoundly impacted by factors such as pH and temperature,” explains James McNeal, Laboratory Manager, SORA Labs. These factors may denature or alter the structure of the enzyme protein and reduce their activity. Some enzymes exhibit broad ranges of efficacious pH or temperature while others are very specific. McNeal elaborated that “many fungally-derived enzymes display an impressive active range of pH and temperature, which makes them suitable for a variety of applications, both in vivo and in industrial/ production settings.” Every function of living cells requires enzymes. Their roles in human physiology include: 1) building required materials, 2) carrying compounds through cell membranes, 3) detoxifying harmful chemicals, 4) neutralizing free radicals and 5) breaking down the foods we eat for use throughout the body.

Enzyme Supplements

Enzyme supplements fall into two broad categories: digestive and systemic. Digestive enzymes are taken with meals and are designed to support digestion. Systemic enzymes are taken on an empty stomach and are intended for action beyond the gastrointestinal (GI) tract. See table 1 for a list of enzymes commonly seen in supplements. The vast majority of these enzymes have been used in both supplements and foods prior to the passage of the Dietary Supplement Health & Education Act (DSHEA) in 1994.

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TABLE 1. Common Enzymes found in U.S. Dietary Supplements ENZYME

DIGESTIVE

SYSTEMIC

COMMON SOURCE ORGANISMS

COMMON ACTIVITY UNITS

CARBOHYDRASES alpha-Amylase

X

Aspergillus oryzae, A. niger, Bacillus subtilis, B. amyloliquefaciens

DU, SKB

Glucoamylase (aka amyloglucosidase)

X

Aspergillus niger, A. oryzae, Rhizopus oryzae

Diastase

X

Aspergillus oryzae

DP, MaltU

Invertase

X

Saccharomyces cerevisiae

INVU, SU

Lactase

X

Aspergillus oryzae

ALU, LacU

alpha-Galactosidase

X

Aspergillus niger

GalU

Cellulase

X

Aspergillus niger, Trichoderma longibrachiatum

CU

Hemicellulase

X

Aspergillus niger, Trichoderma longibrachiatum

HCU

AGU

Pectinases

X

Aspergillus niger

beta-Glucanase

X

Trichoderma longibrachiatum

endoPG, AJDU BGU

Xylanase

X

Trichoderma longibrachiatum

XU

PROTEASES Bromelain

X

X

Ananas comosus

PU, GDU, MCU

Papain

X

X

Carica papaya

PU, GDU, MCU

Protease

X

X

Aspergillus oryza, A. niger, A. melleu, Bacillus subtilis, B. licheniformis

HUT, SAP, AP, PC

Peptidase

X

X

Aspergillus niger

HUT, SAP, AP

Chymotrypsin

X

X

bovine pancreas

USP

Trypsin

X

X

porcine pancreas

USP

Pepsin

X

X

porcine stomach

USP

LIPASES Lipase

X

Aspergillus niger, Candida rugosa, Rhizopus oryzae

LU, FIP

Pancreatin

X

porcine pancreas

USP

Pancrealipase

X

porcine pancreas

USP

CatU, Baker U

OTHER ENZYMES X

Aspergillus niger

Lactoferrin

X

bovine liver

Lactoperoxidase

X

bovine milk

Lysozyme

X

hen egg

X

bovine liver, Cucumis melo

Catalase

Super Oxide Dismutase (SOD)

X

X

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McCord-Fridovitch (MFU)

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10-15%

HCI—secreted in stomach; activates pepsin, denatures proteins PEPSIN—secreted in stomach, activated by gastric acid

polypeptides

SMALL INTESTINE

STOMACH

of protein digestion begins in the stomach

AMINOPEPTIDASES—secreted by pancreas into the small intestine; include trypsin, chymotrypsin, elastase & carboxypeptidase

oligopeptides & free amino acids AMINOPEPTIDASES—secreted by the intestinal brush border membrane

tri-, dipeptides & free amino acids

Figure 2. Healthy Fat Digestion

LINGUAL LIPASE—secreted in the mouth; begins fat digestion in the mouth & continues action in the stomach GASTRIC LIPASE—secreted in the stomach

20% SMALL INTESTINE

STOMACH

MOUTH

amount digested by lingual & gastric lipases before entering duodenum

BILE SALTS—produced by the gall bladder; effectively emulsifying dietary fats for improved enzymatic access PANCREATIC LIPASES—includes lipases and esterases; complete the process of fat digestion

monoacylglyceride & 2 free fatty acids

Figure 3. Healthy Carbohydrate Digestion

SALIVARY AMYLASE—secreted in the mouth; begins starch digestion & continues action in the stomach until inactivated by gastric acidity

30-40%

amount starch digestion completed by salivary amylase

SMALL INTESTINE

This product category includes the bulk of the enzyme supplements on the U.S. market today. Like many probiotics, they support improved nutrient availability and may help prevent occasional gastric distress. Anthony Collier, president and CEO, National Enzyme Company, explains, “Raw foods are rich in enzymes and can play a pivotal role in human digestion. By contrast, the typical American diet consists of highly processed enzyme-deficient cooked foods, rich in artificial ingredients and other chemicals.” Digestive supplements replace food enzymes lost in cooking and processing. These supplements may also compensate for digestive enzyme deficiencies or counter food intolerances. Our ability to digest the foods we eat may be negatively influenced by many factors including diet, stress, illness, medication and age. According to Dr. Edward Howell, the upper portion of the human stomach functions as a food-enzyme stomach. “When raw food with its enzymes is eaten, it goes into this peristalsisfree food-enzyme section of our stomach where these food enzymes digest the food.” Dr. Howell explained “digestion continues in the food-enzyme section of the stomach for one-half to one hour” or until the rising acidity inactivates the food enzymes.2 It is in this same section of the stomach that many supplemental digestive enzymes are most effective. “Dr. Howell did extensive research to validate his theories,” says Collier. “He was 100-percent a German scientist and this motivated him to access all related research, a monumental task in the days before the internet. One fact that Howell discovered was the enlarged size of the human pancreas in populations consuming enzyme-deficient processed foods. This was key evidence supporting his Food Enzyme Concept.”

Figure 1. Healthy Protein Digestion

MOUTH

Digestive Enzyme Supplements

PANCREATIC AMYLASE—secreted by the pancreas; continues starch digestion

maltose, trisaccharides, oligosaccharides & -limit dextrins DISACCHARIDASES—produced by the brush border membrane; include lactase, sucrase & glucoamylase; complete digestion of complex carbohydrates & sugars

simple sugars: fructose, glucose & galactose

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To further explore Dr. Howell’s theory, National Enzyme Company conducted a pilot study to explore whether taking digestive enzyme supplements with a “modern cooked meal” could mitigate or decrease various markers of inflammation, including a reduction in leukocytosis. Numerous markers of inflammation were explored in the randomized, double blind, placebo-controlled pilot clinical study with 10 healthy volunteers. Blood was drawn immediately prior to and 45 minutes after eating the meal. On average, all measurable markers of inflammation were reduced as a result of taking digestive enzymes during the meal. NEC’s Chief Medical Consultant, Paul Nemiroff, M.D., Ph.D., FACS, states, “The potential health implications of this are tremendous. Less inflammatory response in the body may be a key factor in mitigating certain ailments. A large full scale study is currently underway that NEC is sponsoring and utilizing a contract research organization that will use the highest standards of clinical research and what is considered the ‘The Gold Standard’ of research often employed by pharmaceutical companies. This study examines the effects of digestive enzymes on various parameters of inflammation.”

Digestion & Indigestion

The human body produces at least 22 different enzymes to break down proteins, fats and carbohydrates to provide energy and building blocks. Protein comprises as much as 20-percent of the average American diet. Digestion of protein begins in the stomach when pepsin is activated in the low pH environment created by the secretion of HCL by cells of the gastric mucosa. In addition to activating pepsin, the acid also helps denature the proteins allowing improved enzyme accessibility to peptide bonds. Studies indicate that 10 to 15 percent of dietary protein digestion

is initiated in the stomach. In the small intestine, the pancreatic proteases (trypsin, chymotrypsin, elastase, and carboxypeptidase) continue the digestion of proteins, creating oligopeptides and free amino acids. Aminopeptidases produced by the intestinal brush-border membrane further hydrolyze the oligopeptides to produce tripeptides, dipeptides and free amino acids.3 Supplementation of proteases ensures complete digestion of proteins. Incomplete protein digestion is linked to the occurrence of food allergies. A rising concern in the Western world, food allergies currently affect as much as 4 percent of the population. Research by Untersmayr et al, reports the negative impact decreased gastric HCL and the resultant lack of pepsin activity on protein digestion and an increased risk of sensitization to food allergens.4 A supplemental source of proteases that is able to work in the altered pH environment may counter the lack of pepsin activity, enhancing protein digestion and limiting allergic responses. Fungal proteases offer an excellent pH profile for activity under these conditions. Gluten intolerance is also a growing concern throughout the world. Gluten is a generic term referring to a group of complex gluconated peptides commonly found in wheat, barley and rye. Rich in proline, glutens are highly resistant to digestion by the proteases of the human digestive tract. In sufficient concentration they may elicit an immune response in sensitive individuals that often includes extreme gastric discomfort. While abstaining from foods containing gluten is the only way to eliminate these problems, researchers are actively pursuing a solution utilizing supplemental proteases to digest the offending peptides.5 Bromelain, papain and the fungal enzyme dipeptidyl peptidase IV (DPPiv) have all been shown to hydrolyze these peptides. These proteases may provide digestive benefits for unavoidable low levels of gluten consumption.6

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Fats are an important part of a healthy diet and currently make up 30 to 40 percent of the typical Western diet. Digestion of fats begins with the production of lingual lipase in the mouth and continues in the stomach with the secretion of gastric lipase, together digesting as much as 20 percent of dietary fats. In the intestine, the fats are emulsified with bile allowing pancreatic lipases improved access for hydrolysis. The digestive end product of each triglyceride is two free fatty acids and a monoacylglyceride.3 While often vilified as a primary cause of obesity, the consumption of adequate levels of fat is a critical part of human metabolism. The proper digestion of dietary fats delivers essential fatty acids (EFAs) and structural building blocks for cell membranes, myelin sheaths and other tissues as well as providing an energy source. Healthy fat digestion is also vital for the absorption of fat soluble vitamins and other nutrients. Insufficient production of lipase by the body can lead to rapid loose stools and the loss of key nutrients. Supplemental lipase can increase fat digestion and improve nutrient assimilation. Danielle Harrison, Scientific and Regulatory Affairs Manager, at National Enzyme Company, reports in vitro studies have shown blends of fungal lipases effectively increase the availability of EFAs from dietary oils. She said, “We conducted the analysis on many different oils and the blend consistently increased the level of essential fatty acids released from the test oils.” Dietary carbohydrates including simple sugars, disaccharides and complex carbohydrates make up as much as 50 percent of the American diet. Carbohydrate digestion begins in the mouth with salivary amylase, which continues until inactivated by stomach acid. Salivary amylase digests as much as 30 to 40 percent of complex carbohydrates such as starch. Once the food passes to the small intestine, pancreatic amylase takes over the digestion of complex

carbohydrates. It is also in the small intestine that the brush border membrane disaccharidases are produced. These enzymes include lactase, sucrase and glucoamylase. The systematic action of these enzymes produces the simple sugars fructose, glucose and galactose.3 Lactase deficiency is the most widely occurring enzyme deficiency in the world, affecting nearly 70 percent of the world’s adult population. Low secretion of the enzyme causes individuals to suffer gastric discomfort including bloating, flatulence, diarrhea and abdominal pain. These symptoms often cause individuals to drastically reduce their consumption of dairy products. often with the unfortunate consequence of reduced calcium intake. Research indicates individuals who avoid dairy foods due to perceived dairy intolerance have a higher risk for osteoporosis.7 Lactase supplements have been shown to reduce gastric discomfort when taken with dairy foods. The secretion of digestive enzymes decreases with age, contributing to increased gastric discomfort, decreased food consumption and/or variety. It can also contribute to potential nutritional deficiencies in elderly individuals. One interesting study reported on the benefit of supplemental lipase in these individuals. The scientists found when fungal lipase was given with a meal, the rate of gastric emptying was accelerated. A slow rate of gastric emptying signals greater satiation and may be a contributing factor in geriatric malnutrition. The accelerated gastric emptying with supplemental lipase resulted in decreased satiation, which in turn may prompt elderly individuals to increase consumption levels.8

Systemic Enzyme Supplements

Many of the enzymes used for systemic applications are the same enzymes that support digestion when taken with meals. However, when taken between meals on an empty stomach they provide systemic support beyond the GI tract.

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“Systemic enzyme products are intended to nutritionally support the healthy functions of various systems of the body,” says Richard Mihalik, Director of Innovation and Product Development for National Enzyme Company. “A few examples include enzyme products for systemic antioxidant support, products to support joint health, products to support muscle health and products to support a healthy glucose metabolism.”

Sources of Enzyme Supplements

Digestive enzyme supplements are designed to support healthy digestion and optimal nutrient absorption. The enzymes in these products may be of animal, plant or microbial origin, and some supplements combine enzymes from different sources. The majority of digestive enzyme supplements in the U.S. market are derived from microbial fermentation. These enzymes offer several advantages including: 1) Broad pH range a) Effective in the upper stomach earlier in the digestive process b) Many exhibit activity in the intestinal environment as well 2) Availability of diverse range of enzymatic activities 3) No requirement for enteric coating 4) Vegetarian a) No ethical concerns b) No meat contamination or BSE issues Another group of vegetarian enzymes are those derived from various plants including bromelain (from pineapple) and papain (from papaya). Both are extracts that include multiple enzymes, but are standardized for their proteolytic enzymes. While both have some benefit in support of protein digestion, they are most commonly used in systemic products to support the immune and

musculoskeletal systems. Superoxide dismutase (SOD) extracted from melon is a potent systemic antioxidant. Most animal enzymes are derived from the stomach and pancreatic tissues of cattle and swine. The mammalian enzymes used in digestive products include pepsin, pancreatin, pancrelipase, trypsin and chymotrypsin. Systemic enzymes derived from animals include the pancreatic proteases trypsin and chymotrypsin as well as lysozyme from egg white, lactoperoxidase from cow’s milk and SOD from cow’s liver.

Markets of Opportunity for Enzyme-Based Products

Supplemental enzyme products have traditionally been marketed to support digestion and improve nutrient availability. Lactase based products for dairy intolerance as well as broadspectrum digestive aids are foundation products on many retailers’ shelves. The rising awareness of gluten intolerance has prompted the development of enzyme products targeting this concern. Still other products are formulated specifically for older adults whose secretion of digestive enzymes may be reduced due to aging. Product development research continues to seek enzymes that offer nutritional benefit to consumers. Various enzyme supplements may also offer immune support; muscle, joint and soft tissue support; and metabolic support. Beyond the general retail channel, today’s nutritional supplement market offers some unique opportunities for enzyme-based products. Sports This product category has seen tremendous growth in the United States as well as in foreign markets including Brazil and many European nations. Patrick Kuruk, Strategic Account Representative, National Enzyme Company, says blends of proteases, such as NEC’s BioCore® EDGE, increase the bioavailability

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of free amino acids including the BCAA leucine. With 23 years of experience in sports nutrition and a master’s of science in exercise physiology, Kuruk knows the importance of proper nutrition for athletes. He explains that “adding EDGE to a sports nutrition protein product can indirectly increase protein synthesis and muscle growth in the recovering athlete.” Blends of carbohydrases may also offer important energy support for the training athlete. Both amino acid availability and energy availability can have a stimulatory effect on muscle development and recovery. Systemic proteases may also specifically benefit training athletes. Studies indicate these types of products may attenuate the pain and inflammation associated with intensive exercise. Collier explains that “systemic proteases can significantly reduce recovery time. One of our patents relates to the ability of such blends to reduce TNF-alpha.” Proteolytic enzymes are often combined with antioxidant ingredients such as super oxide dismutase, quercetin, resveratrol or grape seed extract to combat increased levels of oxidative damage that occur along with intensive exercise. Studies support the use of these products to reduce the occurrence of delayed onset muscle soreness (DOMS).9 Immune support is also of vital concern to athletes. Studies have shown the intensive training by high level athletes has a negative impact on the immune system. Intense exercise induces significant changes in the body including elevated stress hormones, pro-inflammatory cytokines and reactive oxygen species. Other facets of the immune system, i.e. natural killer (NK) cells activity, T-lymphocyte and upper airway neutrophil function, are suppressed during recovery from endurance type exercise. This suppression can last for up to 72 hours during which time athletes are at increased risk for contracting infection.10 Nutritional support can play a pivotal role in helping maintain wellness. Certain

systemic enzymes may also support athletes during this critical time. Mihalik highlights the benefits of lactoferrin and lysozyme for this application. Health Care Providers The Nutrition Business Journal is predicting growth potential in this market, stating it will be “one of the most vibrant and fastest-growing sales channels in the nutrition industry for the next 10 years.” This growth is attributed in part to the expanding knowledge and use of nutritional supplements. Once largely limited to pioneering chiropractors and other alternative medicine providers, in-office supplement sales are becoming more widely embraced across the medical professions. Opportunities for enzyme supplements in these markets abound. Products designed for oral health may be sold through dental offices while both digestive products and systemic products may be useful supplements in general practices. Still other enzyme products may be specifically designed to address the unique digestive needs of a given population. For instance, many children diagnosed with autistic spectrum disorder deal with digestive issues. Several companies have developed targeted digestive products to address this specialized need. As noted previously, gluten intolerance is a growing concern in the United States and this market channel offers a unique opportunity for products designed to reduce gluten’s negative GI impact. Certain supplemental proteolytic enzymes have limited action against these peptides and can be beneficial in reducing gastric discomfort. Further, research supports the removal the carbohydrate portion of the compound for improved detoxification of gluten.11 Mihalik defines a well-formulated product for gluten sensitivity as including enzymes “that work on both the carbohydrate portions of the molecules as well as the variety of protein bonds present in the complex protein structures

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to achieve the most complete degradation possible. Every enzyme extract available from different suppliers has a little different activity and side activity profile that a formulator needs to be aware of to make the best formulation possible.” There is tremendous opportunity for enzyme-based products in the supplement market. The growing incidence of digestive disorders indicates that our modern lifestyle is detrimental to gastrointestinal health and general wellness. Collier emphasizes that “taking digestive enzymes with each meal supports maximum nutrient availability from the foods we eat as well as reducing inflammation. These supplements are beneficial for all age groups.” In addition to digestive enzyme supplements there are also expanding opportunities for systemic enzyme products as well as other enzyme products. Enzymes offer a unique activity profile • that can enhance many different formulations.

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References 1.

Guarner et al. Map of Digestive Disorders & Diseases. April 2008. http://www.worldgastroenterology.org/assets/downloads/pdf/wdhd/2008/events/ map_of_digestive_disorders_2008.pdf 2. Howell. Enzyme Nutrition: The Food Enzyme Concept. (Avery: 1985) pp 9-10. 3. Goodman. Insights into digestion and absorption of major nutrients in humans. Adv Physiol Edu. 2010 Jun; 34(2): 44-53. 4. Untersmayr & Jensen-Jerolim. The role of protein digestibility and antacids on food allergy Outcomes. J Allergy Clin Immunol. 2008 June ; 121(6): 1301–1310. 5. Shan et al. Identification and Analysis of Multivalent Proteolytically Resistant Peptides from Gluten: Implications for Celiac Sprue. J Proteome Res. 2005 ; 4(5): 1732–1741. 6. Ehren et al. A Food-Grade Enzyme Preparation with Modest Gluten Detoxification Properties. PLoS One. 2009; 4(7): e6313. 7. Jackson & Savaiano. Lactose Maldigestion, Calcium Intake and Osteoporosis in African-, Asian-, and Hispanic-Americans. J Am Coll Nutr. 2001; 20(2): 198S-207S. 8. Nakae et al. Effects of aging and gastric lipolysis on gastric emptying of lipid in liquid meal. J Gastroenterol. 1999 Aug; 34(4): 445-559. 9. Udani et al. BounceBack capsules for reduction of DOMS after eccentric exercise: a randomized, double-blind, placebo-controlled, crossover pilot study. J Int Soc Sports Nutr. 2009 Jun; 6:14. 10. Gleeson. Immune function in sport and exercise. J Appl Physiol. 2007; 103: 693-699. 11. Phelan et al. Coeliac disease: the abolition of gliadin toxicity by enzymes from Aspergillus niger. Clin Sci Mol Med. 1977 Ju; 53(1): 35-43.

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