Microbial Enzyme Therapy: Clinical Applications of Fungal Enzymes

Chapter 106 Microbial Enzyme Therapy

Clinical Applications of Fungal Enzymes

image Introduction

Enzymes derived from fungal species such as Aspergillus oryzae, A. niger, and Rhizopus spp. have been shown to be safe and effective in the treatment of a variety of clinical disorders. In some cases, fungal enzymes may be more effective than animal-derived enzymes or other available therapies. Some fungal enzyme preparations are particularly well suited for clinical application because of their inherent ability to resist degradation by stomach acid and their ability to hydrolyze physiologically or pathologically important substrates over a wide pH range.

Clinically, fungal enzyme preparations are most often administered orally at mealtime to aid digestion by hydrolyzing dietary substrates such as fats, carbohydrates, and proteins. They have also been used intravenously for the treatment of vascular obstruction, thrombotic disorders, and ischemic disease. Controlled studies in humans and animals have demonstrated efficacy of various fungal enzyme preparations administered orally or parenterally in a wide range of conditions, including the following:

This chapter reviews evidence of efficacy for fungal enzyme preparations in a number of the above conditions. It also presents indirect evidence that some portion of orally administered fungal enzymes may be absorbed intact in an enzymatically active form. To the extent that such absorption does occur, fungal enzyme supplements administered orally between meals may be of possible benefit as an adjunct in the treatment of systemic conditions, such as the following:

image Acid-Stable Fungal Enzymes

Oral supplementation with acid-stable fungal enzymes, also known as plant enzymes or microbial enzymes, has been shown to be safe and effective in the treatment of a number of disorders in humans and animals. In individuals with gastrointestinal pH imbalances, these enzymes may offer advantages over conventional pancreatin and enteric-coated pancreatic enzyme preparations.2,710

Pancreatic enzymes have optimal activity in neutral to alkaline conditions around pH 7 and above. They are unstable in acidic conditions. As a result, exposure to gastric acid can destroy up to 90% of orally administered pancreatic lipase and 65% of pancreatic trypsin according to some studies.10 Enteric-coated preparations are designed to protect pancreatic enzymes from gastric acidity; however, these do not work reliably in all cases.2,10,11 This is because most patients with pancreatic insufficiency are not able to concentrate bicarbonate sufficiently to alkalinize the upper small intestine. As a result, enteric-coated tablets or capsules often fail to dissolve and deliver their enzymes in the duodenum or jejunum as intended. The resulting jejunal hyperacidity can also inhibit pancreatic enzyme activity even if enteric coatings do dissolve as intended.2,7,10,12 Gastric hyperacidity can also lead to impaired fat digestion by causing acidic jejunal pH.12 Although H2 receptor antagonists, such as cimetidine, are often used along with pancreatin to lessen intragastric inactivation, this approach is unsuccessful in improving lipid digestion in many patients and carries the possible risk of adverse side effects.13

Studies show that certain acid-stable fungal enzyme preparations are naturally stable and enzymatically active in both acid and alkaline pH conditions. For example, lipase preparations derived from both A. oryzae and R. arrhizus were shown to be active and stable in the broad range of pH 2 to pH 10.7,8 As a result, such preparations do not require enteric coatings or coadministration of pH-altering drugs. They are effective even in patients with gastrointestinal pH imbalances, such as pancreatic insufficiency, jejunal hyperacidity, and gastric hyperacidity, which can limit the effectiveness of pancreatic enzymes.

Due to their broad pH range of activity, acid-stable fungal enzymes begin digesting food in the acid environment of the stomach and continue working in the alkaline pH of the small intestine.2,10,14 As discussed in this chapter, the following fungal enzymes have been shown to aid digestion in humans when administered orally at the time of food consumption:

image Treatment of Pancreatic Insufficiency and Other Digestive Disorders

Studies compared the efficacy of pancreatic enzymes and acid-stable fungal lipase in the treatment of exocrine pancreatic insufficiency in humans and animals. Some studies showed that acid-stable fungal lipase is effective at a substantially lower dose of enzyme activity than that required for pancreatin to reduce pathologically elevated fecal fat levels, stool weight, and diarrhea.7,8

A controlled, crossover-design clinical trial in 17 patients with severe pancreatic insufficiency compared the effects of an acid-stable fungal enzyme preparation to conventional pancreatic enzymes and enteric-coated pancreatin. One group of nine patients with duodenopancreatectomy and bowel resection (Whipple procedure) were found to have pancreatic enzyme levels less than 10% of normal on stimulated secretion before the trial. A second group of eight nonsurgical patients had stimulated pancreatic enzyme levels less than 29% of normal. Both groups were placed on a diet containing 100 g/day of fat. Stools were collected for 72 hours before treatment beginning 5 days after discontinuing all medications and supplemental enzymes. Thereafter, all patients were placed on consecutive 2-week periods of treatment, beginning with enteric-coated pancreatin (100,000 International Pharmaceutical Federation [FIP] lipase units [LU]), followed by conventional pancreatin (360,000 FIP LU), and finally, acid-stable fungal lipase (75,000 FIP LU). The fungal enzyme preparation and both of the pancreatic enzyme preparations also contained protease and amylase activity. Stools were collected for the last 72 hours of each treatment period and analyzed for fecal fat content and stool weight. All three of the enzyme treatment protocols led to a significant reduction in fecal fat excretion in both groups (P <0.05), and all patients became virtually symptom-free with regard to diarrhea and abdominal discomfort. Of note, the enteric-coated pancreatin dosage was one third higher and the conventional pancreatin dosage was nearly five times higher than that required for fungal lipase to produce comparable clinical improvement.8

A similar randomized, placebo-control, crossover-design study in dogs compared the effectiveness of 4000 LU of acid-stable fungal lipase derived from A. oryzae to 60,000 LU of lipase from pancreatin in the treatment of surgically-induced pancreatic insufficiency and steatorrhea. Dogs in the placebo group had significant weight loss due to malabsorption as well as pathologically elevated fecal fat content and stool weight. Compared with placebo, dogs in both enzyme treatment groups experienced significant reductions in fecal fat and stool weight, with no significant weight loss. In this study, the enzyme dose of pancreatin was 15 times higher than that required for the acid-stable fungal lipase to produce comparable clinical results.7

One controlled clinical trial showed that an acid-stable fungal lipase derived from R. arrhizus was effective at reducing steatorrhea by 56.5% and stool weight by 45.2% compared with placebo in 7 patients with pancreatic insufficiency. The study also demonstrated that the fungal lipase retained greater than 80% of its enzyme activity under conditions of simulated gastric acidity at pH 3 for 1 hour.15

Another study in 100 outpatients evaluated the efficacy of a fungal enzyme preparation containing lipase derived from R. arrhizus and protease and amylase from A. oryzae in a range of gastrointestinal complaints, including epigastric pain and pressure, flatulence, heartburn, belching, and nausea. Investigators reported that 96% of patients experienced some relief of symptoms and rated treatment outcomes as good to very good in 65% of patients.16

Some clinical trials reported on the efficacy of enzyme preparations containing protease, amylase, cellulase, and hemicellulase derived from A. oryzae in combination with pancreatic enzymes in the treatment of a range of digestive disorders.17,18 One double-blind, placebo-controlled, crossover design study in a group of 31 outpatients (ages 17 to 75 years) and 23 geriatric hospital inpatients (ages 70 to 90 years) found that this enzyme combination was significantly effective in the global improvement of diverse gastrointestinal symptoms (P <0.05) that included pain, nausea, heartburn, bloating, flatulence, constipation, and diarrhea.17

image Treatment of Lactose Intolerance

Deficient secretion of intestinal lactase (β-galactosidase) can produce signs and symptoms of dietary lactose intolerance, including abdominal pain, diarrhea, bloating, flatulence, and an increase in breath hydrogen excretion. Studies indicate that lactase deficiency occurs in more than half of the adult human population.19 Some degree of lactose maldigestion is also a common problem in children, occurring in 76% of apparently healthy children in one study and 56% in another controlled trial.20 Maldigestion of lactose can result from genetic nonpersistence of intestinal lactase some time after weaning as well as from acquired lactase deficiencies. Deficient lactase production may or may not produce clinical symptoms of lactose intolerance.3 A study of 232 children with intestinal biopsies found that lactase activity decreased significantly with age and correlated with degree of intestinal injury. Other studies also showed that intestinal secretion of lactase, sucrase, and maltase were decreased in conditions with intestinal mucosal injury and morphologic changes, including those seen in celiac disease and chronic diarrhea.2124

A number of controlled human studies showed that fungal lactase administered orally at the time of milk consumption or added to milk at mealtime was each effective at preventing or treating signs and symptoms of intolerance in lactose-intolerant individuals.3,20,25 One double-blind, placebo-controlled study showed that oral supplementation with fungal lactase taken at the time of lactose consumption was significantly effective at reducing breath hydrogen excretion and treating clinical symptoms in 18 children with lactose intolerance (ages 8 to 14 years). Test subjects were given tablets containing β-galactosidase derived from A. oryzae co-ingested with a lactose solution (3000 Food Chemicals Codex [FCC] lactase units [ALU]/5 g lactose) after a minimum fast of 8 hours. Breath hydrogen was measured every 30 minutes and clinical symptoms were monitored for the 120-minute test period. Lactase treatment successfully lowered breath hydrogen to below lactose malabsoprtion threshold levels in 89% of patients (P <0.001). In the placebo group, 89% experienced abdominal pain, 83% bloating, 61% diarrhea, and 44% experienced flatulence. In the lactase group, only 6% experienced abdominal pain, 6% had diarrhea, and none of the test subjects experienced bloating or flatulence.3

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Sep 12, 2016 | Posted by in MANUAL THERAPIST | Comments Off on Microbial Enzyme Therapy: Clinical Applications of Fungal Enzymes

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