Advances Advances

I N O R T H O M O L E C U L A R R E S E A R C H
VOLUME 4 ISSUE 3

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Digestive Health
What your gut is telling you
I N O R T H O M O L E C U L A R R E S E A R C H

Health Problems of Digestive Origin

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The Digestive Connection to Inflammatory Bowel Disease, O R T H O M OReflux L E and C Autism U L A R Acid

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ADVANCES
Supplement Support for Digestive System Problems
I N O R T H O M O L E C U L A R
Botanicals, Nutrients and Enzymes to Support Healthy Digestive Function

R E S E A R C H

RESEARCH-DRIVEN

BOTANICAL

INTEGRATIVE

ORTHOMOLECULAR

INNOVATIVE

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The Gut-Brain Connection Autoimmunity and the Gut: Taking a Closer look at the Immune System Function and Celiac & IBD The Ups and Downs of Heartburn The World of Probiotics: Good Bugs vs. Bad Bugs

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Botanical Supplement Support for the Digestive System Nutrient Supplements for the Digestive System The Breakdown on Digestive Enzymes

Published in Canada by Advanced Orthomolecular Research Inc. Publisher/Editor-in-Chief Jaime Thomas, BSc Research & Writing Dr. Traj Nibber, PHD Dr. Colin OBrien, ND Dr. Cameron McIntyre, ND Dr. Chantal Ann Dumas, ND (Qc) Dr. Mary Chou, PHD Mariam Al-Kawally, BSc Graphic Design/Art Production Neil Bromley Alvin Cha email: graphics@aor.ca
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Advances in Orthomolecular Research is published and distributed through integrative physicians, health care practitioners, and progressive health food retailers. The content of this magazine is provided for informational purposes only, and is not intended as medical advice for individuals, which can only be provided by a healthcare professional. Contents and design 2013 AOR. Any reproduction in whole or part and in print or electronic form without express permission is strictly forbidden. Permission to reproduce selected material may be granted by contacting the publisher.
Volume 4 Issue 3

ADVANCED
ORTHOMOLECULAR RESEARCH

Advances

Health Problems of Digestive Origin

The Gut-Brain Connection

Have you ever experienced butterflies in the stomach before an important meeting? Does attempting to cure the blues with Ben and Jerrys sound familiar? If so, then you are already acquainted with the existence of a connection between our moods and our gut. Indeed, the brain and the digestive system are linked by complex pathways where information flows back and forth on a continual basis: certain feelings and thoughts can stimulate an exaggerated gut response, while sensitized nerves in the gut can trigger changes in the brain. The Nervous System and the Second Brain The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body, through the relaying of information by chemical messengers called neurotransmitters. The human nervous system consists of two main parts: the central nervous system (CNS) and the peripheral nervous system (PNS). The brain and the spinal cord belong to the CNS, while the PNS consists mainly of nerves connecting the CNS to every other part of the body. The PNS is comprised of the somatic nervous system (SNS) and the autonomic nervous system (ANS). The enteric nervous system (ENS) is a semiindependent part of the ANS whose function is to control the gastrointestinal (GI) system. The ENS comes complete with a network of more than 100 million neurons, neurotransmitters and proteins, combined with a complex neuronal circuitry that enables it to control the bowel and produce gut feelings separate from the brains impulses. In each situation, the gut must assess conditions such as: progress of digestion, presence of nutrients and acidity level, among others and then decide on a course of action and initiate a reflex. This amazing piece of work continues to function even when the vagus nerve - the primary neural conduit between the gut and the brain - is severed!1 Its location in the GI tract, right next to the systems that it controls, makes perfect sense from an evolutionary standpoint. The ENS was first described by Dr. John Newport Langley in 1921 and it was coined the second brain by Dr. Michael D. Gershon in 1996 in reference to the complexity of its functions. When Gershon, who has been called the father

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of neurogastroenterology, suggested that the gut might in fact be using some of the same neurotransmitters as the brain, his theory was widely ridiculed. Vigilance Emotional Life arousal feelings events Since the early 80s however, the concept of the enteric nervous system and the role of neurotransmitters in the gut have been accepted by the scientific community. The connection between Stress Stress the two brains is accountable for the EMS Interoceptive Exteroceptive direct relationship between emotional stress and physical distress. It explains why conditions such as anxiety, depression, irritable bowel syndrome, ulcers and Parkinsons disease manifest symptoms both at the brain and at the Autonomic Sensory Neuroendocrine response modulation response gut level. Psychology or Physiology, Which One Comes First? Psychology clearly plays an important role in gut disorders. According to Dr. GI pathopsychology Emeran Mayer, professor of medicine, symptoms physiology and psychiatry at U.C.L.A., the majority of patients with anxiety and depression present alterations of their GI function. Dr. Mayer also Figure 1. Emotional Motor System (EMS) Pathways (Adapted From: Mayer, EA. 2000.) reports that up to 70 percent of the patients he treats for chronic gut disorders had experienced (IL)-1, and IL-6 - generates an acute stimulation of the early childhood traumas. This observation is corroborated hypothalamic-pituitary-adrenal (HPA) axis. In other by recent studies in animal models which demonstrate that words, GI inflammation triggers an increased firing of the early life stress is associated with chronic GI diseases. guts sensory neurons, culminating in a kind of sensory Stress affects the gut in several ways. In response to a hyperactivity. Serotonin provides another interesting perceived stressor, the brain triggers a response along two argument supporting the gut-over-brain theory. This key major bodily paths: the hypothalamic-pituatary-adrenal axis neurotransmitter essential to our well-being is stored at 95 and the autonomic nervous system. The resulting increased percent in the ENS where it is synthesized. Among other secretion of cortisol, adrenaline and noradrenaline directly things, serotonin acts as a go-between, keeping the brain up affects the ENS. Corticotropin-releasing-factor (CRF), a to date with what is happening in the gut. Contrary to earlier peptide found in both the brain and the gut, is another assumptions, it has been found that 90 percent of the fibers in substance which appears to have major significance in the vagus nerve carry information from the gut to the brain, the stress response. CRF increases anxiety-like behavior, and not the other way around. Finally, the emerging concept abdominal pain, colon secretions, muscle contractions that bacteria teeming in the gut - collectively known as the (motility) and increased permeability within the lining microbiome - can affect not only the gut but also the mind, of the bowel. CRF also stimulates a type of immune cell may shed additional light on our understanding of the gutcalled mast cells. Another interesting experiment on rodents brain axis. demonstrates what most clinicians have already observed, Commensal Gut Microbiota namely the correlation between stress and a leaky gut. The We are all born with a sterile gut, but over time it gets study showed that when young rats were separated from colonized by a diverse and distinct brew of bacterial species their mothers, the layer of cells lining their gut weakened and determined by genetics and by bacteria surrounding us. The became more permeable, allowing bacteria from the intestine incredible 100 trillion microbes - more than ten times the to pass through the bowel walls and stimulate immune cells. amount of cells in our entire body! - that make the GI tract On the flip side, several factors lend credence to physiology their playground, are absolutely critical to our health. Over as the source of intestinal dysfunctions. For example, when the last few years, increasing evidence from studies in rodents the mast cells activate an immune response resulting are pointing to an effect of commensal gut microbiota on in mucosal inflammation, the release of inflammatory the CNS. Researchers have found that the gut microbiome cytokines - tumour necrosis factor (TNF-), interleukin can influence neural development, brain chemistry, and a

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Healthy Status
Healthy CNS function

Stress/Disease
Alterations in behaviour, cognition, emotion, nociception

Normal gut physiology

Abnormal gut function

Physiological levels of inflammatory cells/mediators Normal gut microbiota

Gut and Brain Function in States of Health and Disease

Increased levels of inflammatory cells/mediators Intestinal dysbiosis

wide range of behavioral phenomena including emotional behavior, pain perception and the stress response. In a 2011 study, Bienenstock and colleagues fed a broth enhanced with the probiotic Lactobacillus rhamnosus to a group of mice, and plain broth to the control group. After 28 days, the researchers subjected the mice to a battery of tests to detect signs of anxiety and depression. What they discovered is that mice who had been fed the probiotic solution demonstrated less fear-response behaviors and anxiety compared to the control group. In the mice that were fed L. rhamnosus, some brain regions showed an increase in the number of receptors for gammaaminobutyric acid (GABA), the main CNS inhibitory neurotransmitter. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. Probioticfed mice also produced lower levels of the stress hormone corticosterone than control mice. Interestingly, when the

vagus nerve was severed, the effects of gut bacteria on brain biochemistry, stress response and behavior evaporated. The researchers concluded that these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression. In another study, Bercik and colleagues investigated the role of Bifidobacterium longum in tempering anxiety and depression related to GI disorders.16 They first infected mice with the parasite Trichuris muris, which caused moderate gut inflammation and anxiety-like behavior linked to decreased hippocampal brainderived neurotrophic factor (BDNF). Lower hippocampal BDNF has been associated with anxiety and depressive behavior. The administration of the probiotic (B. longum) normalized both behavior and BDNF level. This result demonstrates that a member of the intestinal microbiota may affect the

brain biochemistry and behavior in adult mice. Some studies also suggest that gut bacteria are closely tied to early brain development and subsequent behavior. According to Dr. Rochellys Diaz Heijtz, a researcher specialized in the neurobiology of common neurodevelopmental psychiatric disorders such as Attention-Deficit/ Hyperactivity Disorder (ADHD) and autism: The data suggests that there is a critical period early in life when gut microorganisms affect the brain and change the behavior in later life. Could Autism Begin in the Gut? Many researchers around the world have accumulated compelling evidence of a link between brain disorders such as Autism Spectrum Disorders (ASDs) and GI dysfunctions. Valicenti-McDermott and his colleagues demonstrated that 70% of the children with ASDs have GI issues. Adams and his team noticed that gastrointestinal symptoms are strongly correlated with the severity of autism. Certain people with ASDs also have abnormal levels of exorphins,

Advances

dietary peptides derived from certain grains (gluteomorphin) and dairy products (caseomorphins). Exorphins have morphine-like opioid activity and can act like narcotics in the body. In a study published last year, Reichelt and his colleagues suggest that autism is based in a genetic polymorphism error of peptide digestion - perhaps of the enzyme diaminopeptidase IV (DPP-IV) - and that the brain stimulant activity of the resulting exorphins can explain most autism symptomatology. A recent meta-analysis confirms that a gluten and casein free (GFCF) diet

can ameliorate core and peripheral symptoms and improve developmental outcome in some cases of autism spectrum conditions. This conclusion is corroborated by many parents reporting significant improvements in their childrens health and behavior when they removed these substances from their diets. Happy Gut, Happy Mind Given the intimate feedback loop between the gut and the brain, we must consider addressing GI dysfunctions when treating mood imbalances and behavioral or developmental issues. References

The use of high quality probiotics including Lactobacillus rhamnosus and Bifidobacterium longum along with digestive support such as DPP-IV enzyme and L-glutamine are proven strategies. Restoring mood balance is also crucial in achieving GI health. Adaptogenic herbs including as Siberian ginseng, ashwagandha, Rhodiola or holy basil combined with adrenal tissue extracts can support a healthy stress response, while substances such as GABA, L-theanine, inositol, SAMe and B complex vitamins can help achieve a balanced mood.

1. Gershon MD. The Second Brain: The Scientific Basis of Gut Instinct and a Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestines. HarperCollins Publishers, Inc., New York, NY; 1998. 2. Rubin RP. A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacological Reviews. 2007; 59: 289-359. 3. American Association of Anatomists. Available at: http://www.anatomy.org/content/michael-gershon Accessibility verified February 20th, 2012. 4. Mayer EA, Naliboff BD, Santo V, et al. Stress and the Gastrointestinal Tract. V. Stress and irritable bowel syndrome. AJP GI. 2000; 280: G519-G524. 5. Bradford K, Elizabeth J, Presson AP, et al. Association between early adverse life events and irritable bowel syndrome. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. 2012; 10(4): 385-390. 6. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861-869 7. Martinez V, Tach Y. Corticotropin-releasing factor and the brain-gut motor response to stress. Can J Gastroenterol. 1999;13 Suppl A:18A-25A. 8. Mayer EA., Saper CB, Ladd CO, et al. Long-term behavioral and neuroendocrine adaptations to adverse early experience. in The biological basis for mind body interactions. 2000; 122: 79101. 9. Malaviya R, Abraham SN. Mast cell modulation of immune responses to bacteria. Immunol. Rev. 2001; 179: 16 24. 10. Theoharis C, Theoharidesa BC, David E. Critical role of mast cells in inflammatory diseases and the effect of acute stress. Journal of Neuroimmunology. 2004; 146:1 12 11. Perlstein RS, Whitnall MH, Abrams JS, et al. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology. 1993; 132:946952. 12. Dreyfus CF, Bornstein M B, Gershon MD. Synthesis of serotonin by neurons of the myenteric plexus in situ and in organotypic tissue culture. Brain Research. 1977;128:125139 13. Gershon MD. The Second Brain: The Scientific Basis of Gut Instinct and a Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestines. 1998 14. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108:16050-160505. 15. Harter MC, Conway KP, Merikangas KR. Associations between anxiety disorders and physical illness. Eur Arch Psychiatry Clin Neurosci. 2003;253:313320. 16. Bercik, P., Verdu, E.F., Foster J.A., Macri, J., Potter M., Huang, X., Malinowski, P., Jackson, W., et al. Chronic Gastrointestinal Inflammation Induces Anxiety-Like Behavior and Alters Central Nervous System Biochemistry in Mice. Gastroenterology. 2010 Dec;139(6):2102-2112 17. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat Neurosci 2007;10:10891093. 18. Hejtz R.D, Wang S, Anuar F, et al. The normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the USA. 2011; 108: 3047-3052. 19. Valicenti-McDermott M., McVicar K, Rapin I, et al. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr. 2006; 27:S128-36. 20. Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism -- comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011; 11: 22. 21.Reichelt, KL, Tveiten D, Knivsberg A. et al. Peptides role in autism with emphasis on exorphins. Microbial Ecology in Health & Disease. 2012:23 22. Whiteley P, Shattock P, Knivsberg AM, et al. Gluten and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012; 6:344.

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Autoimmunity and the Gut: Taking a Closer Look at Immune System Function and Celiac & IBD
Integrity of the Gut The intestines are the largest mucosal interface between the environment and us. A single layer of epithelial cells is all that separates the bloodstream and the contents of the intestines. The small intestine has the complex and crucial role of allowing nutrients inside the body while keeping bacteria, toxins, and wastes outside. The tight junctions separating the intestinal cells assume some of these functions. The tight junctions arent cemented as previously thought but are rather dynamic structures. Research has revealed that tight junctions are made up of a complex meshwork of proteins, the interaction of which dictates their competency. To date, multiple proteins that make up

the tight junction strands have been identified: occludin,1 members of the claudin family,2 and the junctional adhesion molecule (JAM), a protein belonging to the immunoglobulin superfamily which has been described as an additional component of tight junction fibrils.3 To meet the many diverse physiological challenges to which the intestinal epithelial barrier is subjected, tight junctions must be capable of rapid and coordinated responses that are involved in developmental, physiological, and pathological processes. To achieve such responses, a complex regulatory system orchestrates the assembly and disassembly of the multiprotein tight junction network. Compromised tight junctions cause increased intestinal permeability, commonly referred to as leaky gut, and can result in the absorption of incompletely digested proteins and antigens that overstimulate the immune system through the bloodstream. Emerging research shows that most autoimmune conditions may share a common root hiding in the intestinal linings of individuals with autoimmune diseases, even years before the symptoms manifest. The Development of Celiac Disease Celiac is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms can include chronic diarrhea, failure to thrive (in children), and fatigue but even these may be absent, and symptoms in other organ systems could occur. Increasingly, diagnoses are being made in asymptomatic persons as a result of increased screening;4 the condition is thought to affect somewhere between 1 in 1,750 and 1 in 105 people in the United States.5 An immune reaction to a main protein component of gluten, gliadin, found in wheat, and similar proteins found in Triticeae crops (which includes other common grains such as barley and rye) can trigger the development of Celiac disease.6

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Upon exposure to gliadin, and specifically to three peptides found in gluten proteins (also known as prolamins), the enzyme known as tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small bowel tissue, causing an inflammatory reaction. That leads to destruction of the villi lining the small intestine (called villous atrophy). This interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. The simple effective treatment is a lifelong gluten-free diet.6 While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy. Early in the development of celiac disease, tight junctions are opened,7,8 most likely secondary to zonulin upregulation,9 and severe intestinal damage ensues.8 Zonulin is normally present in the intestines to control the passage of fluids, macromolecules, and leukocytes, but this protein appears to be overexpressed in patients with autoimmune conditions, resulting in increased intestinal permeability. The upregulation of the zonulin innate immunity pathway is directly induced by exposure to the diseases antigenic trigger, gliadin.10 Gliadin has also been shown to be a potent stimulus for macrophage proinflammatory gene expression and for cytokine release.11 Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, auto antibody responses are normalized, the autoimmune process shuts off and, consequently, the intestinal damage (which represents the biological outcome of the autoimmune process) heals. The Autoimmune Triad Alessio Fasano, MD, a pediatric gastroenterologist, research scientist, and founder of the University of Maryland Center for Celiac Research, believes all autoimmune conditions have three factors in common: a genetic susceptibility, antigen exposure, and increased intestinal permeability.12 Besides celiac disease, several other autoimmune diseases, including type

Indigestible gluten fragment Leaky Gut/Permeable Intestine In a healthy intestine, links known as tight junctions hold the intestinal cells together to prevent unusual permeability. In persons with celiac disease, these junctions are not tight and come apart; this allows indigestible gluten particles to move into the underlying tissues and cause an inflammatory response. Reducing the leakiness between these tight junctions will potentially ease autoimmune conditions including celiac disease.

Enterocyte Tight junction

Dysfunctional Tight Junctions in Celiac Disease

1 diabetes, multiple sclerosis, and rheumatoid arthritis, are characterized by increased intestinal permeability secondary to non-competent tight junctions that allow the passage of antigens from the intestinal flora, challenging the immune system to produce an immune response that can target any organ or tissue in genetically predisposed individuals, Fasano wrote in the February 2012 issue of Clinical Reviews in Allergy and Immunology.12 While it was previously believed that the autoimmune process remained ongoing once activated, this recent evidence indicates that the process could be modulated and possibly reversed by interrupting one of the modifiable factors involved in the autoimmune triad. SIBO as a Contributor to Inflammation Small intestinal bacterial overgrowth (SIBO) has recently been recognized as an underlying cause of many cases of inflammatory bowel disease (IBD), clinical relapses of Crohns disease, and celiac patients

unresponsive to a gluten-free diet.13-15 SIBO is a chronic infection of the small intestine, resulting in the excessive fermentation of dietary carbohydrates and the accompanying flatulence, bloating, abdominal pain, diarrhea, and constipation. SIBO and autoimmunity are related in several ways. SIBO is common in many autoimmune diseases such as: IBD, scleroderma, celiac disease, and Hashimotos hypothyroidism, although the exact nature of these associations isnt fully known. Increased intestinal permeability, which has been demonstrated in SIBO, is one of the three underlying causes of autoimmunity, as demonstrated by Fasano and his team, along with an environmental trigger and genetic predisposition. SIBO, with its high likelihood of generating leaky gut, needs to be corrected for both prevention and treatment of autoimmunity. SIBO can be successfully treated with antibiotics and possibly by natural means and specific dietary protocols. Rifaximin and neomycin usually are preferred

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1 gluten

Indigestible fragments Disrupted junction Damaged area

Zonulin

Tight junction

3 2
Gluten fragments

Gluten induces enterocytes

1. Tight junctions are loosened when undigested gluten fragments induce the intestinal absorptive cells (enterocytes) to release the protein zonulin. 2. Numerous gluten fragments accumulate beneath the intestinal absorptive cells after they cross the intestinal lining. 3. Immune cells called intraepithelial lymphocytes attack the intestinal absorptive cells as a result of gluten causing them to secrete interleukin-15.

because their poor absorbability into the bloodstream maximizes their efficacy within the digestive tract while minimizing systemic side effects. Elemental diet formulas which

are special nutrient drinks that do not contain whole foods, can provide all energy requirements for a period of two to three weeks and is also an alternative treatment option. References

In summary, the classical paradigm of autoimmune pathogenesis involving a specific genetic makeup and exposure to environmental triggers has been challenged by the addition of a third element: the loss of intestinal barrier function. Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of the intestinal barrier function secondary to dysfunction of intercellular tight junctions, seem to all be key ingredients involved in the pathogenesis of autoimmune diseases. This new theory implies that, once the autoimmune process is activated, it is not self-perpetuating; rather, it can be modulated or even reversed by preventing the continuous interplay between genes and environment. As tight junction dysfunction allows this interaction, new therapeutic strategies including the use of dietary supplements aimed at re-establishing the intestinal barrier function offer innovative approaches for the treatment of these devastating diseases.

1. Furuse M, Hirase T, Itoh M et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123: 17771788. 2. Furuse M, Fujita K, Takashi H et al. Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to Occludin. J Cell Biol. 1998;141:15391550 . 3. Martin-Padura I, Lostaglio S, Schneemann M et al. Junctional Adhesion Molecule, a novel member of the Immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998; 142: 117127. 4. Van Heel D, West J. Recent advances in coeliac disease. Gut. 2006; 55 (7):103746. 5. Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? NIH Consensus Development Conference on Celiac Disease. 2005; 128 (4 Suppl 1):S4751. 6. Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009; 373 (9673):148093. 7. Madara JL, Trier JS. Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Invest. 1980;43: 254261. 8. Schulzke JD, Bentzel CJ, Schulzke I et al. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatric Research. 1998; 43:435441. 9. Fasano A, Not T, Wang W. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355:15181519. 10. Clemente MG, S De Virgiliis, J S Kang et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52:218223. 11. Nikulina M Habich C, Flohe SB et al. Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol. 2004;173:19251933. 12. Fasano A. Leaky gut and autoimmune diseases. Clinic Rev Allerg Immunol. 2012;42(1):71-78. 13. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlated with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98(2):412-419. 14. Klaus J, Spaniol U, Adler G et al. Small intestinal bacterial overgrowth mimicking acute flare as a pitfall in patients with Crohns Disease. BMC Gastroenterol. 2009;9:61. 15. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol. 2003;98(4):839-843.

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The Ups and Downs of Heartburn

Heartburn is a burning sensation in the chest that can extend to the neck, throat, and face. It is often worsened by bending over or lying down. It is the primary symptom of gastroesophageal reflux disease (GERD), which is the movement of stomach acid into the esophagus. GERD is caused by frequent acid reflux, the backup of stomach acid into the esophagus. When swallowing, the lower esophageal sphincter which is a circular band of muscle around the bottom part of the esophagus, relaxes to allow food and liquid to flow down into your stomach. Then it closes again. However, if this valve relaxes abnormally or gets weak over time, stomach acid can flow back up into the esophagus, causing frequent heartburn episodes (Figure 1). This constant backwash of acid can irritate the lining of the esophagus, causing it to become inflamed. Chronically, the inflammation can erode the esophagus, causing complications such as bleeding or breathing problems. Heartburn Affects Many People On average, 5 million Canadians experience heartburn and/or acid regurgitation at least once each week. GERD patients are absent from work 16% of each year due to their symptoms. In Canada, this represents a workforce productivity loss of 1.7 billion hours amounting to $21 billion every year. In 2004, Canadians received 12.4 million prescriptions for antacid medications. Conventional medications dont seem to be the answer to the problem since 42% of GERD patients are dissatisfied with the outcome of drug therapy. Risk Factors for the Development of GERD There are several potential risk factors for the development of GERD, with the most common two being obesity and aging in general. GERD risk increases with age as the body becomes less efficient in carrying out digestive processes. Other risk factors for the development of GERD are having a hiatal hernia, pregnancy, excess alcohol consumption, smoking, dry mouth, asthma, diabetes, delayed stomach emptying usually from over eating or as a result of having connective tissue disorders such as scleroderma, or Zollinger-Ellison syndrome. In addition, certain drugs such as:

diazepam (Valium), meperidine (Demerol), theophylline, morphine, prostaglandins, calcium channel blockers, nitrate heart medications, anticholinergic and adrenergic drugs (drugs that limit nerve reactions), including dopamine, can relax the lower esophageal sphincter, leading to GERD issues. Complications of GERD Chronic inflammation from GERD can lead to the following complications: Esophageal narrowing (stricture) Damage to cells in the lower esophagus from acid exposure leads to formation of scar tissue. The scar tissue narrows the food pathway, causing difficulty swallowing. Ulcers - Stomach acid can severely erode tissues in the esophagus, causing an open sore to form. The esophageal ulcer may bleed, cause pain and make swallowing difficult. Precancerous changes to the esophagus (Barretts esophagus) - In Barretts esophagus, the color and composition of the tissue lining in the lower esophagus change. These changes are associated with an increased risk of esophageal cancer and esophageal rupture over time. Treatment Options for GERD - The Pros and Cons of Using Standard Medications Antacids (e.g. Rolaids, Tums): work to neutralize stomach acid and may provide quick relief. But antacids alone wont heal an inflamed esophagus damaged by stomach acid. Overuse of some antacids can cause side effects, such as diarrhea or constipation. H2 blockers (e.g. Tagamet, Zantac): reduce the production of stomach acid. This makes the stomach less acidic so that any digestive juices that get into the esophagus are less irritating. This relieves symptoms and allows the esophagus to heal. Proton Pump inhibitors (PPIs) (e.g. Nexium, Prevacid): work by blocking the pump that transports acid into the stomach, thereby decreasing the acidity and the overall volume of gastric acid. Proton pump inhibitors are also used to treat stomach ulcers caused by

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Esophagus

Relaxed lower esophageal sphincter

Inflamed esophagus Acid reflux Stomach

Figure 1. Acid Reflux (Retrieved From: www.mayoclinic.com)

bacteria (Helicobacter pylori) or drugs (non-steroidal anti-inflammatory drugs, NSAIDs). They are also used to promote healing in erosive esophagitis. Common side effects from these medications: Some of the common side effects of using these medications can include constipation, diarrhea, nausea, abdominal pain, dizziness, drowsiness, headache, runny nose, sore throat, rash and weakness. Heliobacter pylori (H. pylori) and GERD A Confusing Issue H. pylori (Camphylobacter) is a gramnegative bacterium found in the stomach. It is frequently observed in patients with chronic gastritis and gastric ulcers, conditions that were not previously believed to have a microbial cause. It is also linked to the development of duodenal ulcers and stomach cancer. However, over 80 percent of individuals infected with the bacterium may be asymptomatic. The relation between H. pylori infection and gastro-oesophageal reflux

disease is controversial. Studies on the prevalence of H. pylori in patients with gastro-oesophageal reflux disease have given conflicting results. Recent guidelines recommend eradication of H. pylori in patients requiring long term proton pump inhibitors, essentially for reflux disease. In a systematic review of 20 GERD studies, the prevalence of H. pylori infection was significantly lower in patients with GERD, than without. However, geographical location was a strong contributor to the differences between studies. Patients from the Far East with reflux disease had a lower prevalence of H. pylori infection than patients from Western Europe and North America, despite a higher prevalence in the general population. What About Other Natural GERD Treatment Options? De-Glycyrrhized Licorice (DGL): Most people dont get ulcers because of over secretion of acid. The cause in many cases is a breakdown in the integrity

of the intestinal lining. While common drugs including antacid medications can block symptoms and promote temporary healing, they dont address the underlying cause. DGL addresses the underlying factors to help promote true healing. Rather than inhibit the release of acid, licorice stimulates the normal defense mechanisms that prevent ulcer formation. Specifically, flavonoids present in DGL inhibit the growth of H. pylori (in vitro), while the whole extract improves both the quantity and the quality of the protective substances which line the intestinal tract, increases the life span of intestinal cells, and improves blood supply to the intestinal lining. Mastic Gum: has been shown to wipe out H. pylori bacteria, the cause behind the majority of gastric and duodenal ulcers. Clinical studies have clearly shown the effectiveness of this resin with 80% of patients receiving mastic gum for two weeks reporting significant improvements in their symptoms.

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Zinc-Carnosine: has received much attention lately thanks to its ability to up-regulate key antioxidant enzymes thereby preventing free radicals from damaging cells. Studies have confirmed that Zinc-Carnosine has antiulcer properties and prevents gastric mucosal injury. Animal studies also show that Zinc-Carnosine is indicated in H. pylori infections as the molecule prevents the development of H. pylori related gastritis. Potassium Nitrate: is a precursor to Nitric oxide. Nitric oxide is a potent vasodilator and increases blood flow to the gastric mucosa, enhancing repair and the inflow of nutrients and oxygen. Higher nitric oxide levels in the stomach were also shown to increase effective peristalsis movements. Studies also clearly demonstrate that Nitric oxide precursors are effective antiinflammatory agents with protective effects against gastritis. Alginic acid: a viscous substance found in algae which absorbs water extremely quickly to form a raft on top of the gastric contents. This raft has two effects: it prevents the gastric contents from being pushed back up the esophagus and also coats the esophagus if the gastric contents were to reach

the esophagus. An added bonus is that alginic acid works extremely quickly providing relief within a few minutes. Many of the previously mentioned ingredients are found in Gastro Relief (an AOR formula). The premise behind Gastro Relief is to provide quick and effective relief from the symptoms of heartburn while addressing any fundamental pathology which would cause the problem. References

Heartburn is a very common condition that needs quick attention. Ignoring symptoms can lead to long term complications. Standard medications may be helpful but may not address the underlying causes, and long term use may result in undesirable side effects. Natural treatments as outlined above can be very effective for many individuals and should be seriously considered as an option for first line treatment.

1. Brogden RN, Speight TM, Avery GS. Deglycyrrhizinised liquorice: a report of its pharmacological properties and therapeutic efficacy in peptic ulcer. Drugs. 1974; 8(5): 330-9. 2. Al-Habbal MJ, Al-Habbal Z, Huwez FU. A double-blind controlled clinical trial of mastic and placebo in the treatment of duodenal ulcer. Clin Exp Pharmacol Physiol. 1984; 11(5): 541-4. 3. Huwez FU, Thirlwell D, Cockayne A, et al. Mastic gum kills Helicobacter pylori. N Engl J Med. 1998; 339(26): 1946. 4. Larauche M, Anton PM, Garcia-Villar R, et al. Protective effect of dietary nitrate on experimental gastritis in rats. Br J Nutr. 2003; 89(6):777-86 5. Mandel KG, Daggy BP, Brodie DA, et al. Review article: alginate-raft formulations in the treatment of heartburn and acid reflux. Aliment Pharmacol Ther. 2000;14(6):669-90. 6. Marone P, Bono L, Leone E,et al. Bactericidal activity of Pistacia lentiscus mastic gum against Helicobacter pylori. J Chemother. 2001; 13(6): 611-4. 7. Matsuu-Matsuyama M, Shichijo K, et al. Protection by polaprezinc against radiation-induced apoptosis in rat jejunal crypt cells. J Radiat Res (Tokyo). 2008; 49(4):341-7. 8. Strugala V, Avis J, Jolliffe IG, et al. The role of an alginate suspension on pepsin and bile acids key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease? J Pharm Pharmacol. 2009; 61(8):1021-8. 9. Ueda K, Ueyama T, Oka M, et al. (Zinc L-carnosine) is a potent inducer of anti-oxidative stress enzyme, heme oxygenase (HO)-1 a new mechanism of gastric mucosal protection. J Pharmacol Sci. 2009; (3):285-94 10. Blaser MJ. Who are we? Indigenous microbes and the ecology of human diseases. EMBO Reports. 2006; 7 (10): 95660. 11. Kahrilas PJ. Gastroesophageal reflux disease. New England Journal of Medicine. 2008; 359(16): 1700-1707. 12. Canadian Digestive Health Foundation. Statistics. Available at: http://www.cdhf.ca/digestive-disorders/statistics.shtml#gerd. Accessiblity verified February 27, 2013. 13. Mayo Clinic. GERD. Available at: http://www.mayoclinic.com/health/gerd/DS00967. Accessiblity verified February 27, 2013.

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Supplement Support for Digestive System Problems

The World of Probiotics Understanding Different Strains of Bacteria, Symbiosis, and Why Many Probiotics Dont Work
The original definition of probiotics was established in 1953 but was somewhat confusing. Today, probiotics simply mean live microorganisms which when reaching the intestines in large numbers will exert positive health effects. Probiotic literally means pro-life or health promoting organisms. There are trillions of bacteria that have set up shop in our intestines (both small and large) and represent a very large and diverse group. Not all of these are friendly; there are a significant number that are hostile such as E. coli or Salmonella or Cryptosporidium that causes food and water poisoning, but overwhelmingly most are friendly. The Vast Microbiota Most of us know some of the more popular ones like the acidophilus or Bifidobacterium species that we read on the food labels in the supermarkets. There is however, no such species as Lactobacillus acidophilus regularis that the Danish food giant Danone claims is present in their Activia yougurt. Still, out of the hundreds of kingdoms of strains, there are only four major groups which predominate. This reflects the difficult nature of the conditions in which they must be able to survive, and equally important, the adaptive mechanisms developed by the bugs to survive. This is significant as not every bacteria can survive or colonize. These bugs are collectively referred to as the microbiota, and represent a reserve pool of several million genes, in contrast to the twenty three thousand that human cells collectively provide. Biologists are fond of viewing organisms as part of an ecosystem which includes ALL other organisms, their habitats, food sources, competitors and so on. Likewise, the best way to view these organisms (largely bacteria) is as colonists of our gastrointestinal tract (GIT) forming a complete ecosystem. Each of the bacteria is an individual in its own right; it competes for food and seeks shelter and space with every other organism whether it is a friend or foe. The GIT is a battle zone, and its a bug-eat-bug world in there. Furthermore, the organisms communicate with each other as well as the host cells (which they easily outnumber by a factor of ten or more) by means of various cellular signaling systems. This cellular chatter or cross-talk occurs day and night, and is responsible for sensing any changes and danger, so as to allow the bugs to respond appropriately. Our evolutionary system functions in a manner which takes into account the interests of both the host (us) and the bugs, with neither wishing the other any harm. In bad times however, for example, during periods of stress, poor diet, inappropriate lifestyle, indiscriminate use of antibiotics and other pharmaceuticals, exposure to environmental toxins etc.,

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the alignment of interest breaks down and our allies begin to misbehave so as to cause disease. The nature and the range of diseases affected by our gut flora is diverse, from obesity, cancer, allergies, diabetes, and a host of inflammatory conditions such as rheumatoid arthritis and other autoimmune conditions, to disorders like autism. What we tend to forget is that the microbial ecosystem is quite unique and different among people. No two digestive systems are the same. Not only are the inhabitants somewhat different, so are the functions these bugs perform. Because the microbes carry such a large array of genes with them, they are able to carry out many more biological functions than what the human genome allows. Friendly Probiotic Bacteria For example, many nutrients like milk or the plant based fibers that we consume may not be effectively broken down by our enzymes present in our digestive juices. However, the microbes have no such issues as they have such a large repertoire of genes that can perform far more tasks. Likewise, in certain populations, for example in Venezuelans, the microbes allow synthesis of certain vitamins like vitamin B2 to a much greater extent than in a Canadian. Microbes in Health and Disease Clearly, the microbes play an important part in disease in terms of both prevention and as a causative factor. Microbes produce chemicals called bacteriocins that can inhibit other nasty bacteria (pathogens). But equally likely, bacteria can and do cause food poisoning, diarrhea, bloating and many other problematic conditions including peptic ulcers, inflammation of the gut, and even cancer. The benefits of probiotics have long been recognized; the Egyptians, Greeks, Romans and subsequent cultures (pun intended) consumed foods treated with bacteria. This is the basis of fermentation techniques, which means letting the bacteria mellow the food e.g. cabbage, meats, milk, soy, vinegar, etc. These early food scientists realized that the bacteria was digesting the food and allowing for better availability of nutrients for our bodies. Of course one of the best examples is the yogurt made famous by the residents of the Caucuses and Bulgaria. The role that the bacteria in our gut play in health and disease is becoming more and more recognized and accepted by researchers worldwide. For example, some elaborate experiments by Professor Jeffery Gordon from Washington University in St. Louis have shown that thin individuals have different bacterial mixes than obese populations.1 Interestingly, when individuals changed their diets and lost weight, their gut bacterial ecosystem changed accordingly and was similar to thin individuals.2 This is a significant finding that suggests if the bacterial mix present in thin individuals is given to obese

individuals, then obese people may lose weight! In fact Gordon has demonstrated this very point in animals.3 The Japanese are world leaders in probiotic and fermentation research. They were the first to study the health benefits of various probiotics for food supplementation back in the 1930s. Unlike the North American consumer mindset which has been largely brainwashed by industry to focus on the number and the different strains of bacteria present in the probiotic supplement, Japanese companies place greater emphasis on the specifics of the strains and how well researched these strains are in human clinical studies; this is a very important point discussed later. Not many strains have relevant human data; in fact, over 95% of the products on the North American market have no clinical data and only promote test tube data. Test tube data is somewhat unreliable in regards to extrapolating how these bugs behave in our complex gastrointestinal ecosystem. Nonetheless, most companies keep stressing the numbers game instead of the actual species and the strains present. What should the consumer look for in terms of selecting the right probiotic supplement? The answer in first, second and third place is, Show me the clinical research; Im not interested in test tube data or animal studies. Rather, I want to see human data. One will find that there is a sparse amount of human data. The most likely answer seems to be, Every other company is offering these strains, and these strains have been used for so long in foods so they must be effective, or, We have a study that ten individuals used it and their diarrhea improved or their immune system was boosted. Unfortunately, these arent very convincing answers, and one small human study does not make for a convincing statement. In fact, one needs a number of studies to be conducted to prove the point that the probiotic is indeed beneficial. Moreover, one needs studies with much greater numbers of participants. Most biostaticians (people that determine whether a study has any statistical power and thus if it is of any significance) will tell you

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that most of these studies prove nothing. No wonder these studies are dismissed by serious researchers. However, there are companies that have researched the right mix of bacteria, using much larger numbers of study participants, and they have done so for thirty, forty or even fifty years! Go with one of these products. Characteristics of a beneficial flora population in the human GIT include: 1) their tolerance to acid, bile and pancreatic enzymes 2) their ability to adhere to the intestinal wall and compete successfully for the Hollywood-like real estate that is our gut 3) their ability to overcome the resistance offered by the existing bacteria present. The normal bacterial residents offer considerable resistance to newcomers via a variety of means including formation of biofilms, crowding out the recent immigrants, altering the pH or by other means 4) their

lack of toxicity (the bacteria do not pass on their genes to human cells or develop resistance to antibiotics). Preferably the probiotics ought to be sourced from humans, compatible with other strains present in the supplement. In other words, the bugs dont eat each other 5) their ability to modulate the immune system rather than cause continual overstimulation 6) are shelf stable or do not require refrigeration. It is not easy for manufacturers to ensure that their strains meet the above criteria. Of course that doesnt prevent them from making exaggerated claims, but the truth is out there and some evidence-based products do indeed meet the above criteria. Take the case of TOA, a Japanese company that has marketed a probiotic blend called Bio-Three for over fifty years, and equally important has kept publishing References

human clinical studies regarding safety and efficacy during that course. The probiotic consists of three lesser known but well researched and documented strains. Two of the strains provide protection against antibiotic-associated or travelers diarrhea and Clostridium difficile, anti-inflammatory effects, improvement of the gut barrier, allergy protection and more. The third strain is a food source for the other two, so as to provide nutrients and keep the two functioning optimally. This strategy is unique and provides for a stable, effective and well researched probiotic which has its own food source, alleviating the need to add additional prebiotics like fructo-oligosaccharides that are all too common in many of the probiotics. Furthermore, the number or guessing game isnt played with such a probiotic; after all, it isnt the number of CFUs (colony forming units) present that is important, it is evidence based documentation and compatibility that is critical. One can have twelve billion CFUs or more, and over a dozen different strains all thrown together but its insignificant if there is no research! Probiotics have been successfully used throughout history. In recent times there have been further advances in the isolation, identification and classification of them. By studying their clinical efficacy, probiotics can provide us with additional weapons to keep our gut healthy and protected. However, this cannot happen by chance or by wishing that a bunch of bacteria thrown into a capsule or tablet will work - research is required.

1. Jumpertz, R et-al.Energy-balance studies reveal association between gut microbes, caloric load, and nutrient absorption in human. Am J Clin Nutr. 2011; 94: 58-65 2. Ley R E et al. Microbial Ecology: human gut microbes associated with obesity. Nature. 2006: 444: 1022-1023 3. Turnbaugh PJ et al. Diet-induced obesity is linked to marked but reversible alteration in the mouse distal gut microbiome. Cell Host. Microbe 2008; 17: 213-223 Additional References: Shanahan F. Probiotics and inflammatory disease: from fads and fantasy to facts and future. Br J Nutr. 2002; 88: s5-s9 Hart A L and Stagg M A. Use of probiotics in the treatment of inflammatory bowel disease. J Clin Gastroenterol. 2003; 36: 111-119 Gill HS, Rutherfurd KJ, Prasad J, et al. Enhancement of immunity in the elderly by dietary supplementation with probiotics Bifidobacterium lactis. Am J of Clin Nutr. 2001; 20: 149-156 Goektepe I, Juneja VK, Mohamed Ahmedna M, et al. Probiotics in Food Safety and Human Health. CRC Press. 2006

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Botanical Supplement Support for the Digestive System

Nature offers many compounds that may be beneficial for alleviating digestive disorders such as IBS, IBD, cancer, ulcers, acid reflux and others. A few of the more widely studied and successfully used natural supplements include: DGL, boswellia, mastica, curcumin, and fiber. DGL (De-glycyrrhizinated licorice) Traditionally, licorice has been used throughout history by many cultures for various diseases. It is a key component in syrups and herbal teas and is useful for treating cough and cold symptoms, as well as for a host of gastric issues, the latter due mainly for its demulcent or soothing properties. Unfortunately, while being highly effective as an anti-viral, anti-inflammatory and immune modulator, licorice does have a shortcoming. One of its components, glycyrrhizin, causes sodium retention and thus raises blood pressure. Glycyrrhizin limits the use of licorice as a natural treatment for gastrointestinal symptoms such as heartburn, healing ulcers and pain relief. Over fifty years ago a new form of licorice lacking glycyrrhizin called deglycyrrhized licorice (DGL) was introduced; it showed that the healing powers of licorice were still retained without the side effects of high blood pressure. DGL is thought to work by several mechanisms, firstly by directly inhibiting the bacteria Helicobacter pylori (H. pylori), the bacteria now strongly linked to causing peptic ulcers and stomach cancer. It is thought that DGL directly kills the H pylori.1 Second, DGL assists the healing of the lining of the stomach wall. It does this by increasing the mucus secretion which protects the stomach cells from attack by the acid present in the stomach, as well as by improving blood flow and quicker delivery of nutrients to the cells so as to speed up the healing process. Studies have shown that when DGL is taken along with aspirin there is a significant reduction in stomach bleeding.2 Unfortunately, there have been no studies in the last three decades; one of the last studies did show that when DGL was taken together with ranitidine, a standard prescription at the time for treatment of ulcers, the rate of remission was increased.3 Interestingly, DGL was effective in both stomach and duodenal ulcers.2 Boswellia Boswellia is a herb that has a long and

established use in various traditional medicines. The Boswellia plant exudes a gummy like resin that is collected and used in various formulations. It is useful for the treatment of nervous disorders including depression and anxiety, for boosting the immune system, for topical use of wound healing and as an anti-bacterial and anti-fungal. Boswellia is probably best known for its anti-inflammatory activity and its use in a variety of conditions including osteoarthritis, rheumatoid arthritis and other autoimmune disorders. Not surprisingly, Boswellias use in digestive health has been a focal point of research for many years. Inflammatory conditions including IBS and IBD (Crohns and ulcerative colitis) have shown significant improvements following Boswellia consumption.4 Animal studies have shown that Boswellia reduces the gastric irritation and the subsequent erosion of the gastric lining caused by non-steroidal anti-inflammatory drugs (NSAIDs) like indomethacin and phenylbutazone.5 The result is that there is significantly less bloodloss as detected in the feces, all the more reason to take Boswellia along with any NSAID therapy. Researchers have shown that Boswellia has a protective effect in mice when they are treated with a chemical called dextran sodium sulfate (DSS) that is used for an animal model for IBD that induces damage to the mucosal lining of the gut.6 Boswellia prevents much of the damage as shown in the histology of the mice gut. The active constituent(s) in Boswellia remain the subject of heated debate. Initially, some researchers viewed boswellic acids (a mixture of eight or so different compounds) to be the active component. However, others thought that specific boswellic acid fractions like acetyl-beta-boswellic acid (AKBA) were the most powerful fraction. Still, others regard an entirely different component called incensole acetate to be the key molecule. Whichever molecule turns out to be active, it is likely the synergy between all these components that is the most important factor.

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Mastic Gum Tree

The mechanism of action of Boswellias biological effects is via multiple pathways typical of the action of many natural ingredients and includes the following: first, the inhibition of NF-B, a key factor involved in copying the portion of DNA involved in inflammation.7 If the copying of the DNA portion involved with inflammation is inhibited, then inflammation will also be slowed or stopped. Second, Boswellia has a powerful immune stimulating effect locally in the gut. Since the gut is the recipient of all sorts of orally consumed foods, pharmaceutical drugs, toxins like alcohol, carcinogens etc., the body is designed to be able to deal with these unwanted and dangerous intruders immediately, by positioning a portion of the immune system right within the gut. Third, Boswellia has antimicrobial activity against bacteria like Staphylococcus which is responsible for food poisoning, and Candida albicans which causes yeast infections.8 Mastica (Mastic Gum) Mastic gum is extracted from the resin of a plant that grows almost exclusively on the Greek island of Chios. It has been traditionally used as a food additive, as an antioxidant to keep foods fresh, and as a gum in combatting various diseases including high cholesterol, weight loss, tooth and gum decay, halitosis and for heartburn and stomach ulcers.

There are currently over seventy known components in mastic gum and no one molecule is considered active on its own, hence there is no standardization for the raw material. A 2010 study from Greece looked at 52 patients divided into four groups.9 Two groups were given a 350mg dose of mastica three times a day, and one was untreated; a fourth group was given conventional antibiotic and prescription therapy for H. pylori. H. pylori is an invasive bacterium that burrows into the stomach lining and is a common cause of stomach ulcers. Five out of the 13 people in the mastica group recovered completely, compared with zero in the untreated group. However, the antibiotic/prescription therapy resulted in complete improvement in 10 out of 13 patients. A 2009 study utilizing the standard animal model of IBD using the DSS in mice, once again confirmed the activity of mastica in relieving the symptoms of IBD.10 Curcumin Curcumin is by far the most dominant of the three biologically active components present in the spice turmeric collectively called curcuminoids, the other two being demethoxy and bisdemethoxy curcumin. Curcumin has traditionally been used in the Indian subcontinent for gastric health, treating periodontal disease,

ulcers of the mouth, duodenal and peptic ulcers, various protozoal diseases from amebiasis to dysentery, various inflammatory conditions and much more. Curcumin is probably the most well researched natural product on the market, and its biological effects on the gut are well documented. Typically, turmeric spice has been added to hot milk and taken orally in copious amounts. There is a reason why curcumin is given in this manner: this is due to the poor bioavailability of the curcumin or the amount that reaches the active site, in this case the gastrointestinal tract. Hot milk improves the delivery of the curcumin molecule, and researchers attribute this increased activity to the various milk proteins and peptides that form a coating or miscelle-like structures that are quickly taken up into the blood. Test tube studies, animal studies, and human clinical studies have shown the following: first, curcumin is poorly absorbed due to its rapid elimination from the body, and hence the need for more bioavailable forms. Second, doses of up to 8000 mg of curucmin per day are safe.11 Third, curcumin has been used in conjunction with other therapies especially in the treatment of various forms of cancer such as pancreatic, stomach, colon and oral cancers in conjunction with chemotherapy and radiation.12 Fourth, curcumin works through multiple pathways rather than exhibiting one specific mechanism which is typical of many pharmaceuticals. Colon cancer is the third leading cause of death in North America. The incidence varies over 20 fold, from the highest in North America to the lowest in India. Population studies suggest that the regular intake of foods such as turmeric may partly be responsible for the lower rates.13 Since curcumin works through more than one pathway, it offers an alternative and an attractive approach to combatting colon cancer. Numerous human studies have shown that curcumin is a good candidate for various forms of cancer as well as inflammatory conditions like

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IBD, but studies require larger numbers of subjects to be able to draw any meaningful significance. An exciting area of research is the development of more bioavailable curcumin products. One approach has been to use piperine (from black pepper) as an adjunct, since it prevents curcumin elimination by knocking out the phase II enzymes that the body uses as a detoxification system to protect itself. However, this may not be safe in that if the phase II enzymes are inactivated, this may allow entry of other toxins and carcinogens along with the curcumin. Alternative and better delivery systems have been developed; one such system is the solid lipid nanoparticle (SLP) developed using natural technology and patented by the researchers at University of California at Los Angeles (UCLA) under the trade name Longvida. Longvida is the most bioavailable curcumin ingredient on the market, and has been shown in clinical study to be over 100 times more bioavailable than regular curcumin. In addition, unlike many of the other products on the market claiming higher bioavailabilities, Longvida compares the blood levels of free curcumin rather than some other detoxified compound that other companies measure. Longvida curcumin products provide a truly enhanced delivery system. Fiber We all know that fiber is good for us, yet the subject is never a part of any polite conversation. All too often fiber is still being thought of as a laxative, yet fiber offers so much more than just being an excellent laxative. Its health benefits go way beyond digestive health. Fiber is a remarkable nutrient that has wide ranging physiological and health benefits including heart health, cholesterol control, glycemic control, insulin response and sensitivity, gut health, satiety, immune enhancement, and as a particularly strong preventative of colon cancer. Indeed, fiber could possibly be one of the most important arsenals in every household to ward off a host of diseases. In fact, the clinical evidence on fiber is more robust than

Figure 1. H. pylori Burrowing Into Stomach Lining

many other nutritional intervention molecules such as vitamins, minerals and many herbs. The Institute of Medicine (IOM) recommends that a daily intake of fiber should be 38g for males, and 25g for females, women requiring more during pregnancy and nursing. However, the average North American adult consumes around half that figure, despite the heavy promotion of the health benefits by the government. Over 90% of North American adults view digestive health as a top priority, yet less than half think that they need more fiber in their diets. Clearly greater education on the role of fiber is required for consumer awareness. What is Fiber? Dietary fiber is the indigestible portion of the plant which usually requires much more chewing, hence the synonymous word roughage. Fiber is abundant in various fruits and vegetables and is commonly found in roots, stems and nuts. Fiber types range from cellulose, the main component of the vegetable kingdom to pectin found in apples and grapefruit, to beta-glucan derived from oats and yeast. Fiber is a collective term used to describe a large and diverse variety of plant constituents that are resistant to breakdown by gastrointestinal enzymes in the small intestines, but which

undergo fermentation in the large intestines. Dietary fiber is classified as water soluble or water insoluble, though plants usually contain some combination of the two. Water insoluble fibers are chiefly derived from cellulose and are abundant in vegetables and cereal grains like wheat and corn. Water insoluble fibers easily absorb water and help to regulate bowel movement by increasing bulk, softening stools, and quickening the time of passage through the intestinal tract. Soluble fibers are generally gel forming, highly viscous, and include pectins, mucilage and various gums like guar and xanthan. Dried beans, oats, and barley are major sources of this type of fiber. The soluble fibers are carried to the large intestines where they are broken down by the gut bacteria to release various beneficial components. SoluFibre - A Clear Solution to Your Daily Fiber Needs. Recently, the Japanese company Taiyo has taken the large molecules of guar gum and broken them down to much smaller units that become completely soluble in water and other beverages within two to three minutes. This process leaves an odourless, tastefree and clear solution. The product is called SoluFibre; it has distinct advantages over other fibers that dont dissolve and often have a distinctive taste. The complete solubility of

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SoluFibre makes the product very user friendly. What Are the Benefits of SoluFibre? 1. Production of short chain fatty acids (SCFA) - Fiber is not digested in the small intestines, but once in the colon it is broken down by the specific bacteria residing there. Various by-products are produced, such as SCFAs including butyrate, as well as other compounds. Butyrate is an energy source for the colon cells. In addition, SCFAs regulate the pH thus making the environment inhospitable to various pathogens. 2. Promoting weight loss - Fiber provides few calories, but it does give one the feeling of fullness or satiety unlike many processed foods which are energy dense (lots of calories) yet provide little or no feeling of satiety. Some studies show that fiber significantly reduces body fat in animals and humans, while others

report no weight loss effect. Women consuming at least one serving of whole grain had a significantly lower mean body mass index (BMI) and waist circumference than women not taking the whole grain. 3. Nutrient absorption - Fiber also enhances mineral absorption of calcium, magnesium, zinc and so on. This effect is particularly useful for pre-teens as well as postmenopausal women. 4. Prebiotic effect - The breakdown product of fiber which occurs via fermentation in the large intestines generates many by-products. The metabolites provide food and nourishment for the friendly bacteria which colonize there. This is called the prebiotic effect. Support and wellbeing for these bacteria is critical, as these bacteria have an important role to play in various biological pathways References

such as immune stimulation, nutrient breakdown, synthesizing vitamins, and in preventing the colonizing of unfriendly bacteria. 5. Improves digestive health - Besides alleviating constipation, a high fiber diet may prevent stress induced diarrhea by preventing the release of various hormones produced by the body which normally quicken the passage of food through the small intestines which results in diarrhea. 6. Fiber and Inflammation - Recent studies show significant reductions in inflammation in subjects consuming high fiber diets. Reduction of inflammatory markers, especially C-Reactive Protein (CRP), has been frequently reported. One of these mechanisms might be the generation of butyrate which is particularly antiinflammatory.

1. Larkworthy W, Holgate PF, McIllmurray MB, et al. Deglycyrrhizinated liqourice duodenal ulcer. Br Med J 1977; 6095: 1123-1126 2. van Marle J, Aarsen PN, Lind A et al. Deglycyrrhizinated liquorice (DGL) and the renewal of stomach epithelium. Eur J Pharmacol 1981; 72: 219-225 3. Morgan AG, Pacsoo C, Taylor P, et al. Does Caved S decrease the gastric ulcer relapse rate during maintenance treatment with ranitidine? Aliment Pharmacol Ther. 1897; 1: 633-638 4. Anthoni C, Laukoetter MG, Rijcken E et al. Mechanisms underlying the anti-inflammatory effects of boswellic acids in experimental colitis. Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1131-G1137 5. Gupta I, Parihar A, Malhotra P, et al. Effects of gum resin of boswellia serrate in patients with choronic colitis. Planta Med. 2001; 67: 391-395 6. Moussaief A and Mechoulam R. Boswellia resin: from religious ceremonies to medical uses; a review of in-vitro, in-vivo and clinical trials. J of Pharmacy and Pharmacology 2009; 61: 1281-1293 7. Poeckel D, Werz O. Boswellic acids: biological actions and molecular targets. Curr Med Chem. 2006; 13: 3359-3369 8. Moussaieff A, Shohami E, Kashman Y et al. Incensole acetate; a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor kappa B activation. Mol Pharmacol. 2007; 72: 267-273 9. Dabos KJ, Sfika E, Vlatta LJ et al. The effect of mastic gum on Helicobacter pylori: a randomized pilot study. Phytomedicine. 2010; 17: 296-299 10. Paraschos S, Mitakou S, Skaltsounis AL et al. Chios gum mastic: A review of its biological activities. Curr Med Chem. 2010: 19: 2292-2302 11. Cheng AL, Hsu CH, Lin JK. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high risk or pre-malignant lesions. Anticancer Res 2001; 21: 2895-2900 12. Rao CV, Rivenson A, Simi B et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 1995; 55: 259-266 13. Sharma RA, McLelland HR, Hill KA et al. Pharmacodynamic and pharmacokinetic study of oral curcumin in patients with colorectal cancer. Clin Cancer Res 2001; 7: 1894-1900 Additional References: Pylkas AM, Juneja LR, Slavin JL et al Comparison of different fibers for in-vitro production of short chain fatty acids by intestinal microflora J of Med Foods 2005; 8: 113-116 Topping D L and Clifton P M Short chian fatty acids and human colonic function: Roles of resistant starch and non starch polysaccharides Physiol Rev 2001: 81: 1031-1064 King DE, Egan BM, Woolson RF, et al. Effectof a high fiber diet vs. a fiber supplemented diet on C-reactive protein level. Arch Intern Med. 2007; 167: 502-506 Huang MT, Lou YR, Ma W, et-al. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon cancer in mice. Cancer Res 1994; 54: 5841-5847 Ammon HP. Boswellic acids in chronic inflammation. Planta Med. 2006; 12: 1100-1116 Asl MN and Hosseinzadeh H. Review of pharmacological effects of Glycyrrhizia sp. And its bioactive components. Phytother Res. 2008; 6: 709-724 Huwez FU, Thirlwell D, Cockayne A, et al. Mastic gum kills Helicobacter pylori. N Engl J Med. 1998; 339: 1946-1948 Hyun-Jo Kim and Neophytou C. Natural anti-inflammatory compounds for the management and adjuvant therapy of Inflammatory Bowel Disease and its drug delivery system. Arch Pharm Res. 2009, 22: 997-1004 Triantafyllou A, Chaviaras N, Sergentanis TN et al. Chios mastic gum modulates serum biochemical parameters in a human population. J Ethanopharmacol. 2007: 111: 43-49

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Nutrient Supplements for the Digestive System

As research continues to grow, it becomes more evident just how crucial the integrity of the digestive system is to overall health. It is the main barrier and first defense between the outer world and inner body. From this basic standpoint, the importance of maintaining a healthy gut lining is monumental. Here is a closer look at some key nutritional therapeutics for the purpose of enhancing gut health: L-Glutamine: Maintaining Gut Integrity L-Glutamine is well known as a major fuel and nitrogen source for colonocytes, as well as a component of glutathione.1 These factors alone make it clear that the amino acid is a key nutrient in the intestinal mucosa and for combatting oxidative stress. Anecdotally, many practitioners swear by L-glutamine in its ability to heal the digestive tract under inflammatory circumstances and suboptimal gut integrity. However, research surrounding this topic is far from conclusive. Much research has shown L-glutamine to have positive applications in regulating or improving intestinal permeability. A double-blind trial of L-glutamine showed improvement in AIDSrelated diarrhea in individuals taking antiretroviral drugs.2 Similarly, patients receiving chemotherapy have been shown to benefit from reduced frequency of diarrhea versus control groups without a decrease in the efficacy of chemotherapeutics.3,4

Testing using the lactulose-manitol ratio test (the preferred measurement for determining the presence or absence of Leaky Gut Syndrome) confirmed measureable improvements in intestinal permeability with L-glutamine supplementation in these individuals. Again, in otherwise healthy children suffering from gastroenteritis, L-glutamine supplementation reduced the duration of acute diarrhea by 26% compared to placebo.5 Animal studies also show improved intestinal permeability and preserved gut mucosal integrity using L-glutamine, although an extraordinarily high dose of 500 mg/kg/day was administered in one particular study.6 Clearly, there is a role for L-glutamine in impaired intestinal permeability and diarrhea cases. The application of L-glutamine for Crohns Disease (CD) is less apparent. Despite multiple studies showing impaired glutamine levels in CD patients,7 oral supplementation with L-glutamine has not necessarily shown to be of benefit. One study found that glutamine did not help to improve intestinal permeability in individuals with CD,8 yet in vitro research shows a significant reduction in levels of inflammatory molecules after simultaneous exposure of glutamine and arginine to the colonocytes of CD.9 Various practitioners and researchers have postulated that clinical trials have not shown a clear benefit in glutamine supplementation with Crohns patients for a few reasons: dosing is not adequate in various studies, glutamine must be studied in combination with other nutritional factors, and depleted glutamine may merely be a secondary marker for a separate causative factor.1,10 It is evident that more research is necessary to determine the exact role that L-glutamine plays in such inflammatory conditions of the digestive tract. Other applications for L-glutamine include decreasing the severity of chemotherapy-induced mucositis and gastrointestinal toxicity.10 Also, parenteral administration of

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Healthy intestinal lining

Damaged intestinal lining

Inflammation

Undigested food particles

Toxins

Gap junction Yeast/Fungi

Intestinal lining Blood stream

Leaky gut Parasites and harmful bacteria

Intestinal Permeability

L-glutamine has shown promising application in those with acute pancreatitis (based on decreased complication rates and mortality rates).11, 12 Essential Fatty Acids: Controversial Benefits There are two types of essential fatty acids (EFA) that the human body cannot synthesize on its own: an omega-3 type, alpha-linolenic acid (ALA), and an omega-6 type, linoleic acid (LA). Both types serve a variety of crucial functions throughout the human physiology, most notably as precursors to various prostaglandins and leukotrienes (thereby regulating inflammatory pathways) and as components of cell membranes.13 Although ALA is converted in the body to the biologically active eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA), its conversion rate is quite limited.13 As a result, health practitioners often recommend supplementation of EPA and DHA directly in the form of fish oil. From a digestive health focus,

these crucial omega-3 fatty acids have shown possible benefit in Crohns Disease (CD), ulcerative colitis (UC), gastritis and proctitis,14,15 although the research is conflicting. For example, certain studies have shown supplementation with fish oil or EPA/DHA to prevent relapses in CD patients while in remission,6,17 yet other studies have failed to find a significant effect, if any effect at all.18,19 Nevertheless, some experts hypothesize that the minimum dose needed for such a condition appears to be quite high (912 grams per day), possibly explaining the equivocal results as not all studies reached this dosage.1 Similarly, research evaluating the efficacy of fish oil in UC patients has shown clinical improvement and decreased medication need,20 yet many studies show disappointing results.21 Prospective cohort studies support a possible protective feature of increased omega-3 fatty acid intake for UC.22 A systematic review was performed in 2012 to better evaluate whether omega-3 fatty acids are indeed useful

in CD or UC patients. Researchers were unable to come to a conclusion on the recommendations for clinical use based on poor study design features (ie. inappropriate placebo, small number of participants, variable designs). Despite this, they did lean toward the idea that available data does not support the use of omega-3 supplementation for the treatment of active and inactive inflammatory bowel disease.23 A previous meta-analysis in 2011 came to similar conclusions.24 For completions sake, it should be noted that supplementation with omega-6 oils has been shown to be clinically relevant as well, particularly in the form of gamma-linolenic acid (GLA, converted from LA within the body). Animal research has shown GLA to protect against induced ulcers25 and GLA does have antineoplastic activity against hepatocellular carcinoma in vitro.26 However, very little research has focused on digestive applications of GLA as opposed to other conditions such as arthritis and eczema. Finally, while the trend in modern medicine has been toward high dose omega-3 supplementation to counterbalance the low ratio of omega3s to omega-6s found in todays diet, some have posed the question of whether we are actually overdosing on omega-3 fatty acids.27 This theory is supported by the fact that EPA and DHA are only converted in small amounts within the body because that is all that we physiologically need. More clinical research must be performed to determine the optimal ratio of EFAs for supplementation and dietary purposes, as well as the exact role in treating clinical conditions. Zinc Carnosine: An Anti-ulcer Agent It has long been known that zinc is essential for the human body in physiological processes such as wound healing, immune function and hormonal regulation.28 However, novel research has examined the role of zinc carnosine ([ZnC], zinc combined with the amino acids beta-alanine and histidine) for its gastroprotective capabilities and potential as a gastric

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ulcer treatment therapy. In fact, its application as an anti-ulcer drug has been in clinical use for quite some time now in Japan.29 Numerous clinical studies of ZnC examining its anti-ulcer effects have shown great safety and efficacy through endoscopic measures. Optimum healing appears to be achieved after 8 weeks of treatment (as high as 72% achieving remarkable improvement in one study), although 4 weeks demonstrates great improvements as well.29 Another study showed that co-administration of ZnC with indomethacin (a NonSteroidal Anti-Inflammatory Drug [NSAID]) eliminated the increase in gut permeability in humans when the NSAID was given alone. In addition, this coadministration also negated the formation of gastric ulcers in rats versus the damage seen when indomethacin was the sole therapy.30 ZnC also shows strong potential as an anti-Helicobacter pylori agent (thereby adding to its role as an antiulcer supplement). In a clinical trial examining the efficacy of H. pylori eradication using ZnC in combination with triple therapy (lansoprazole, amoxicillin and clarithromycin), significant improvements were seen when compared to triple therapy alone.31 These results have been attributed to its bactericidal, antiurease and anti-adhesive properties toward H. pylori specifically.32 Aside from anti-bacterial action, the mechanism of action for ZnC appears quite complex and multi-targeted. L-carnosine specifically prevents gastric epithelial injury by inhibiting DNA fragmentation,33 whereas ZnC together acts as an antioxidant, induces the expression of Heat Shock Protein 72 (HSP72) and inhibits Nuclear Factor kB (NF-kB) in the colonic mucosa.34 This increase in HSP72 activity and decreased NF-kB level has been shown to have cytoprotective effects on digestive organs. Other actions include the restoration of glutathione levels in injured gastric mucosa, promotion of growth factor formation, promotion of

Gastric Ulcer

polyamine synthesis and inhibition of proinflammatory cytokine production (such as Tumor Necrosis Factor-alpha [TNF-]) all of which are essential processes in mucosal protection and ulcer healing in the gut.35 Overall, the actions of ZnC make it a suitable pairing for optimal gut health and protection. As an added benefit, ZnC has also shown application in improving taste sensitivity in cases of idiopathic taste disorders.36 Nitric Oxide: Not Just a Vasodilator Classically, nitric oxide (NO) has been considered for its cardiovascular role as a potent vasodilator. However, many are unaware that the effects of NO are much more far reaching; it is also a proven anti-microbial, a necessary agent for tissue protection under ischemic circumstances and a gastroprotective agent.37 With this in mind, NO and its precursors (nitrates

and nitrites) have tremendous therapeutic potential that is still yet to be fully realized. From a gastroprotective standpoint, research has focused on the ability of NO to prevent and treat gastric ulcers. More specifically, nitrates, nitrites and NO have been shown to mitigate gastric ulcerations commonly caused by non-steroidal anti-inflammatory drugs (NSAIDs), endotracheal intubation and Helicobacter pylori through a variety of mechanisms.38,39,40 NO appears to mitigate epithelial permeability, reduce tissue inflammation, increase gastric mucosal blood flow and, subsequently, increase mucus generation.38,39 Collectively, these actions provide supportive protection in bacterial overgrowth and they help to offset the depletion of gastric NO due to common medical interventions.41

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Keeping in mind the crucial role that a well-balanced gut microflora plays in our digestive health, NO helps to regulate this ecosystem through its broad-spectrum antibiotic effect. In vitro, NO and nitrites have proven to combat Shigella, Yersinia and Salmonella species, as well as Helicobacter pylori, Clostridium botulinum and Pseudomonas aerguinosa.40, 42, 43 This inhibition of H. pylori by nitrites and

NO may be a separate and additive protective mechanism for gastric ulcer prevention, while simultaneously promoting healing of the mucosal lining.43 Therapeutically, the most effective way to increase NO levels in the body and provide gastrointestinal protection is to deliver nitrates directly and drive the nitratenitritenitric oxide pathway (also known as the References

NOx3,2,1 pathway). This delivery method holds many advantages over the classic L-arginine-Nitric oxide pathway including stimulation of the entero-salivary nitrate cycle. In the most basic sense, this cycle allows nitrate conversion to nitrite in the oral cavity by commensal bacteria, followed by reduction to NO in the stomach.37 The cycle continues as nitrates and remaining nitrites are rapidly absorbed into the blood stream and recirculated to the salivary glands, where further reduction and activation of NO can take place.37 Interestingly, animal research shows that the gastroprotective effect of nitrate supplementation is eliminated if topical antibiotics are used in the oral cavity to disrupt the oral microflora.44 As a final note, administering NO precursors in a clinical setting may be contraindicated in patients suffering from reflux esophagitis, as NO also appears to trigger relaxation of the lower esophageal sphincter.45 However, given the gastroprotective effects discussed above, clinical judgment must be exercised, as this aggravating effect is merely theoretical.

1. Yarnell E. Natural approach to gastroenterology. WA, Healing Mountain Pub: 2011. pp 987-988. 2. Bushen, OY, Davenport JA, Lima AB, et al. Diarrhea and reduced levels of anti-retroviral drugs: improvement with glutamine or alanyl-glutamine in a randomized control trial in northeast Brazil. Clin Infect Dis. 2004; 38:1764-1770 3. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of uorouracil induced intestinal toxicity: A double blind, placebo controlled, randomised trial. Gut. 2001; 48(1):28-33 4. Li Y, Yu Z, Liu F, et al. Oral glutamine ameliorates chemotherapy-induced changes of intestinal permeability and does not interfere with the antitumor eect of chemotherapy in patients with breast cancer: A prospective randomized trial. Tumori. 2006; 92(5):396-401 5. Yalcin SS, Yurdakok K, Tezcan I, et al. Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea. J Pediatr Gastroenterol Nutr. 2004; (38):494-501 6. Dos Santos RG, Viana ML, Generoso SV, et al. Glutamine supplementation decreases intestinal permeability and preserves gut mucosa integrity in an experimental mouse model. JPEN J Parenter Enteral Nutr. 2010; 34(4):408-413 7. Balasubramanian K, Kumar S, Singh RR, et al. Metabolism of the colonic mucosa in patients with inammatory bowel diseases: An in vitro proton magnetic resonance spectroscopy study. Magn Reson Imaging. 2009; 27(1):79-86 8. Hond ED, Hiele M, Peeters M, et al. Eect of long-term oral glutamine supplements on small intestinal permeability in patients with crohns disease. JPEN J Parenter Enteral Nutr. 1999; 23:7-11 9. Lecleire S, Hassan A, Marion-Letellier R, et al. Combined glutamine and arginine decrease proinammatory cytokine production by biopsies from crohns patients in association with changes in nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways. J Nutr. 2008; 38(12):24812486 10. Gaby, A. Nutritional medicine. Concord, N.H, Fritz Perlberg Publishing. 2011. Pp. 1221. 11. Sahin H, Mercanligil SM, Inan N, et al. Effects of glutamine-enriched total parenteral nutrition on acute pancreatitis. Eur J Clin Nutr. 2007; 61:1429 1434 12. Fuentes-Orozco C, Cervantes-Guevara G, Mucino-Hernandez I, et al. L-alanyl-glutamine supplemented parental nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. JPEN J. Parenter Enteral Nutr 2008; 32:403-411

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13. Gaby, A. Nutritional medicine. Concord, N.H, Fritz Perlberg Publishing. 2011. Pp 227-234 14. Almallah YZ, Richardson S, OHanrahan T, et al. Distal procto-colitis, natural cytotoxicity and essential fatty acids. Am J Gastroenterol. 1998; 93:804809 15. Kremer JM, Malamood H, Maliakkal B, et al. Fish oil dietary supplementation for prevention of indomethacin induced gastric and small bowel toxicity in healthy volunteers. J Rheumatol. 1996; 23(10):1770-1773 16. Belluzzi A, Brignola C, Campierei M, et al. Eect of enteric-coated sh-oil preparation on relapses in crohns disease. N Engl J Med. 1996; 334(24):15571560 17. Romano C, Cucchiara S, Barabino et al. Usefullness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohns disease: a double-blind, randomized, placebo-controlled study. World J Gastroenterol. 2005; 11:7118-7121 18. Feagan BC, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in crohns disease. The epic randomized controlled trials. JAMA. 2008; 299(14):1690-1697 19. Lorenz-Meyer H, Bauer P, Nicolay C, et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohns disease. N Engl J Med 1996; 334:1557-1560 20. Salomon P, Kornbluth AA, Janowitz HD. Treatment of ulcerative colitis with fish oil n-3-omega-fatty acid: an open trial. J Clin Gastroenterol. 1990; 12:157-161 21. Dichi I, Frenhane P, Dichi JB, et al. Comparison of omega-3 fatty acids and sulfasalazine in ulcerative colitis. Nutrition. 2000;16:87-90 22. John S, Luben R, Srethsa SS et al. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study. Eur J Gastroenterol Hepatol. 2010 May; 22(5):602-6 23. Cabr E, Maosa M, Gassull MA. Omega-3 fatty acids and inflammatory bowel diseases - a systematic review. Br J Nutr. 2012; 107(2):240-52 24. Turner D, Shah PS, Steinhart AH, et al. Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses. Inflamm Bowel Dis. 2011; 17(1):336-45 25. Das UN, Reddy DN, Rao PN, et al. Essential fatty acids and peptic ulcer disease. Gut. 1987; 28:914-915 26. Itoh S, Taketomi A, Harimoto N, et al. Antineoplastic eects of gamma linolenic acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010; 47(1):81-90 27. Peskin BS, Habib A. The Hidden Story of Cancer Find Out Why Cancer Has Physicians on the Run and How a Simple Plan Based on New Science Can Prevent It. Pinnacle Pr. 2012. 28. Gaby A. Nutritional medicine. Concord, N.H, Fritz Perlberg Publishing. 2011. Pp 151. 29. Matsukura T, Tanaka H. Applicability of zinc complex of L-carnosine for medical use. Biochemistry. 2000; 65(7):817-823 30. Mahmood A, FitzGerald AJ, Marchbank T et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007 Feb; 56(2):168-175 31. Kashimura H, Suzuki K, Hassan M et al. Polaprezinc, a mucosal protective agent, in combination with lansoprazole, amoxicillin and clarithromycin increases the cure rate of Helicobacter pylori infection. Aliment Pharmacol Ther. 1999; 13:483-487 32. Sunair M, Tanaka N, Kuwayama H, et al. Effect of Z-103, a new antiulcer agent, on Helicobacter pylori antimicrobial, antiurease, and antiadhesive activities. Jpn Pharmacol Ther. 1994; 22(9):31-5 33. Suzuki H, Mori M, Seto K et al. Polaprezinc, a gastroprotective agent: attenuation of monochloramine-evoked gastric DNA fragmentation. J Gastroenterol. 1999; 34(11):436 34. Odashima M, Otaka M, Jin M et al. Zinc L-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppression of NF-kB activation. Life Sciences. 2006;79:22452250 35. Ko JK, Leung CC. Ginger extract and polaprezinc exert gastroprotective actions by anti-oxidant and growth factor modulating effects in rats. Gastroenterology and Hepatology. 2010; 25:1861-1869 36. Sakagami M, Ikeda M, Tomita H et al. A zinc-containing compound, Polaprezinc, is effective for patients with taste disorders: randomized, doubleblind, placebo-controlled, multi-center study. Acta Otolaryngol. 2009 Oct; 129(10):1115-20 37. Lundberg, JO, Weitzberg, E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nature Publishing Group. 2008; Vol 7:156-167 38. Bjorne HH, Petersson J, Phillipson M,et al. Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Invest. 2004; 113:106-114 39. Petersson J, Phillipson, M, Jansson, E. A. et al. Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am J Physiol Gastrointest Liver Physiol. 2007; 292:718-724 40. Dykhuizen RD, Fraser A, McKenzie H, et al. Helicobacter pylori is killed by nitrite under acidic conditions. Gut. 1998; 42:334-337 41. Bjorne, H., Govoni, M., Tornberg, D. C. et al. Intragastric nitric oxide is abolished in intubated patients and restored by nitrite. Crit. Care Med. 2005; 33:17221727 42. Carlsson, S., Wiklund, N. P., Engstrand, L, et al. Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide. 2001; 5:580586 43. Dykhuizen R, Frazer R, Duncan C, et al. Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defence. Antimicrob Agents Chemother. 1996; 40:14221425 44. Miyoshi, M, Kasahara E, Park AM, et al. Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat. Free Radic. Res. 2003; 37:8590 45. Yarnell E. Natural approach to gastroenterology. WA. Healing Mountain Pub. 2011. Pp 1343.

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The Breakdown on Digestive Enzymes

Digestive enzymes are naturally present in all living organisms to aid in the digestion of food by breaking down large food carbohydrates, lipids and protein macromolecules into smaller building blocks that can be easily absorbed and utilized by the organism. The Classification of Digestive Enzymes Digestive enzymes are classified based on their target substrate, whether it is carbohydrate, lipid, or protein. Within each class of enzyme lie many types of enzymes, each targeting different substrates, and digesting them into different sizes. Proteases and peptidases break down proteins into smaller peptides and amino acids. Amino acids, the smallest building blocks of protein, can be combined into different sequences to make diverse small or large protein molecules (peptides) that the body needs to perform various crucial functions, including replicating DNA, immune responses, building muscle, or as enzyme building blocks, among other functions. In fact, out of the 22 different standard amino acids, 9 are essential amino acids because the human body cannot synthesize them and must obtain them either by digesting consumed protein or from amino acid supplementation. Lipases break apart fat into fatty acids and glycerol. Fatty acids are an extremely important source of fuel in the human body and store large amounts of energy. Glycerol is an important building block of fats synthesized by the body. Carbohydrases catalyze the splitting of carbohydrates such as starch and sugars into simple sugars such as glucose. Glucose is an important source of energy for many of the body functions and is the brains primary source of energy. The Role of Digestive Enzymes Digestion starts in the oral cavity. The simple physical digestion performed by chewing allows a higher surface area to be exposed to the saliva which contains an array of digestive enzymes that start the chemical digestion of food. These enzymes include carbohydrases such as amylase, as well as lipase. Unlike lipids and carbohydrates however, protein digestion is started in the stomach by the peptidase pepsin, the major digestive enzyme produced in the stomach. The semi-digested product then moves to the duodenum, where it gets further degraded by a secretion from the pancreas known as Pancreatic Juice containing more amylase, protease and

lipase. Digestion is completed in the small intestine by numerous brush border enzymes that break down the semi-digested products into minute particles. This process releases amino acids, sugars, fatty acids, vitamins, minerals and other essential nutrients that get absorbed through the walls of the small intestine and to a lesser extent, the colon. The Importance of Digestive Enzymes It may be argued that under optimal conditions a healthy human body does not need digestive enzyme supplementation. However, with more than 20 million Canadians and up to 70 million Americans afflicted with digestive diseases,1,2 it is apparent that the digestive capability of many is not functioning optimally. In fact, many people diagnosed with digestive disorders do not have any serious symptoms,1 and unless diagnosed, may never know that they have digestive disorders. Mild digestive enzyme deficiency or the consumption of an amount of food greater than the enzymatic digestive capability of the body will result in some undigested food passing through to the colon. Since the body cannot absorb nutrients from undigested food as well as it does from digested food, many nutrients can get excreted unutilized. Additionally, when food arrives at the colon undigested, it is metabolized by indigenous colonic microbial flora, leading to over production of carbon dioxide, methane, and/or hydrogen, which are absorbed and eliminated via the lungs, but can also lead to feelings of bloating, flatulence, abdominal pain, discomfort and even diarrhea or vomiting in some cases.3,4 Inadequate enzymatic digestion of food can lead to avoidance of nutritious food for fear of unwanted gastrointestinal symptoms. Even in cases where the problematic food is consumed, improper digestion prevents full access to all of the nutrients present, resulting in nutrient malabsorption. Nutrient deficiency can cause serious decline in health, including degenerating eyesight, impaired immunity, mood swings, poor wound healing, and decline in the health of skin,

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Table 1: Enzyme sources and units accepted by Health Canada, and available conversions Enzyme Class Enzyme Source type Sources Units Available conversions Fungal protease Fungal Aspergillus flavus var. oryzae HUT, SAP None Aspergillus niger Bacterial protease/ Bacterial Bacillus subtilis PC None neutral protease Papain, Bromelain Plant Carica papaya (Papaya) PU, GDU 1 GDU ~ 15,000 PU Ananas comosus var. comosus (Pineapple) Protease Animal Bos taurus (cow) pancreas USP units 1 Ph.Eur. Unit = 1 BP Unit = Sus scrofa (pig) pancreas 1 FIP Unit ~ 62.5 USP Units Fungal lipase Fungal Aspergillus flavus var. oryzae LU None Aspergillus niger Rhizopus oryzae Lipase Animal Bos taurus (cow) pancreas USP units 1 Ph.Eur. Unit = 1 BP Unit = Sus scrofa (pig) pancreas 1 FIP Unit ~ 1 USP Unit Alpha-Galactosidase Fungal Aspergillus niger GalU None Lactase, beta-galac- Fungal Aspergillus flavus var. oryzae ALU None tosidase Alpha-Amylase Fungal Aspergillus flavus var. oryzae DU None Aspergillus niger Rhizopus oryzae Alpha-Amylase Plant Hordeum vulgare (Barley) DU None Alpha-Amylase Animal Bos taurus (cow) pancreas USP units 1 Ph.Eur. Unit = 1 BP Unit = Sus scrofa (pig) pancreas 1 FIP Unit ~ 4.15 USP Units Glucoamylase/ Fungal Aspergillus niger AGU None amyloglucosidase/ Aspergillus oryzae acid maltase Rhizopus niveus Rhizopus oryzae Cellulase Fungal Aspergillus niger CU None Trichoderma longibrachiatum Trichoderma reesei Hemicellulase Fungal Aspergillus niger HCU None Aspergillus oryzae Trichoderma longibrachiatum Trichoderma reesei Invertase/sucrase Fungal Aspergillus niger INVU, SU None Saccharomyces cerevisiae
bones and various other organs in the body. Enzyme supplementation can help improve the digestibility of many foods, which can improve nutrient absorption, and decrease or even eliminate many of the gastrointestinal complaints resulting from improperly digested food. Take Lactase for Example Lactose intolerance is a symptom of a very common enzymatic deficiency, more accurately described as lactase deficiency. Lactase is a carbohydrase

Carbohydrases

Lipases

Proteases

that breaks down lactose (a sugar naturally abundant in milk and other dairy products) into the simpler sugars glucose and galactose, both of which can then be absorbed by the body and utilized for various crucial functions. Lactase quickly digests lactose in the small intestine so that little or no lactose reaches the colon. However, lactase levels naturally drop by varying degrees in most individuals after weaning; in fact most lactose intolerant individuals

can handle one glass of milk (about 12 grams of lactose) with minor or no symptoms, while 15-18 grams of lactose are tolerated when offered with other nutrients, and intolerance becomes progressively more frequent at quantities larger than 18 grams.4 When lactase levels are deficient, undigested lactose reaches the colon where it is fermented by the microbial flora. This leads to an over production of gases causing bloating and flatulence,

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Table 2: Enzyme targets, digestion products and foods rich in enzyme targets Enzyme Class Enzyme type Target substrate Digestion product Foods rich in target substrate Proteases Proteases Large and mid-sized protein molecules Lipids (fat) Mid-sized peptides and individual amino acids Fatty acids and glycerol Protein present in soy, spirulina, whey protein, dairy, tofu, seafood, among others White and red meat, dairy products, egg yolk, oils (such as olive oil and coconut oil), nuts (almonds, pistachios, walnuts, hazelnuts), coconut, among others Starch, such as that present in rice, potatoes, wheat, corn, bananas, chestnuts, beans such as fava beans, lentils and peas and others Legumes (beans, peanuts), cruciferous vegetables (cauliflower, broccoli, cabbage, Brussels sprouts, among others) Sweet fruit such as pineapple and apricot Fibrous vegetables and fruit such as persimmons, potato skins, corn, celery Dairy products (such as milk, and to a lesser extent cheese and yogurt)
vegetables and fruits. However, an overabundance of fibrous vegetable and fruit intake, especially in cases of delayed gastric emptying or hypochlorhydria (low stomach acidity), can cause polymerization of the semi-broken down food in the stomach. This can create a sticky complex acting as glue, which can bind to other foodstuffs resulting in a dark, hard, sticky foreign body that can keep growing, known as phytobezoar.9 Phytobezoars can cause symptoms of epigastric pain, nausea, or vomiting10 and can progress to gastric ulcers.9 Phytobezoars can also migrate into the intestine causing intestinal blockages.9 Since phytobezoars are bound by cellulose, enzymatic therapy by cellulase has proven to be effective in many cases.11 Cellulose is a complex carbohydrate, also known as fiber; it is the structural component of the cell wall of green plants and many forms of algae. Cellulose is digested by the enzyme cellulase, however because the human body does not contain or produce cellulase, cellulose is mostly undigestible by the human body. Low dose cellulase

Lipases

Lipase

Amylase, Glucoamylase

Complex, long chain carbohydrate molecules (starch) Complex and branching sugars

Mid and small chain carbohydrates (such as maltose) and simple sugars (such as glucose) Simple sugars (such as glucose)

Carbohydrases

Alpha-Galactosidase

Invertase Cellulase, Hemicellulase Lactase

Sucrose Cellulose (fibre) Lactose

Simple sugars (fructose and glucose) Simple sugar (glucose) Simple sugars (glucose and galactose)
Some Clinical Studies on Enzyme Supplementation Alpha-galactosidase is an enzyme that breaks down complex and branching carbohydrates, such as those found in legumes, and cruciferous vegetables (see table 2). What is interesting about this enzyme is that it is not produced by the human body, therefore the complex and branching carbohydrates pass through the stomach and upper intestine undigested. They are then fermented by the indigenous colonic microbial flora, producing excess gas which can lead to feelings of bloating, abdominal distension and flatulence;3 this is commonly associated with eating beans and other cruciferous vegetables. Alphagalactosidase supplementation was clinically shown to reduce gas production following a meal rich in fermentable carbohydrates, since supplementation decreases the amount of fermentable carbohydrates by breaking them down before they can be metabolized by the colonic flora.3 It is well known that a healthy diet should contain an abundance of fibrous

in addition to acidifying the colon and increasing the osmotic load, causing loose stools and diarrhea.5 It has been reported that the clinical representation of lactose intolerance may also extend to systemic complaints such as headache, vertigo, memory impairment, lethargy, muscle and joint pains, allergy, cardiac arrhythmia, mouth ulcers, and sore throat.6,7 It has been hypothesized that lactose fermentation by the colonic flora could generate toxic metabolites such as acetaldehyde and protein toxins which can alter cell signaling mechanisms and can therefore be responsible for these systemic symptoms.6,8 Avoidance of lactose can lead to a decrease in the intake of many important nutrients, most notably calcium and other nutrients crucial for bone health. Supplementating with the enzyme lactase helps improve the digestion of lactose before it wreaks havoc in the colon, thus it can be seen how lactase supplementation can help alleviate symptoms of lactose intolerance and improve nutrient intake and absorption.

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supplementation along with a healthy diet abundant in fibrous raw vegetables and fruits is therefore useful to help reduce the risk of phytobezoar formation since the cellulase can break down cellulose before it becomes problematic. An exciting preliminary clinical study was published in which elite cyclists were supplemented with an enzyme combination containing the fungal carbohydrases amylase, cellulase and hemicellulase, in addition to a meal replacement prior to exercise. The results of this study show an increase in endurance (or time to exhaustion) during exercise by 43%, which was attributed to the more rapid digestion of carbohydrates provided in the meal replacement, thereby improving the availability of simple sugars to be absorbed and utilized by the cells for energy.12 In another clinical study published by Glade and colleagues in 2001,13 an enzyme combination containing the fungal carbohydrases amylase, cellulase and lactase as well as lipase and bromelain (a protease found in pineapple) was given to bedridden nursing-home patients. Total digested protein concentration increased significantly, which means faster and higher availability of protein for absorption and use in crucial pathways required by the body. Albumin concentration also increased slightly, which is crucial for hormone transport, especially thyroid hormones.14 Albumin is also a marker of inflammation (since it is down-regulated in inflammatory states), helps prevent the photodegradation of folic acid,15 and is a very abundant and important antioxidant.16 Finally, the study showed an increase in lymphocyte counts, and it is well known that a higher lymphocyte count is a (beneficial) marker of a more active immune system. Short bowel syndrome is a malabsorption disorder that is caused by either the surgical removal of the small intestine, or due to the complete dysfunction of a large segment of the bowel. With a large section of the small intestine out of commission, large amounts of nutrients do not get absorbed,

oral cavity + salivary glands

stomach duodenum pancreas

colon

small intestine

leading to abdominal pain, diarrhea or steatorrhea, malnutrition and fatigue. Many small bowel syndrome patients suffer from deficiencies in vitamins A, D, E, K and B12, folic acid and minerals calcium, magnesium, iron, zinc, which can manifest as anemia, easy bruising, muscle spasms, poor blood clotting and bone pain, all of which are due to the decreased colonic absorption of nutrients present in food. It was shown in a clinical study that providing short bowel syndrome patients with an enzyme powder consisting of fungal lipase, the carbohydrases amylase, cellulase, lactase, as well as bromelain (protease) resulted in considerable improvement of symptoms and improved digestion, since enzyme supplementation provided the body with easier access to the nutrients available in food.17 Enzyme Units and Conversions Unlike many other substances, enzymes are not measured by weight, but rather by activity. The activity of an enzyme is defined as The amount of enzyme that catalyzes the conversion of 1 micromole of substrate per minute, or in the case of digestive enzymes, the amount of

enzyme required to digest 1 micromole of the appropriate substrate (i.e. protein, fat or carbohydrates) in 1 minute under the conditions optimal for said specific enzyme which can include certain temperature, pH, substrate used, etc. The optimal conditions required for each enzyme to display its most efficient digestive capabilities differ. Enzyme activity is a more appropriate measure of how much actual enzyme youre getting than weight, because 10 mg of one enzyme can digest substrates much more efficiently than the exact same weight of another enzyme due to differences in enzyme activity strengths. In this case, the higher the activity, not the weight, the more beneficial the enzyme can be. A common issue faced by many aiming to increase their enzyme intake is that many enzyme manufacturers use different enzyme units to represent their enzyme activity. Unfortunately, the different enzyme units imply different assay methods, which can include different testing conditions. Enzymes work differently under different conditions, and each enzyme has its own optimal conditions where

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it displays its most efficient digestive capability. Therefore mathematical conversion between the units may not be possible or accurate and has to be obtained experimentally by carrying out all the relevant assays on each enzyme using all the different conditions. In the case of pancreatic enzymes, the relevant enzymatic assays for many different units have been carried out and the results well studied, therefore the conversion between the studied different units in the case of pancreatic enzymes is possible (See table 1). However, while it is possible to convert between pancreatic lipase FIP, USP and LU units, it is not possible to use the same conversion for lipase from another source such as fungal lipase, since both lipases behave differently under different pHs.

The good news is, in order to allow the consumer to properly compare different brands and products, Health Canada has mandated that all manufacturers use the same internationally recognized units for all their enzyme products18 (see table 1). This will make choosing the product easier in the near future. Enzyme Supplementation and You The human body is adaptable and can handle much of what we throw into it; therefore digestive enzymes should only be taken when needed. The appropriate digestive enzymes may be useful for you if you consistently suffer from gastrointestinal discomfort from a certain type of food, or if you know you may be having a meal that could cause a larger than normal burden on your digestive system. In both cases, your body is not producing enough enzymes References

to break down the food eaten, and the left over undigested food is excreted without optimal nutrient extraction, in addition to being fermented in the colon causing gastrointestinal problems and damage. Therefore, the occasional extra help from digestive enzyme supplementation can help the digestibility of food, improve nutrient intake and alleviate most if not all of the gastrointestinal symptoms associated with improper digestion due to overwhelming the bodys natural enzymes with more than they can handle. You can refer to table 2 to determine which enzyme can best digest the food known to be problematic for you. As with most supplements, it is always best to consult your qualified health care practitioner for questions and to know if enzyme supplementation is right for you.

1. Canadian Digestive Health Foundation. Statistics. Available at: http://www.cdhf.ca/digestive-disorders/statistics.shtml. Accessibility verified February 25, 2013. 2. National Digestive Diseases Information Clearinghouse (NDDIC). Digestive Diseases Statistics for the United States. Available at: http:// digestive.niddk.nih.gov/statistics/statistics.aspx. Accessibility verified February 25, 2013. 3. Di Stefano M, Miceli E, Gotti S, et al. The Effect of Oral -Galactosidase on Intestinal Gas Production and Gas-Related Symptoms. Dig Dis Sci. Jan 2007; 52(1):78-83. 4. Mattar R, Ferraz D, Carrilho FJ. Lactose Intolerance: Diagnosis, Genetic, and Clinical Factors. Clinical and Experimental Gastroenterology. July 5 2012; 5:113-121. 5. Lomer MC, Parkes GC, Sanderson JD. Review Article: Lactose Intolerance in Clinical Practice - Myths and Realities. Aliment Pharmacol Ther. Jan 15 2008; 27(2):93-103. 6. Matthews SB, Waud JP, Roberts AG, et al. Systemic Lactose Intolerance: A New Perspective on an Old Problem. Postgrad Med J. March 2005; 81(953):167173. 7. Harrington LK, Mayberry JF. A Re-appraisal of Lactose Intolerance. Int J Clin Pract. Oct 2008; 62(10):1541-1546. 8. Campbell AK, Matthews SB, Vassel N, et al. Bacterial Metabolic Toxins: A New Mechanism for Lactose and Food Intolerance, and Irritable Bowel Syndrome. Toxicology. Dec 30 2010;278(3):268-276. 9. Hamilton S, Farber JL, Rubin E. The Gastrointestinal Tract. In: Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1999:700. 10.Zarling E, Thompson L. Nonpersimmon Gastric Phytobezoar: a Benign Recurrent Condition. Arch Intern Med. May 1984;144(5):959-961. 11.Lee SP, Holloway WD, Nicholson GI. The Medical Dissolution of Phytobezoars Using Cellulase. Br J Surg. Jun 1977; 64(6):403-405. 12.Frank L, Baer J, Lambert C, et al. The Effects of a Pre-Exercise Feeding With or Without Fungal Carbohydrases (Carbogen) on Blood Parameters and Exercise Performance in Elite Cyclists: A Preliminary Study. International Journal of Sport Nutrition and Exercise Metabolism. Sep 2002;12(3):310-317. 13.Glade MJ, Kendra D, Kaminski MV. Improvement in Protein Utilization in Nursing-Home Patients on Tube Feeding Supplemented With an Enzyme Product Derived From Aspergillus niger and Bromelain. Nutrition. Apr 2001;17(4):348-350. 14.Pardridge WM. Carrier-Mediated Transport of Thyroid Hormones through the Rat Blood-Brain Barrier: Primary Role of Albumin-Bound Hormone. Endocrinology. Sep 1 1979;105(3):605-612. 15.Vorobey P, Steindal AE, Off MK, et al. Influence of Human Serum Albumin on Photodegradation of Folic Acid in Solution. Photochem Photobiol. Jun 2006;82(3):817-822. 16.Roche M, Romdeau P, Singh NR, et al. The Antioxidant Properties of Serum Albumin. FEBS Lett. Jun 11 2008;582(13):1783-1787. 17.Kaminski MV, Jan P. Oral Enzyme Supplement in Short Bowel Home TPN Patients. Journal of the American College of Nutrition. 1998;17(5):528. 18.Health Canada. Listing of Monographs: Pre-Cleared Information. Available at: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monosReq. do?lang=eng. Accessibility verified February 25, 2013.

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The following table is intended to give a general overview of AORs Digestive formulas and the main areas of digestive health targeted by each product.
AOR Product Type of Product
Constipation Advanced Biotics AOR Zymes Boswellia or Maxi Boz II Curcumin Active, CurcuVIVA, Curcumin-95 Digestase DPP Zyme DGL-760 Gastro Relief Green Lipped FFA Inflammation Relief L-Glutamine Liver Support Mastica Chios Probiotic 3 Probiotic Formula Enzymes Botanical Extract Botanical Extract * * Diarrhea *** * * *

Health Applications
Digestion *** *** Inflammation * * *** *** * Nausea Ulcers * IBD/IBS * * *** ***

Enzymes Enzymes Botanical Extract Combo Formula Essential Fatty Acids Botanical Formula Amino Acid Combo Formula Botanical Extract Probiotic Formula

* * *

* * *

*** *

* *** *

* * *** *** * * * * * * *** * *

* * ***

* * * * * *** *** ***

* *** *** *** *

* * *

* * * * * * *

*** * *

* *** *** * *

Saccharomyces Probiotic Yeast Boulardii Solufibre TriphLax-750 Vitamin C Botanical Extract Botanical Formula Essential Vitamin

*** strong evidence, multiple modes of action * some evidence, single mode of action

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