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By Oscar Umahro Cadogan
European Officer of Research & Information, FMD Europe Ltd.

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Adjuvant supplements for coeliac disease

Introduction

The prime problem in coeliac disease is a strong immune reaction to the gliadin part of the gluten found in wheat, barley and rye. There is presently some debate as to whether oats also are a problem for coeliacs or not. They do contain gluten-like proteins called avenins, but these are somewhat different from those found in the other glutenous grains. Some studies show that newly diagnosed coeliacs recover as well on an otherwise gluten-free diet containing moderate amounts of pure oats not contaminated with wheat as those on a completely gluten-free diet123. There is, however, no doubt that the gliadin found in wheat, rye and barley is toxic to coeliacs4.

 

Persistent abnormalities

Regardless of what sort of gluten-free diet coeliacs stick to, their GI tract does not always heal completely. Cellular abnormalities can still be detected in the upper layers of cells in the surface of the small intestine after several years on a gluten-free diet5. Coeliacs also tend to have persistent abnormal gastro-intestinal microflora678.

 

 

 

 

Genetics

Several genetic traits that greatly increase the chance of developing coeliac disease have been identified9. One is a defect in the genes coding for dipeptidyl peptidase IV (DPP IV)10, which is a digestive enzyme that breaks down proteins and protein fragments, called peptides, rich in proline and glutamine by removing single amino acids or dipeptides (two amino acids linked together) from their ends. Gliadin from glutenous grains and some of the proteins found in dairy products are rich in glutamine and proline. As a result of this enzyme defect, coeliacs have problems breaking down such proline and glutamin-rich proteins and peptides, including gliadin and casein. The incompletely digested gliadin will then lead to the initiation of the immune reactions characteristic of coeliac disease that lead to intestinal damage. By removing all sources of gluten, and hence gliadin, from the diet, this exposure is prevented. Thus, the aggressive immune response that damages the surface of the small intestine is ameliorated.

However, removing gliadin from the diet does not correct the impaired digestive capacity initially present in coeliac due to genetic defects in DPP IV production. It is thus fair to conclude that coeliacs have impaired digestion, even when on a gluten-free diet and their small intestine has healed, because although that will limit damage to the mucosa of the small intestine, and thus overall digestion of disaccharides and small peptides, they still lack the capacity for thoroughly breaking down proteins and peptides rich in proline and glutamine. This includes other common food proteins, such as casein in diary products. Fortunately, incompletely digested fragments of these proteins are not as toxic as the gliadin fragments coeliacs react to. This does not make such protein fragments completely harmless, however.

 

Other genetic abnormalities or variations involved in the development and/or perpetuation of coeliac disease have also been discovered. However, none of these seem to relate to the production of enteric digestive enzymes.

 

 

 

Enzymes

Supplementation with the proper enzymes can further improve protein digestion in coeliacs on a gluten-free diet. As mentioned above, even gluten-free diets do not result in a complete normalization of digestive capacity in coeliacs, because genetic defects lead to a diminished production of DPP IV and possibly other peptidases as well. This functional lack is permanent and therefore already established before the initiation of coeliac disease. When proteins are not digested completely, they can provoke the production of immunoglobulins and initiate inflammatory responses. Unless broken down to single amino acids or very short peptides, protein is very hard to absorb. Unabsorbed protein in the intestines can be acted upon by putrefactive bacteriae, such as Clostridia and Bacteroides spp., leading to the production of toxins such as P-cresol, benzoate, p-hydroxyphenylacetate and p-hydroxypropionate. These toxins are at the very least a burden on the body’s detoxification pathways. Using supplementary digestive enzymes along with meals should improve protein breakdown in coeliacs and thereby increase the absorption and utilization whilst decreasing the production of protein-derived microbial toxins, such as P-cresol and phenylacetate and -propionate in the gastrointestinal system.

Some research has shown that glutenous flour incubated with Aspergillus-derived digestive enzymes prior to ingestion, removes its toxigenic properties in coeliacs11. This suggests that such digestive enzymes are capable of breaking the same bonds in proteins as DPP IV does, as well as any digesting any other toxic fragments found in gliadin. The American Coeliac Association is in fact currently supporting research into the development of enzymes that might potentially allow coeliacs to ingest glutenous grains without harm, because the enzymes will break down the gliadin1213.

 

It remains a question whether that is possible. Enzymes that are highly efficient at breaking down gliadin and that are active in the gastrointestinal system already do exist –Aspergillus-derived enzymes fit this bill –but will they be able to break down the gliadin fast enough following ingestion to avoid immune activation? At the moment, no one knows. Hence, it is not recommended for coeliacs to try even minute amounts of glutenous foods although using enzymes, which are capable of digesting gliadin in vitro, at the same time. However, using extra digestive enzymes, such as those derived from Aspergillus spp., whilst on a gluten-free diet is warranted for coeliacs to augment the digestion of other proteins.

 

 

 

Essential fatty acids

The acute phase of coeliac disease is characterized by inflammation in the surface of the small intestine, which leads to atrophy and disappearance of microvilli. Removing the offending substance, gliadin in the case of coeliac disease, is obviously of prime importance. Furthermore, limiting the inflammatory response created by the exposure to gliadin makes sense. Essential fatty acids (EFAs) can be of help in this regard. The omega-3 fatty acid eicosapentanoic acid (EPA) is the parent of the anti-inflammatory series-3 eicosanoids and also inhibits the production of the potent proinflammatory series-2 eicosanoids from arachidonic acid (AA). The omega-6 fatty acid di-homo--linolenic acid (DGLA) is the precursor of the anti-inflammatory series-1 eicosanoids. Thus, supplementing with extra EPA and DGLA or their precursors, -linolenic acid (ALA) and linoleic as well as -linolenic acid (LA and GLA) respectively, can help limit the inflammation seen in active coeliac disease and thereby potentially increase the speed of recovery and the rate of small intestinal repair.

 

 

 

Probiotics

Most coeliacs excrete large amounts of microbially-derived compounds in urine. The levels are often high enough to imply bacterial or protozoal overgrowth of the small intestine. Whilst the excretion of such microbial compounds is lowered when on a gluten-free diet, it rarely falls down to the normal background concentrations found in non-coeliacs without microbial overgrowth of the small intestine. Thus, it might be that they coeliacs from persistent GI microflora abnormalities that are not corrected by a gluten-free diet alone.

One measure that can be taken to deal with abnormal GI microflora is probiotic supplementation with Lactobacilli, Bifidobacteriae and other species of bacteriae as well as other microbes that are normal, beneficial and non-detrimental residents of the human GI system. Adding more probiotic organisms will at the very least increase the ratio of beneficial:non-beneficial residents of the GI tract. In some cases, probiotic supplementation might completely displace the aberrant microflora.

 

Certain strains of Lactobacilli, such as salivarius, produce large amounts of proteases and peptidases that help digest proteins. Other Lactobacilli produce large amounts of lactase and similar disaccharidases that digest lactose and other simple sugars. The enzymes that digest simple sugars, the disaccharidases, are all located in the surface of the small intestine. When the surface of the small intestine is damaged, as in active coeliac disease, there is a partial or complete loss of disaccharidases, leading to severe problems with digesting and absorbing these. Microbes ferment the undigested simple sugars instead. Because of their production of proteases and disaccharidases, Lactobacilli can partially compensate for the inherited impairment of digestive capacity seen in all coeliacs and other people with damage to the surface of the small intestine.

Beneficial lactic acid-producing bacteriae, such as Lactobacilli and Bifidobacteriae are also capable of modulating the immune response in the surface of the gastrointestinal system14. Their presence in the intestines is recognized and detected by the immune system15. This leads to immune activation with an increased production of white blood cells. To avoid this recognition from leading to an inflammatory response, which could lead to their own eradication or damage to the surface of the intestine, such lactic acid-producing bacteriae make immune cells in the surface of the gastrointestinal system produce anti-inflammatory compounds such as interleukin-10 (IL-10)16. This does not weaken the immune system, but actually strengthens it, as has produced more white blood cells when it recognizes the lactic acid-producing bacteriae. Only it will not unleash them on these bacteriae, because of the production of the above-mentioned anti-inflammatory compounds. These white blood cells are then available to deal with other unwanted microbes and other foreign substances at very short notice.

The anti-inflammatory compounds produced due to the presence of lactic acid-producing bacteriae are also capable of inhibiting excessive immune reactions. Thus supplementing with sufficient amounts of probiotic bacteriae ought to help cull the inflammation seen in coeliac disease, whether it is the very aggressive immune response during acute flare-ups caused by the ingestion of gliadin or the low-grade inflammation seen permanently in some coeliacs although they have been on a gliadin-free diet for years.

 

 

 

Antioxidants

Antioxidants are of prime importance during inflammatory reactions, such as those seen is active coeliac disease. They can help attenuate some of the tissue damage caused by the immune system and also help lower the production of pro-inflammatory signaling substances, such as series-2 eicosanoids.

The pro-inflammatory series-2 eicosanoids derived from arachidonic acid are produced by the enzymes cyclo- and lipooxygenase. Both of these intentionally oxidize arachidonic to create series-2 eicosanoids that initiate and/or perpetuate the inflammatory cascade. Most fat-soluble antioxidants are capable of inhibiting cyclo- and lipooxygenase to some extent. After all, they do inhibit the oxidation of fatty acids. In doing so, they lower the production of series-2 eicosanoids and can thus help attenuate inflammation.

Once the inflammatory response has been initiated, the immune system releases free radicals, reactive oxygen species (ROS) and degrading enzymes at the site of inflammation. Together, they degrade tissue, both foreign and local. The body uses antioxidants to contain the free radicals and ROS in an attempt to localize oxidation to the tissue or foreign objects attacked. If the antioxidants mobilized are insufficient, the free radicals and ROS spill over into healthy tissue, causing unintentional damage. This can lead to perpetual inflammation, as the immune system is called upon to degrade the damaged tissue. Since there were not enough antioxidants in the first place, further spillage of free radicals and ROS into surrounding healthy tissues is a very likely consequence causing yet a round unintentional damage to more surrounding healthy tissue. Many of the degrading enzymes released during inflammation, such as elastase and hyularonidase can also be inhibited by at least certain antioxidants, such as the tannins found in green tea and grapes.

 

Because of the excessive demand for antioxidants during perpetuated inflammation, such as that seen in active coeliac disease, shortages can easily occur, both locally and systemically. Research has shown that enteric and erythrocyte glutathione levels are lowered during active coeliac disease171819. Glutathione is one of the primary antioxidants in the human body. It is regenerated by many of the dietary antioxidants we consume through food or supplements, such as vitamin C20, vitamin E, flavanoids and carotenoids. Some researchers suspect that dietary antioxidants are used primarily for regenerating glutathione and other endogenous antioxidants produced within the human body as opposed to being directly involved in the inactivation of free radicals and ROS.

Taking the above into consideration, it makes sense to supplement with extra antioxidants in coeliac disease, whether in the active phase or whilst on a gliadin-free diet. The antioxidants found in grapeseed are very interesting in this regard, as they have been shown to inhibit cyclo- and lipooxygenase as well as some of the degrading enzymes released by white blood cells during inflammation21. They also have a high bioavailability and seem to penetrate connective tissue rich in glycosaminocans very well22. Since the intestinal tissue is rich in glycosaminocans, one might expect grapeseed-derived antioxidants to have high penetration into the tissues in the small intestine and colon.

 

 

 

Fiber and prebiotics

Fiber is an important foundation for a properly functioning gastrointestinal system and digestive system. Considering the fact that coeliacs have a less than perfectly functioning digestive system, supplementing with fiber makes a lot of sense.

Foodstuffs that “feed”the normal and beneficial gastrointestinal flora are called prebiotics. Most water-soluble fibers are prebiotics. Lactobacilli, Bifidobacteriae and other beneficial inhabitants of the gastrointestinal system ferment these, producing L-lactic acid, butyrate and other things beneficial to the lining of the gastrointestinal canal. Without prebiotics, the normal beneficial microflora in the gastrointestinal system most likely would not be able to survive, as it would starve. So would the cells in the lining in the surface of the gastrointestinal canal. Lactobacilli produce L-lactic acid and N-acetyl--glucosamine amongst other things. L-lactic acid lowers the pH of the intestinal lumen, preventing the growth of pathogenic and non-beneficial microbes and also improves the functioning of pancreatic enzymes. N-acetyl--glucosamine is as building material of the wall of the small intestine and might play a role in the production of secretory immunoglobulin A, which is the first line of defense against pathogenic microbes in the alimentary canal. Bifidobacteriae and other beneficial anaerobic bacteriae in the colon also produce L-lactic acid. Furthermore, they produce short chain fatty acids (SCFAs) such as butyrate. Butyrate is the primary energy source of the cells lining the colon. A lack of butyrate has been associated with increased levels of colon cancer and seems to be one of the main problems in ulcerative colitis.

 

Insoluble fiber, which is not metabolized by beneficial bacteriae and microorganisms in the digestive system, also has beneficial effects. It adds bulk to the contents of the intestines, thereby promoting a faster of excretion of feces. Since feces is primarily waste material, it is important to excrete at a sufficient pace to avoid re-absorption of the toxins contained within it. Insoluble fiber also has the ability to bind several toxins in feces, thereby preventing their absorption.

 

One should be aware, however, that some coeliacs suffer from upper small intestinal overgrowth of microbes. The upper parts of the small intestine, the duodenum and the proximal jejenum, usually house only low counts of microorganisms compared to the ileum and colon. In certain situations, such as with the extensive damage to the surface of the small intestine seen in active coeliac disease, microbes can gain a foothold in the upper small intestine and cause havoc. This part of the small intestine is very rich in nutrients, which will be metabolized by these microbes. This can lead to the production of toxins such as D-lactic acid and other acids that are not beneficial; tartarate, citramalate and -ketoglutarate from Candida; and dihydroxyphenylpropionate by Clostridia, that are normally only resident in the colon in low numbers. Such a state will also lead to malabsorption because the microbes impair digestion and absorption. In the case of upper small intestinal microbial overgrowth, water-soluble fiber is not recommended as it can spur the growth of the microbes already present in excessive numbers.

In short, an argument can be made for ingesting plenty of fiber in coeliac disease, both soluble and insoluble, unless there is microbial overgrowth in the upper small intestine. Since coeliacs cannot have wheat, rye and barley or significant amounts of pure oats, supplementation can be necessary to get the 40 gr of fiber daily, which is recognized as the minimum amount that causes true benefit.

 

 

REFERENCES

 

1 Janatuinen EK et al. No harm from five year ingestion of oats in coeliac disease. Gut 2002 Mar;50(3):332-5.
2 Picarelli A et al. Immunologic evidence of no harmful effects of oats in celiac disease. American Journal of Clinical Nutrition 2001 Jul;74(1):137-40.
3 One should, however, be aware that what is termed a “gluten-free”diet can include foods that contain up to 200 ppm gliadin, as these can legally be labeled gluten-free. Experts are not in complete agreement as to whether this limit is low enough. Swedish experts on gluten and coeliac disease have proposed a lower limit of only 30-40 ppm gliadin.
4 Thompson T. Wheat starch, gliadin, and the gluten-free diet. Journal of The American Dietitic Association 2001 Dec;101(12):1456-9.
5 Wahab PJ et al. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. American Journal of Clinical Pathology 118(3):459-463, 2002
6 Lindblad BS, Rafter JJ. Increased excretion of a brain depressor amine in infantile coeliac disease and in healthy infants on a high protein milk diet. Acta paediatrica Scandinavica 1980 Sep;69(5):643-6.
7 Tamm AO. Biochemical activity of intestinal microflora in adult coeliac disease. Nahrung 1984;28(6-7):711-5
8 Lindblad BS et al. Absorption of biological amines of bacterial origin in normal and sick infants. Ciba Foundation Symposium 1979 Jan 16-18;(70):281-91
9 Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, Paparo F, Gasperi V, Limongelli MG, Cotichini R, D'Agate C, Tinto N, Sacchetti L, Tosi R, Stazi MA. The first large population based twin study of coeliac disease. Gut 2002 May;50(5):624-8.
10 Clot F, Babron MC, Percopo S, Giordano M, Bouguerra F, Clerget-Darpoux F, Greco L, Serre JL, Fulchignoni-Lataud MC. Study of two ectopeptidases in the susceptibility to celiac disease: two newly identified polymorphisms of dipeptidylpeptidase IV. Journal of Pediatric Gastroenterology Nutrition 2000 Apr;30(4):464-6.
11 Phelan JJ et al. Coeliac disease: the abolition of gliadin toxicity by enzymes from Aspergillus Niger. Clinical Science in Molecular Medicine 1977
12 Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides. American Journal of Physiology. Gastrointestinal and Liver Physiology 2002 Oct;283(4):G996-G1003
13 Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla C. Structural basis for gluten intolerance in celiac sprue. Science 2002 Sep 27;297(5590):2275-9.
14 Blum S, Schiffrin EJ. Intestinal Microflora and Homeostasis of the Mucosal Immune Response: Implications for Probiotic Bacteria? in: Tannock GW (ed.). Probiotics and Prebiotics: Where Are We Going? Norfolk, UK: Caister Academic Press, 2002, p. 311-2.
15 Ibid. p. 313-4.
16 Ibid. p. 319.
17 Rivabene R, Mancini E, De Vincenzi M. In vitro cytotoxic effect of wheat gliadin-derived peptides on the Caco-2 intestinal cell line is associated with intracellular oxidative imbalance: implications for coeliac disease. Biochimica et Biophysica Acta. 1999 Jan 6;1453(1):152-60.
18 Wahab PJ, Peters WH, Roelofs HM, Jansen JB. Glutathione S-transferases in small intestinal mucosa of patients with coeliac disease. Japanese Journal of Cancer Research 2001 Mar;92(3):279-84
19 Boda M, Nemeth I. Decrease in the antioxidant capacity of red blood cells in children with celiac disease. Acta Paediatrica Hungaria 1992;32(3):241-55.
20 Lenton KJ, Sane AT, Therriault H, Cantin AM, Payette H, Wagner JR. Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency. American Journal of Clinical Nutrition 2003 Jan;77(1):189-95.
21 Fine AM. Oligomeric proanthocyanidin complexes: history, structure, and phytopharmaceutical applications. Alternative Medicine Review 2000 Apr;5(2):144-51.
22 Harmand MF, Blanquet P. The Fate of Total Flavanolic Oligomers (OFT) Extracted from Vitus vinifera L. in the rat. European Journal of Drug Metabolism and Pharmacokinetics 1978;1:15-30.

 
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