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By Oscar Umahro Cadogan
European Officer of Research & Information, FMD Europe Ltd. |
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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
diet.
There is, however, no doubt that the gliadin found in wheat, rye and
barley is toxic to coeliacs.
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 diet.
Coeliacs also tend to have persistent abnormal gastro-intestinal microflora. |
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Genetics
Several genetic traits
that greatly increase the chance of developing coeliac disease have
been identified.
One is a defect in the genes coding for dipeptidyl peptidase IV (DPP
IV),
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.
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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
coeliacs.
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 gliadin.
| 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. |
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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.
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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 system.
Their presence in the intestines is recognized and detected by the
immune system.
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).
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 disease.
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 C,
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. |
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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 inflammation.
They also have a high bioavailability and seem to penetrate
connective tissue rich in glycosaminocans very well.
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.
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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.
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