The intestinal
lining has the paradoxical role of selectively letting into the body
those chemicals, which it needs, and keeping out what is toxic. The
permeability of this barrier is an especially important factor in
maintaining the integrity of these critical functions. The leaky gut
syndrome exists when some factor makes the spaces between the small
intestinal epithelial cells wider than normal, and allows the
transgression of macromolecules, bacteria and bacterial fragments,
and other toxic substances through these spaces and into the
internal milieu. This surprisingly common problem occurs in a wide
variety of clinical situations, and, as one would suspect, has
profound negative consequences on the body. The importance of this
increase in small intestinal permeability is not to be taken
lightly, as it is always associated with two very important and
potentially serious pathophysiological processes that pertain to
effects on liver detoxification and on the immune system.
The liver is the
major detoxifying organ of the human body. All products absorbed
across the intestinal barrier, must pass through the liver, before
entering the general circulation. There is a homeostatic balance
between the size of the toxic load presented to the liver, and the
liver’s capacity to metabolize this load. Unless the liver’s
detoxification system has sufficient reserve capacity to adjust to
an increased toxic load, serious consequences can, and often do,
result.
Liver
detoxification is a process that occurs in the Kupffer cells of the
liver, and involves two separate chemical phases, oxidation and
conjugation. The first phase of liver detoxification, which involves
the cytochrome p450 oxidative enzyme system, converts some of the
toxic load into substances that have free radical activity as well
as carcinogenic properties. As long as the second phase of liver
detoxification can quickly metabolize this load of free radicals and
carcinogens by their chemical conjugation with glycine, glutathione,
glucuronide, or sulfate, there is no problem. These inert conjugated
products are simply secreted into the bile, which then pass into the
stool, and are excreted from the body. However, when the reserve
capacity of this phase two system is exhausted, the liver can no
longer metabolize this production of free radicals and carcinogens
before they overflow and cause damage locally, as well as leak into
the general circulation, where they can create profound biochemical
damage in distant parts of the body.
The reserve
capacity and balance of these liver detoxification phases can be
revealed by challenging the system with small doses of aspirin,
acetaminophen, and caffeine, and measuring how the liver metabolizes
them (called a liver detoxification profile test). The specific
biochemical pathways involved in liver detoxification can be
isolated and quantitated, allowing for specific therapeutic
nutritional support that can improve the capacity of these processes
to handle increased toxic loads quickly and safely.
As mentioned
earlier in our discussion of dysbiosis, the gastrointestinal tract
is the largest immune organ in the human body. It is appropriately
strategically positioned at the interface of the external and
internal milieu, where it is able to defend the body against
invasion by substances foreign to it. In the presence of leaky gut
syndrome, wherein intestinal permeability is increased, there is a
transgression of macromolecules, translocation of bacteria and
bacterial fragments, and passage of many chemicals that normally
could not get across the gut lining, into the internal milieu. The
immune system responds to this invasion by producing specific
antibodies that are designed to neutralize these foreign substances.
This process can
result in four problems. First, the immune system’s nutrient
supplies and reserve function are taxed. Second, it sets the stage
for possible autoimmune complications. If one of the transgressing
macromolecules has the same antigenic configuration as some other
tissue within the body (i.e. joint, nerve, lung, skin, etc.), the
resulting antibody produced and directed against the original
macromolecule will not be able to distinguish the difference between
them, and will attack and destroy both. Third, when the total
antigenic load to the body is substantially increased for a
prolonged period, the development of a “hyperimmune state” can
follow. Fourth, the antigen antibody reaction within the gut wall
itself can create an inflammatory reaction that can further
aggravate the leak in the gut, thereby setting the stage for a
vicious cycle that is self-perpetuating.
Thus, it becomes
crystal clear that the presence of a leaky gut syndrome, with its
liver and immune ramifications, always creates a metabolic price for
the human body. This pathophysiological process is particularly
important in patients with clinical disease, but even in the absence
of clinical symptoms, it will tax “wellness reserves,” and can
eventually lead to serious clinical sequellae.
There are at least
four situations wherein the leaky gut syndrome is self-perpetuating.
First, in food allergy induced leaky gut syndrome, the offending
food stimulates an allergic reaction in the gut lining that induces
increased permeability. The increased permeability allows the
passage of additional materials across the intestinal lining that
further stimulate the immune system to form antigen- antibody
complexes that cause additional aggravation of the leak in the gut
lining. Unless the vicious cycle is interrupted by avoiding the
offending food or blocking the allergic reaction, the process will
self sustain, and continue to tax the hepatic, immune and
gastrointestinal system’s nutritional reserves and clinical
functions.
Second, in the
malabsorption malnutrition induced leaky gut syndrome, there is a
lack of nutritional supply to the small intestinal lining that
results in atrophic changes in the intestinal epithelium that
results in increased permeability. The increase in permeability
aggravates the malabsorption by the intestinal cells, and results in
worsening of the intestinal atrophy and of the leaky gut syndrome.
This cycle can be interrupted by providing proper nutritional
support to the small intestinal epithelial cells.
Third, dysbiosis
itself can aggravate the leaky gut syndrome. When there is
disordered gut ecology, there can be an associated translocation of
bacteria and bacterial fragments across the small intestinal lining
that can induce an antigen antibody reaction, which can further
aggravate intestinal permeability. Clearing the dysbiosis can break
the cycle by removing the bacteria that are translocating across the
gut lining and thereby stop the immune reaction.
Fourth, in the
leaky gut syndrome associated with unbalanced liver detoxification,
as previously explained, there is an overflow of free radicals into
the bile, forming “toxic bile.” This toxic bile is secreted into the
intestinal tract where it causes further direct injury to the small
intestinal epithelium and results in worsening of intestinal
permeability. In this situation, in order to break the vicious
cycle, it is important to control the underlying problem that has
caused the leaky gut syndrome in first place.
The widespread
frequency and critical importance of the leaky gut syndrome has been
largely underrated in clinical medical practice. It has been
reported in association with an enormous range of acute and chronic
diseases, as well as in asymptomatic persons (see chart). In one
study that tested for leaky gut syndrome in an intensive care unit,
all patients studied had the leaky gut syndrome, regardless of what
was wrong with them. Because of the incredibly high incidence of
chronic diseases today, and the high frequency of leaky gut syndrome
in chronic diseases, it seems reasonable to test for intestinal
permeability at least in these patients routinely. It could be
further argued that it is an appropriate general screening test in
everyone.
The diagnosis of
leaky gut syndrome depends upon how the small intestinal surface
epithelial cells respond to an oral challenge with two inert sugars,
mannitol and lactulose. This test is simple, sensitive, reliable,
inexpensive, and easy for the patient to complete. These non
metabolizable sugars are ingested, and urine is collected over the
ensuing six hours. Mannitol is a monosaccharide (a simple sugar like
glucose) that is actively transported across the small intestinal
epithelial surface into the internal milieu. Because it is non
metabolizable and is then excreted into the urine, the amount that
is present in the urine is a measure of the amount that was
transported into the body (a test measuring absorptive capacity, or
tendency to malabsorption).
Lactulose is a
disaccharide (a larger molecule like sucrose) that cannot pass
across the small intestinal epithelial cell membrane, and can only
get into the internal milieu by passing between the intestinal
epithelial cells. This does not happen normally except in very small
amounts. However, when the spaces between these epithelial cells are
abnormally wide, these large lactulose molecules can then more
easily enter into the internal milieu. Because lactulose, like
mannitol, is also non metabolizable, it is excreted into the urine
after passing into the body. The amount of lactulose that is
collected into the urine is a measure of the size of the leak in the
gut. Interpretation of this test depends upon the amounts of
mannitol and lactulose that is absorbed into the body, as well as
the ratio of lactulose: mannitol that has been excreted.
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