From the perspective of function, the contents of
the gut lumen lie outside the body and contain a toxic/antigenic load
from which the body needs to be protected. Protection is supplied by complex
mechanisms which support one another: intestinal secretions (primarily mucus and
secretory IgA), the mucosal epithelium, and intramural lymphocytes [1]. This
primary, intestinal barrier is supported by the liver, through which all
enterically-derived substances must pass before entering the arterial
circulation for transport to other tissues and organs. Kupffer cells in the
hepatic sinusoids remove absorbed macromolecules by phagocytosis. Hepatic
microsomal enzymes alter gut-derived chemical substrates by oxidation and by
conjugation to glycine and glutathione(GSH) for excretion into bile and for
circulation to the kidneys. The cost of detoxification is high; reactive
intermediates and free radicals are generated and anti-oxidants like GSH are
consumed [2, 3]. Any compromise of intestinal barrier function increases the
production of oxygen radicals and carcinogens by the liver's cytochrome P-450
mixed-function oxidase system. The excretion of oxidation by-products into bile
and the reflux of this "toxic" bile into the pancreatic ducts may be the major
cause of chronic pancreatic disease.[4, 5]
Compromised intestinal barrier function can also cause disease directly, by
immunological mechanisms.[6-9] Increased permeability stimulates classic
hypersensitivity responses to foods and to components of the normal gut flora;
bacterial endotoxins, cell wall polymers and dietary gluten may cause
"non-specific" activation of inflammatory pathways mediated by complement and
cytokines. [10] In experimental animals, chronic low-grade endotoxemia causes
the appearance of auto-immune disorders.[11-13]
Leaky Gut Syndromes are clinical disorders associated with increased
intestinal permeability. They include inflammatory and infectious bowel diseases
[14-19], chronic inflammatory arthritides [9, 20-24], cryptogenic skin
conditions like acne, psoriasis and dermatitis herpetiformis [25-28], many
diseases triggered by food allergy or specific food intolerance, including
eczema, urticaria, and irritable bowel syndrome [29-37], AIDS [38-40], chronic
fatigue syndromes [Rigden, Cheney, Lapp, Galland, unpublished results], chronic
hepatitis [41], chronic pancreatitis [4, 5], cystic fibrosis [42] and pancreatic
carcinoma. Hyperpermeability may play a primary etiologic role in the evolution
of each disease, or may be a secondary consequence of it which causes immune
activation, hepatic dysfunction, and pancreatic insufficiency, creating a
vicious cycle. Unless specifically investigated, the role of altered intestinal
permeability in patients with Leaky Gut Syndromes often goes unrecognized. The
availability of safe, non-invasive, and inexpensive methods for measuring small
intestinal permeability make it possible for clinicians to look for the presence
of altered intestinal permeability in their patients and to objectively assess
the efficacy of treatments. Monitoring the intestinal permeability of
chronically ill patients with Leaky Gut Syndromes can help improve clinical
outcomes.
TRIGGERS AND MEDIATORS OF THE LEAKY GUT
Leaky Gut Syndromes are usually provoked by exposure to substances which
damage the integrity of the intestinal mucosa, disrupting the desmosomes which
bind epithelial cells and increasing passive, para-cellular absorption.
The commonest causes of damage are infectious agents (viral, bacterial and
protozoan) [43-46], ethanol [47, 48], and non-steroidal anti-inflammatory drugs
[20, 49, 50]. Hypoxia of the bowel (occurring as a consequence of open-heart
surgery or of shock) [51, 52], elevated levels of reactive oxygen metabolites (biliary,
food-borne or produced by inflammatory cells) [53], and cytotoxic drugs [54-56]
also increase para-cellular permeability.
THE FOUR VICIOUS CYCLES
CYCLE ONE: ALLERGY
The relationship between food sensitivities and the leaky gut is complex and
circular. Children and adults with eczema, urticaria or asthma triggered by
atopic food allergy have baseline permeability measurements that are higher than
control levels [57-59]. Following exposure to allergenic foods, permeability
sharply increases. Most of this increase can be averted by pre-treatment with
sodium cromoglycate [32, 34, 57-59], indicating that release from mast cells of
atopic mediators like histamine and serotonin is responsible for the increase in
permeability. It appears that an increase in intestinal permeability is
important in the pathogenesis of food allergy and is also a result of food
allergy.
Claude Andre, the leading French research worker in this area, has proposed
that measurement of gut permeability is a sensitive and practical screening test
for the presence of food allergy and for following response to treatment [57].
In Andre's protocol, patients with suspected food allergy ingest 5 grams each of
the innocuous sugars lactulose and mannitol. These sugars are not metabolized by
humans and the amount absorbed is fully excreted in the urine within six hours.
Mannitol, a monosaccharide, is passively transported through intestinal
epithelial cells; mean absorption is 14% of the administered dose (range 5-25%).
In contrast, the intestinal tract is impermeable to lactulose, a disaccharide;
less than 1% of the administered dose is normally absorbed. The differential
excretion of lactulose and mannitol in urine is then measured. The normal ratio
of lactulose/mannitol recovered in urine is less than 0.03. A higher ratio
signifies excessive lactulose absorption caused by disruption of the desmosomes
which seal the intercellular tight junctions. The lactulose/mannitol challenge
test is performed fasting and again after ingestion of a test meal. At the
Hospital St. Vincent de Paul in Paris, permeability testing has been effectively
used with allergic infants to determine which dietary modifications their
mothers needed to make while breast feeding and which of the "hypoallergenic"
infant formulas they needed to avoid in order to relieve their symptoms [60].
CYCLE TWO: MALNUTRITION.
Disruption of desmosomes increases absorption of macromolecules. If the
epithelial cells themselves are damaged, a decrease in trans-cellular
absorption may accompany the increased para-cellular absorption. Because
nutrients are ordinarily absorbed by the trans-cellular route,
malnutrition may occur, aggravating strucutural and functional disturbances
[61]. Under normal conditions, intestinal epithelium has the fastest rate of
mitosis of any tissue in the body; old cells slough and a new epithelium is
generated every three to six days [62, 63]. The metabolic demands of this
normally rapid cell turnover must be met if healing of damaged epithelium is to
occur. When they are not met, hyperpermeability exacerbates [64, 65].
Correction of nutritional deficiency with a nutrient-dense diet and
appropriate supplementation is essential for the proper care of patients with
Leaky Gut Syndromes. Specific recommendations are made in the last section of
this review. Because of the association between hyperpermeability and pancreatic
dysfunction, pancreatic enzymes may also be required.
CYCLE THREE: BACTERIAL DYSBIOSIS
Dysbiosis is a state in which disease or dysfunction is induced by organisms
of low intrinsic virulence that alter the metabolic or immunologic responses of
their host. This condition has been the subject of a recent review article [66].
Immune sensitization to the normal gut flora is an important form of dysbiosis
that has been implicated in the pathogenesis of Crohn's disease and ankylosing
spondylitis[67-81]. Recent research findings suggest that bacterial
sensitization is an early complication of altered permeability and exacerbates
hyperpermeability by inducing an inflammatory enteropathy [82, 83]. This has
been most studied in the response to NSAIDs. Single doses of aspirin or of
indomethacin increase para-cellular permeability, in part by inhibiting
the synthesis of protective prostaglandins [20, 49, 50, 84, 85].
Hyperpermeability is partially prevented by pre-treatment with the
prostaglandin-E analogue, misoprosterol. Chronic exposure to NSAIDs produces a
chronic state of hyper-permeability associated with inflammation, which can not
be reversed by misoprosterol but which is both prevented and reversed by the
administration of the antibiotic, metronidazole [83, 86]. The effectiveness of
metronidazole in preventing NSAID-induced hyperpermeability probably reflects
the importance of bacterial toxins in maintaining this vicious cycle. A single
dose of bacterial endotoxin, administered by injection, increases the gut
permeability of healthy humans [87]. Chronic arthritis can be induced in rats by
injection of cell wall fragments isolated from normal enteric anaerobes[88].
Patients with rheumatoid arthritis receiving NSAIDs have increased antibody
levels to Clostridium perfringens and to its alpha toxin,
apparently as a secondary response to NSAID therap[89].
There is ample documentation for a therapeutic role of metronidazole and
other antibiotics in Crohn's disease and rheumatoid arthritis[90-98]. The
mechanism underlying the response has been in dispute. In the case of
tetracyclines, one group has asserted that mycoplasma in the joints cause
rheumatoid arthritis, others have countered this argument by demonstrating that
minocycline is directly immunosuppressive in vitro [99]. Because all
patients with arthritis have used NSAIDs, and because NSAID enteropathy is
associated with bacterial senisitization, it is possible that the the
antibiotic-responsiveness of some patients with inflammatory diseases is a
secondary effect of NSAID-induced bacterial sensitization which then exacerbates
the Leaky Gut Syndrome. Altering gut flora through the use of antibiotics,
synthetic and natural, probiotics, and diet is a third strategy for breaking the
vicious cycle in Leaky Gut Syndromes. With regard to diet, patients whose
disease responds to vegetarian diets are those in whom the diet alters gut
ecology; if vegetarian diets does not alter gut ecology, the arthritis is not
improved[100].
CYCLE FOUR; HEPATIC STRESS
The liver of Leaky Gut patients works overtime to remove macromolecules and
oxidize enteric toxins. Cytochrome P-450 mixed-function oxidase activity is
induced and hepatic synthesis of free radicals increases. The results include
damage to hepatocytes and the excretion of reactive by-products into bile,
producing a toxic bile capable of damaging bile ducts and refluxing into the
pancreas [4, 5]. In attempting to eliminate toxic oxidation products, the liver
depletes its reserves of sulfur-containing amino acids [101]. These mechanisms
have been most clearly demonstrated in ethanol-induced hepatic disease [47].
Sudduth [102] proposes that the initial insult is the ethanol-induced increase
in gut permeability which creates hepatic endotoxemia. Endotoxemia can further
increase permeability, alter hepatic metabolism, and stimulate hepatic synthesis
of reactive species which are excreted in bile. This toxic bile, rich in free
radicals, further damages the small-bowel mucosa, exacerbating hyperpermeability.
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