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 . 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.  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and irritable bowel syndrome [29-37], AIDS [38-40], chronic fatigue syndromes [Rigden, Cheney, Lapp, Galland, unpublished results], chronic hepatitis , chronic pancreatitis [4, 5], cystic fibrosis  and pancreatic carcinoma.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) , 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 . 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 .
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 . 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 . 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 . Chronic arthritis can be induced in rats by injection of cell wall fragments isolated from normal enteric anaerobes. 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.
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 . 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.
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 . These mechanisms have been most clearly demonstrated in ethanol-induced hepatic disease . Sudduth  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.
A Practical Approach
Suspect a pathological increase in gut permeability when evaluating any patient with the diseases listed in Table 1 or the symptoms listed in Table 2. Measure permeability directly using the lactulose/mannitol challenge test. Indirect measures of gut permeability include titres of IgG antibody directed against antigens found in common foods and normal gut bacteria. These tests may be useful but cannot substitute for the direct permeability assay, especially when one is following the response to treatment.
IF ALL COMPONENTS OF THE LACTULOSE/MANNITOL TEST ARE NORMAL, repeat the challenge after a test meal of the patient's common foods. If the test meal produces an increase in lactulose excretion (signifying hyperpermeability) or a decrease in mannitol excretion (signifying malabsorption), specific food intolerances are likely and further testing for food allergy is warranted. Once the patient has been maintained on a stable elimination diet for four weeks, repeat the lactulose/mannitol challenge after a test meal of foods permitted on the elimination diet. A normal result assures you that all major allergens have been identified. An abnormal result indicates that more detective work is needed.