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].