IF THE INITIAL FASTING MANNITOL ABSORPTION IS LOW, suspect malabsorption. This result has the same significance as an abnormal D-xylose absorption test. Look for evidence of celiac disease, intestinal parasites, ileitis, small bowel bacterial overgrowth and other disorders classically associated with intestinal malabsorption and treat appropriately. After eight weeks of therapy, repeat the lactulose/mannitol challenge. An improvement in mannitol excretion indicates a desirable increase in intestinal absorptive capacity. The lactulose/mannitol assay has been proposed as a sensitive screen for celiac disease and a sensitive test for dietary compliance [46, 103-106]. For gluten-sensitive patients, abnormal test results demonstrate exposure to gluten, even when no intestinal symptoms are present. Monitoring dietary compliance to gluten avoidance by testing small bowel permeability is especially helpful in following those patients for whom gluten enteropathy does not produce diarrhea but instead causes failure to thrive, schizophrenia or inflammatory arthritis [107-115].
In the case of relatively mild celiac disease or inflammatory bowel disease, mannitol absorption may not be affected but lactulose absorption will be elevated. A recent study published in the Lancet found that the lactulose-mannitol ratio was an accurate predictor of relapse when measured in patients with Crohn's disease who were clinically in remission [116].
IF THE INITIAL FASTING LACTULOSE IS ELEVATED, OR IF THE INITIAL FASTING LACTULOSE/MANNITOL RATIO IS ELEVATED, consider the possibility of mild inflammatory bowel disease or gluten enteropathy. There are four other primary considerations:
(A) Exposures. Does the patient drink ethanol, take NSAIDs or any potentially cytotoxic drugs? If so, discontinue them and have the lactulose/mannitol challenge repeated three weeks later. If it has become normal, drug exposures were the likely cause of leaky gut. If it has not, bacterial sensitization may have occurred. This may be treated with a regimen of antimicrobials and probiotics. My preference is a combination of citrus seed extract, berberine and artemisinin (the active alkaloid in Artemisia annua), which exerts a broad spectrum of activity against Enterobacteriaceae, Bacteroides, protozoa and yeasts [117-120].
If the patient has no enterotoxic drug exposures, inquire into dietary habits. Recent fasting or crash dieting may increase permeability. Counsel the patient in consuming a nutritionally sound diet for three weeks and repeat the test.
Patients with chronic arthritis may have difficulty stopping NSAIDs. Alternative anti-inflammatory therapy should be instituted, including essential fatty acids, anti-oxidants or mucopolysaccharides[121-125]. Changing the NSAID used may also be helpful. NSAIDs like indomethacin, which undergo enteroheaptic recirculation, are more likely to damage the small intestine that NSAIDs that are not excreted in bile, like ibuprofen [126]. Nabumetone (relafen) is a pro-NSAID that is activated into a potent NSAID by colonic bacteria; the active metabolite is not excreted in bile. Nabumetone is the only presently available NSAID that does not increase small intestinal permeability.
(B) Infection. The possibilities include recent acute viral or bacterial enteritis, intestinal parasitism, HIV infection and candidosis. Stool testing is useful in identifying these. Repeat the permeability test six weeks after initiating appropriate therapy.
(C) Food allergy. Approach this probability as described in the section above on food allergy in patients with normal fasting test results. The difference lies in degree of damage; food intolerant patients with abnormal fasting permeability have more mucosal damage than patients with normal fasting permeability and will take longer to heal.
(D) Bacterial overgrowth resulting from hypochlorhydria, maldigestion, or stasis [41, 127, 128]. This is confirmed by an abnormal hydrogen breath test. Most of the damage resulting from bacterial overgrowth is caused by bacterial enzyme activity. Bacterial mucinase destroys the protective mucus coat; proteinases degrade pancreatic and brush border enzymes and attack structural proteins. Bacteria produce vitamin B12 analogues and uncouple the B12-intrinsic factor complex, reducing circulating B12 levels, even among individuals who are otherwise asymptomatic [129, 130]. In the absence of intestinal surgery, strictures or fistulae, bacterial overgrowth is most likely a sign of hypochlorhydria resulting from chronic gastritis due to Helicobacter pylori infection. Triple therapy with bismuth and antibiotics may be needed, but it is not presently known whether such treatment can reverse atrophic gastritis or whether natural, plant-derived antimicrobials can achieve the same results as metronidazole and ampicillin, the antibiotics of choice.
Bacterial overgrowth due to hypochlorhydria tends to be a chronic problem that recurs within days or weeks after antimicrobials are discontinued. Keith Eaton, a British allergist who has worked extensively with the gut fermentation syndrome, finds that administration of L-histidine, 500 mg bid, improves gastric acid production in allergic patients with hypochlorhydria, probably by increasing gastric histamine levels [personal communication]. Dietary supplementation with betaine hydrochloride is usually helpful but intermittent short courses of bismuth, citrus seed extract, artemisinin, colloidal silver and other natural antimicrobials are often needed. The first round of such treatment, while the patient is symptomatic, should last for at least twelve weeks, to allow complete healing to occur. Repeat the lactulose/mannitol assay at the end of twelve weeks, while the patient is taking the antimicrobials, to see if complete healing has been achieved. The most sensitive test for recurrence of bacterial overgrowth is not the lactulose/mannitol assay but the breath hydrogen analysis.
Atrophic Therapies
Many naturally occurring substances help repair the intestinal mucosal surface or support the liver when stressed by enteric toxins. Basic vitamin and mineral supplementation should include all the B vitamins, retinol, ascorbate, tocopherol, zinc, selenium, molybdenum, manganese, and magnesium. More specialized nutritional, glandular and herbal therapies are considered below. These should not be used as primary therapies. Avoidance of enterotoxic drugs, treatment of intestinal infection or dysbiosis, and an allergy elimination diet of high nutrient density that is appropriate for the individual patient are the primary treatment strategies for the Leaky Gut Syndromes. The recommendations that follow are to be used as adjuncts:
(1) Epidermal Growth Factor (EGF) is a polypeptide that stimulates growth and repair of epithelial tissue. It is widely distributed in the body, with high concentrations detectable in salivary and prostate glands and in the duodenum. Saliva can be a rich source of EGF, especially the saliva of certain non-poisonous snakes. The use of serpents in healing rituals may reflect the value of ophidian saliva in promoting the healing of wounds. Thorough mastication of food may nourish the gut by providing it with salivary EGF. Purified EGF has been shown to heal ulceration of the small intestine [131].
(2) Saccharomyces boulardii is a non-pathogenic yeast originally isolated from the surface of lichee nuts. It has been widely used in Europe to treat diarrhea. In France it is popularly called "Yeast against yeast" and is thought to help clear the skin in addition to the gut. Clinical trials have demonstrated the effectiveness for S. boulardii in the treatment or prevention of C. difficile diarrhea, antibiotic diarrhea and traveler's diarrhea[132, 133]. Experimental data suggest that the yeast owes its effect to stimulation of SIgA secretion[134]. SIgA is a key immunological component of gut barrier function.
Passive elevation of gut immunoglobulin levels can be produced by feeding whey protein concentrates that are rich in IgA and IgG. These have been shown to be effective in preventing infantile necrotizing enterocolitis[135].
(3) Lactobacillus caseii var GG is a strain of lactobacillus isolated and purified in Finland. Like S.boulardii, Lactobacillus GG has been shown effective in the prevention of traveller's diarrhea and of antibiotic diarrhea and in the treatment of colitis caused by C. difficile. Lactobacillus GG limits diarrhea caused by rotavirus infection in children and in so doing improves the hyperpermeability associated with rotavirus infection.[136-139] The mechanism of action is unclear. The ability of other Lactobacillus preparations to improve altered permeability has not been directly tested, but is suggested by the ability of live cultures of L. acidophilus to diminish radiation-induced diarrhea, a condition directly produced by the loss of mucosal integrity.
(4) Glutamine is an important substrate for the maintenance of intestinal metabolism, structure and function. Patients and experimental animals that are fasted or fed only by a parenteral route develop intestinal villous atrophy, depletion of SIgA, and translocation of bacteria from the gut lumen to the systemic circulation. Feeding glutamine reverses all these abnormalities. Patients with intestinal mucosal injury secondary to chemotherapy or radiation benefit from glutamine supplementation with less villous atrophy, increased mucosal healing and decreased passage of endotoxin through the gut wall[140-143].
(5) Glutathione (GSH) is an important component of the anti-oxidant defense against free radical-induced tissue damage. Dietary glutathione is not well absorbed, so that considerable quantities may be found throughout the gut lumen following supplementation[144]. Hepatic GSH is a key substrate for reducing toxic oxygen metabolites and oxidized xenobiotics in the liver. Depletion of hepatic glutathione is a common occurence in Leaky Gut Syndromes contributing to liver dysfunction and liver necrosis among alcoholics and immune impairment in patients with AIDS. The most effective way to raise hepatic glutathione is to administer its dietary precursors, cysteine or methionine. Anti-oxidant supplementation for Leaky Gut Syndromes should therefore include both GSH and N-acetyl cysteine. Because protozoa are more sensitive to oxidant stress than are humans and because most anti-parasitic drugs and herbs work by oxidative mechanisms, high dose anti-oxidant supplementation should be witheld during the treatment of protozoan infection, especially during treatment with Artemisia.
(6) Flavonoids are potent, phenolic anti-oxidants and enzyme inhibitors with varied effects depending on the tissues in which they act. Quercetin and related flavonoids inhibit the release of histamine and inflammatory mediators. Taken before eating, they may block allergic reactions which increase permeability. Catechins have been used in Europe to treat gastric ulcerations. The flavonoids in milk thistle (silymarin) and in dandelion root (taraxacum) protect the liver against reactive oxygen species[145].
(7) Essential fatty acids (EFAs) are the substrates for prostaglandin synthesis. Differential feeding of EFAs can profoundly affect prostanoid synthesis and the systemic response to endotoxin. In experimental animals, fish oil feeding ameliorates the intestinal mucosal injury produced by methotrexate and, additionally, blunts the systemic circulatory response to endotoxin[146]. The feeding of gamma-linolenic acid (GLA), promotes the synthesis of E-series prostaglandins, which decrease permeability. EFAs should be consumed in the most concentrated and physiologically active form to avoid exposure to large quantities of polyunsaturated fatty acids from dietary oils. Consumption of vegetable oils tends to increase the free radical content of bile and to exacerbate the effects of endotoxin[147].
(8) Fiber supplements have complex effects on gut permeability and bacterial composition. Low fibre diets increase permeability. Dietary supplementation with insoluble fibre, such as pure cellulose, decreases permeability. Dietary supplementation with highly soluble fibre sources, such as fruit pectin or guar gum, has a biphasic effect. At low levels they reverse the hyperpermeability of low residue diets, probably by a mechanical bulking effect which stimulates synthesis of mucosal growth factors. At high levels of supplementation, they produce hyperpermeability, probably by inducing synthesis of bacterial enzymes which degrade intestinal mucins[148-151]. For maximum benefit with regard to intestinal permeability, dietary fibre supplementation should therefore contain a predominance of hypoallergenic insoluble fibre.