Because it is something of a mystery disease that can show itself as a bewildering array of other conditions, you could have Leaky Gut Syndrome and not even realize it.
The reason is that Leaky Gut Syndrome is one of the many concepts in medicine that cuts across the boundary lines of specific diseases.
It is a major example of an important medical phenomenon: distress in one organ causes disease in another. That is why it is vital to look beyond the symptoms and discover the root cause of illness.
Conditions that Can Signal Leaky Gut Syndrome
Do you have:
chronic fatigue syndrome or fibromyalgia?
Then you may also have Leaky Gut Syndrome, because it causes or contributes to these conditions.
That's why getting a better understanding of Leaky Gut Syndrome may help you find a more effective solution to your condition.
I am telling you about Leaky Gut Syndrome because it is a vitally important, but often undiagnosed, condition that is key to recovering from many illnesses and regaining robust good health.
An Integrated Approach to Leaky Gut Syndrome
I've been evaluating patients for Leaky Gut Syndrome for over twenty years, and have been writing about my integrated approach to this condition. My article "Leaky Gut Syndromes: Breaking the Vicious Cycle" is available online at the Foundation for Integrated Medicine. (1)
Through my clinical experience and further research I came to understand how gastrointestinal health in general, and Leaky Gut Syndrome in particular, contributes to many seemingly unrelated conditions.
To share my knowledge and help my colleagues learn more about this important topic I wrote a chapter titled "Integrative Approach to the Gastrointestinal System" for the textbook Integrative Medicine: Principles for Practice in 2004 and coauthored the book-length monograph Gastrointestinal Dysregulation: Connections to Chronic Disease, in 2008.
I have found Leaky Gut Syndrome especially relevant for many people with chronic fatigue syndrome.
Scientific Research Connects Leaky Gut with Chronic Fatigue and Depression
Recent research from Belgium confirms my observations about Leaky Gut Syndrome and chronic fatigue syndrome and suggests a treatment plan that can alleviate chronic fatigue and also major depression (2, 3, 4).
The Belgian researchers found that people in their study with either chronic fatigue syndrome or major depressive disorder showed laboratory evidence of Leaky Gut Syndrome, when compared to a healthy control group.
More importantly, they demonstrated that treatment with diet and specific nutrients not only reversed laboratory signs of the Leaky Gut Syndrome, but also improved symptoms of fatigue, malaise and depression (5).
I'll describe my approach to this condition, and what lessons we can take away from the research from Belgium.
But first, I want to give you some background on Leaky Gut Syndrome and explain why the concept is still so controversial.
What is Leaky Gut Syndrome?
Because it connects apparently unrelated disorders, Leaky Gut Syndrome is one of the most misunderstood concepts in medicine today.
To begin with, Leaky Gut is not a single disease or syndrome; it's a pathological condition that occurs as part of many different diseases and syndromes. The term refers to an abnormal increase in the permeability of the small intestine. Increased intestinal permeability is a component of many different disorders.
Leaky Gut Syndrome is associated with:
inflammatory and infectious bowel diseases (6-12),
several types of arthritis (13-18),
chronic liver disease (21),
pancreatic disease (22)
as well as numerous conditions triggered by food allergy, including eczema, hives, and irritable bowel syndrome (29-37).
Why is increased small intestinal permeability such a problem?
The small intestine is the largest organ in your body and two-thirds of your immune system lies within its walls. The small intestine continuously activates itself by sampling the molecules that pass through the intestinal lining.
Leaky Gut Syndrome is increased permeability of this lining, and it alters the molecules which prime your immune system for action by allowing molecules that don't ordinarily pass through the gut lining to get access to your immune system.
Sometimes, Leaky Gut Syndrome plays a primary role in the evolution of an illness.
Crohn's disease is a serious chronic intestinal disorder that effects almost a million people in the United States. People who develop Crohn's disease may have a genetically induced increase in intestinal permeability that creates the inflammation in the bowel. This predisposing leakiness can be found in close relatives of patients with Crohn's diseases, suggesting that it precedes the development of inflammation.
Leaky Gut Syndrome can occur as a result of another disease.
Celiac disease is an inherited intolerance to gluten, a group of proteins found in wheat, barley and rye. Celiac disease affects about one person in a hundred in North America and often goes undiagnosed, even when people have severe symptoms. The inflammation caused by active celiac disease causes the leaky gut, which in turn causes some of the complications associated with celiac disease.
Leaky Gut Syndrome can also be caused by the treatment for another disease.
In rheumatoid arthritis, for example, the drugs used to relieve pain and inflammation can damage the intestinal lining, leading to Leaky Gut Syndrome within two weeks. Leaky Gut Syndrome, in turn, is associated with aggravation of arthritis.
For most conditions, the precise role of Leaky Gut Syndrome remains unclear, but it seems to be part of a vicious cycle that makes the condition get worse over time. Allergic reactions to food, for example, cause a transient increase in intestinal permeability. If this happens frequently, it may increase the number or severity of food allergies.
In chronic fatigue syndrome and major depressive disorder, Leaky Gut Syndrome activates the intestinal immune system to produce chemicals called cytokines that spread inflammation through your body.
Inflammation is an important trigger for symptoms like fatigue, malaise, pain, and depression.
When should you suspect Leaky Gut Syndrome?
If you have:
pain in multiple joints,
a chronic skin condition,
chronic diarrhea or abdominal pain,
a feeling of being infected but your doctor can't find the infection,
or if you use aspirin or anti-inflammatory drugs on a regular basis, or if you're a heavy drinker of alcohol.
Recent research in animals has indicated that Leaky Gut Syndrome may also be associated with difficulty losing or gaining weight, but its association with obesity is still under investigation [32, 33].
How can the possibility of Leaky Gut Syndrome be evaluated?
There are only a few laboratories that test for Leaky Gut Syndrome and all require a doctor's order. Talk to your doctor about what test might be appropriate. High levels of antibodies to common food proteins or to normal intestinal bacteria may indicate increased intestinal permeability. Many research studies have used a challenge test involving a special solution consisting of two sugars, and seeing how much of each appears in urine. A blood test for celiac disease is essential.
Five Steps to Help Heal Leaky Gut Syndrome
Get rid of anything that might be causing or contributing to increased intestinal permeability:
Stop drinking alcohol for at least a month.
Stop using aspirin, ibuprofen, naproxen and other non-steroidal anti-inflammatory drugs (NSAIDS). I wrote about the side effects of these common pain relievers in a recent Huff Post article "Why Medication Can Be Dangerous to Your Health."
Have a stool test for intestinal parasites. There is extensive medical literature on intestinal parasites causing symptoms like fatigue, joint pain and skin disorders, without causing diarrhea. I discuss these in a chapter I wrote titled, "Intestinal Protozoan Infestation and Systemic Illness", for the Textbook of Natural Medicine, 3rd Edition, in 2005 .
Adopt an anti-inflammatory dietary pattern. I explain the benefits of eating to reduce inflammation, and provide a plan to achieve that, in my book, The Fat Resistance Diet. The principles are simple to understand: avoid foods with added sugar and refined starches, made from white flour. Decrease consumption of saturated fat and most vegetable oils, using extra virgin olive oil instead. Eat at least 9 servings of fruits and vegetables a day and at least 4 servings of fish per week.
There are dietary supplements that help the small intestine heal and restore its functional integrity. The most important of these are the amino acid L-glutamine and the amino sugar N-acetyl- glucosamine, which are readily available in health food stores.
These are but a few introductory steps toward an integrated approach to this condition. There is a vast amount of scientific literature on Leaky Gut Syndrome, a sample of which appear in the references below from journals such as The Lancet, The British Medical Journal and The Annals of Internal Medicine.
For a more information about my approach, see my article Leaky Gut Syndromes: Breaking the Vicious Cycle.
Now I'd like to hear from you...
Do you suffer from any of the symptoms associated with Leaky Gut Syndrome?
How has the conventional medicine system responded to your symptoms?
Have you tried lifestyle changes or dietary supplements, or do you plan to?
Please let me know your thoughts by posting a comment below.
Leo Galland, MD
Leo Galland, M.D. is an internist practicing in New York City and the Director of the Foundation for Integrated Medicine. Dr. Galland is the founder of Pill Advised, an online health application for learning about medications, supplements and food. Sign up for FREE to discover how your medications and vitamins interact. Watch his videos on YouTube and join the Pill Advised Facebook page.
1) Townsend Letter for Doctors, August/September 1995, p. 63. "Leaky Gut Syndromes: Breaking the Vicious Cycles." Galland L.
2) J Affect Disord. 2007 Apr;99(1-3):237-40."Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability." Maes M, Mihaylova I, Leunis JC.
3) Neuro Endocrinol Lett. 2008 Jun;29(3):313-9. "An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS." Maes M, Mihaylova I, Kubera M, Leunis JC.
4) Neuro Endocrinol Lett. 2008 Feb;29(1):117-24."The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression." Maes M, Kubera M, Leunis JC.
5) Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. "Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria." Maes M, Leunis JC.
6) Gastroenterology, 1989. 97(4): p. 927-31."Intestinal permeability in patients with Crohn's disease and their healthy relatives." Katz, K.D., et al.
7) Br Med J, 1982. 285(6334): p. 20-1. "Intestinal permeability in children with Crohn's disease and coeliac disease." Pearson, A.D., et al.
8) Dig Dis Sci, 1990. 35(5): p. 582-8. "Relationship between intestinal permeability to [51Cr]EDTA and inflammatory activity in asymptomatic patients with Crohn's disease." Pironi, L., et al.
9) Gut, 1994. 35(1): p. 68-72. "Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives." Munkholm, P., et al.
10) Ann Intern Med, 1986. 105(6): p. 883-5. "Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor." Hollander, D., et al.
11) Gut, 1992. 33(3): p. 320-3. "Intestinal permeability in patients with Crohn's disease and their first degree relatives." Teahon, K., et al.
12) Parasite. 2008 Sep;15(3):261-5 "Pathophysiology of enteric infections with Giardia duodenalius." Buret AG.
13) Clin Exp Rheumatol, 1990. 8(1): p. 75-83. "A short review of the relationship between intestinal permeability and inflammatory joint disease." Rooney, P.J., R.T. Jenkins, and W.W. Buchanan
14) Br J Rheumatol, 1987.26(2): p. 103-7. "Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral nonsteroidal anti-inflammatory drug therapy?" Jenkins, R.T., et al.
15) Clin Exp Rheumatol, 1990. 8(5): p. 523-4."Reflections on the link between intestinal permeability and inflammatory joint disease." Mielants, H.
16) Gut, 1991. 32(12): p. 1470-2. "Increased intestinal permeability in ankylosing spondylitis--primary lesion or drug effect?" [see comments]. Morris, A.J., et al.
17) Rheumatol, 1985. 12(2): p. 299-305. "Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis." Smith, M.D., R.A. Gibson, and P.M. Brooks, J.
18) Rheum Dis Clin North Am, 1991. 17(2): p. 363-71."Fasting, intestinal permeability, and rheumatoid arthritis." Skoldstam, L. and K.E. Magnusson
19) Q J Med, 1985. 56(221): p. 559-67. "Small intestinal permeability in dermatological disease." Hamilton, I., et al.
20) Gut. 1999 Jul;45(1):70-6 "Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea." Sharpstone D, Neild P, Crane R, Taylor C, Hodgson C, Sherwood R, Gazzard B, Bjarnason I.
21) Dig Liver Dis. 2010 Mar;42(3):200-4 "Intestinal permeability in patients with chronic liver diseases: Its relationship with the aetiology and the entity of liver damage." Cariello R, Federico A, Sapone A, Tuccillo C, Scialdone VR, Tiso A, Miranda A, Portincasa P, Carbonara V, Palasciano G, Martorelli L, Esposito P, Cartenì M, Del Vecchio Blanco C, Loguercio C.
22) J. Pediatr., 1992. 120: p. 696-701. "Correlation of intestinal lactulose permeability with exocrine pancreatic dysfunction." Mack, D.R., et al.
23) Lancet, 1981. 1(8233): p. 1285-6. "Intestinal permeability in patients with eczema and food allergy." Jackson, P.G., et al.
24) Digestion, 1989. 42(2): p. 104-9."Intestinal permeability to 51Cr-labelled ethylenediaminetetraacetate in food-intolerant subjects." Scadding, G., et al.
25) Lancet, 1981. i: p. 1285-1286. "Intestinal permeability in patients with eczema and food allergy." Jacobson, P., R. Baker, and M. Lessof
26) Clin Allergy, 1986. 16(6): p. 543-51. "Gastrointestinal permeability in children with cow's milk allergy: effect of milk challenge and sodium cromoglycate as assessed with polyethyleneglycols (PEG 400 and PEG 1000)." Falth-Magnusson, K., et al.
27) Clin Allergy, 1985. 15(6): p. 565-70. "Gastrointestinal permeability in atopic and non-atopic mothers, assessed with different-sized polyethyleneglycols (PEG 400 and PEG 1000)." Falth-Magnusson, K., et al.,
28) Clin Allergy, 1984. 14(3): p. 277-86. "Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized polyethyleneglycols (PEG 400 and PEG 1000)." Falth-Magnusson, K., et al.
29) J Allergy Clin Immunol, 1991. 88(5): p. 737-42. "Identical intestinal permeability changes in children with different clinical manifestations of cow's milk allergy." Jalonen, T.
30)J Pediatr Gastroenterol Nutr, 1990. 11(1): p. 72-7. "Modifications of intestinal permeability during food provocation procedures in pediatric irritable bowel syndrome." Barau, E. and C. Dupont
31) Ann Allergy, 1990. 64(4): p. 377-80."Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration." Paganelli, R., et al.
32) Am J Physiol Gastrointest Liver Physiol. 2007 Feb;292(2):G518-25 "Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palù G, Martines D.
33) Gut. 2009 Aug;58(8):1091-103 "Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability." Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM.
34) Textbook of Natural Medicine, 3rd Edition, Volume 2, J. Pizzorno and M. Murray, editors, Churchill Livingstone Elsevier, St. Louis, 2005, pp. 655-660. "Intestinal Protozoan Infestation and Systemic Illness", Galland L.
This information is provided for general educational purposes only and is not intended to constitute (i) medical advice or counseling, (ii) the practice of medicine or the provision of health care diagnosis or treatment, (iii) or the creation of a physician--patient relationship. If you have or suspect that you have a medical problem, contact your doctor promptly.
BY LEO GALLAND, M.D.
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.
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.
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 .
(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 . 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.
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 .
(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. 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.
(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. 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.
(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. 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.
(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.
(9) Gamma oryzanol, a complex mixture of ferulic acid esters of phytosterosl and other triterpene alcohols derived from rice bran, has been extensively researched in Japan for its healing effects in the treatment of gastric and duodenal ulceration, thought to be secondary to its potent anti-oxidant activity[152, 153].
Altered intestinal permeability is a key element in the pathogenesis of many different diseases. Hyperpermeability initiates a vicious cycle in which allergic sensitization, endotoxic immune activation, hepatic dysfunction, pancreatic insufficiency and malnutrition occur; each of these increases the leakiness of the small bowel. Effective treatment of the Leaky Gut Syndromes requires several components: avoidance of enterotoxic drugs and allergic foods, elimination of infection or bacterial overgrowth with antimicrobials and probiotics, and dietary supplementation with trophic nutrients. Direct measurement of intestinal permeability allows the clinician to plan appropriate strategies and to gauge the effectiveness of treatment, using objective parameters.
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