more things to consider---leaky gut

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Leaky Gut Syndromes: Breaking the Vicious Cycle

© Leo Galland M.D., F.A.C.N.

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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. de

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.

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.

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.

( 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.

© 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. 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.

(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].

Summary

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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Table 1

Diseases Associated with Increased Intestinal Permeability

Inflammatory bowel disease

Infectious enterocolitis

Spondyloarthropathies

Acne

Eczema

Psoriasis

Urticaria

HIV infection

Cystic fibrosis

Pancreatic insufficiency

AIDS, HIV infection

Hepatic dysfunction

Irritable bowel syndrome with food intolerance

CFIDS

Chronic arthritis/pain treated with NSAIDs

Alcoholism

Neoplasia treated with cytotoxic drugs

Celiac disease

Dermatitis herpetiformis

Autism

Childhood hyperactivity

Environmental illness

Multiple food and chemical sensitivities

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Table 2

Symptoms Associated with Increased Intestinal Permeability

Fatigue and malaise

Arthralgias

Myalgias

Fevers of unknown origin

Food intolerances

Abdominal pain

Abdominal distension

Diarrhea

Skin rashes

Toxic feelings

Cognitive and memory deficits

Shortness of breath

Poor exercise tolerance