Introduction

Recognition that intestinal flora have a major impact on human health first developed with the birth of microbiology in the late nineteenth century. It is generally accepted that our relationship with indigenous gut flora is “Eu-symbiotic,” meaning a state of living together that is beneficial. Metchinkoff popularized the idea of “Dys-symbiosis, or Dysbiosis,” a state of living with intestinal flora thathas harmful effects. He postulated that toxic amines produced by bacterial putrefaction of food were the cause of degenerative diseases, and that ingestion of fermented foods containing Lactobacilli could prolong life by decreasing gut putrefaction(1). Although Metchnikoff’s ideas have been largely ignored in the United States, they have influenced four generations of European physicians. The notion that dysbiotic relationships with gut microflora may influence the development of inflammatory diseases and cancer has received considerable experimental support over the past two decades, but the mechanisms involved are far more diverse than Metchnikoff imagined.

The stool of healthy human beings consuming a Western diet contains 24 x 105¡ bacteria/gram. Twenty species comprise 75% of the total number of colonies; non-spore forming anaerobes predominate over aerobes by a ratio of 5000:1(2). Organisms cultured from mucosal surfaces are significantly different from those found in stool and vary among different parts of the gastrointestinal tract. The bacterial concentration in the stomach and small intestine is several orders of magnitude less than in the colon. The major mucosal organisms there are coccobacilli(1) and streptococci(3). The predominant organisms cultured from gastric and duodenal aspirates, are yeasts and Lactobacilli(2), living in the lumen. In the colon, the presence of these organisms is overshadowed by spirochetes and fusfform bacteria on the mucosal surface and anaerobic rods like Eubacterium, Bacteroides and Bifidobacterium in the lumen. Benefits and adverse effects of the normal gut microflora are listed in Table 1 & 2 and have been described elsewhere(4).

Materials and Methods

Clinical Assessment

lntestinal dysbiosis should be considered as a mechanism promoting disease in all patients with chronic gastrointestinal, inflammatory or autoimmune disorders, food allergy and intolerance, breast and colon cancer, and unexplained fatigue, malnutrition or neuropsychiatric symptoms.

The most useful test for this condition is a Comprehensive Digestive Stool
Analysis (CDSA) which includes:

a) biochemical measurements of digestion/maldigestion (fecal chymotrypsin,
fecal triglycerides, meat and vegetable fibers, pH), intestinal absorption/
malabsorption (long chain fatty acids, fecal cholesterol, and total short
chain fatty acids)

b) metabolic markers of intestinal metabolism

c) identification of the bacterial microflora, including friendly, pathogenic
and imbalanced flora

d) detection of abnormal gut mycology

The authors have developed a Gut Dysbiosis Score (Table 3) to make the
CDSA more useful.

Interpretation of Gut Dysbiosis Score (Refers to Table 3)

Excess meat or vegetable fibers or triglycerides (one point each) suggest mal-
digestion. This is a common effect of bacterial overgrowth but can also con-
tribute to its cause.

Excess cholesterol or fatty acids (one point each) is indicative of malabsorp-
tion; bacterial overgrowth produces this by interfering with micelle forma-
tion.

Low concentrations of butyrate or SCFA (two points each) indicate insuffi-
cient anaerobic fermentation of soluble fiber. This may result from a low fiber
diet deficiency of Bifidobacteria.

High concentrations of butyrate or SCFA (two points each) is indicative of
increased anaerobic fermentation.

Alkaline stool pH (two points) often accompanies a low butyrate. When it is
associated with a normal butyrate it signifies increased ammonia production,
reflecting a diet high in meat or excessive urease activity of intestinal bacte-
ria. Bacterial cultures can provide more direct evidence of dysbiosis. The
most common finding is:

A lack of Lactobacillus or of E.Coli on stool culture (3 points each) High
levels of uncommon or atypical Enterobacteriaceae or of Klebsiella, Proteus
or Pseudomonas, may reflect small bowel overgrowth of these organisms
(score 1 point for each.)

Total Score-7 points or more is always associated with clinical dysbiosis;
5-6 is probable dysbiosis; 3-4 is borderline. There are rare cases in which a
score less than 3 occurs in a dysbiotic stool. These cases are usually under
treatment at the time the stool is obtained. In severe cases abnormal blood
tests may be found. There may be erythrocyte macrocytosis, low circulating
vitamin B12 or hypoalbuminemia. Urinary excretion of essential amino acids
may also be low, signifying impaired assimilation of dietary protein.

Discussion

Based on available research and clinical data, we now believe that
there are four patterns of intestinal dysbiosis: putrefaction, fermenta-
tion, deficiency, and sensitization.

Putrefaction

This is the classic Western degenerative disease pattern advanced by
Metchnikoff. Putrefaction dysbiosis results from diets high in fat and
animal flesh and low in insoluble fiber. This type of diet produces an
increased concentration of Bacteroides sp. and a decreased concentra-
tion of Bifidobacteria sp. in stool. It increases bile flow and induces
bacterial urease activity(1). The alterations in bacterial population
dynamics which result from this diet are not measured directly by the
[Comprehensive Digestive Stool Analysis (CDSA)]. The changes occur
primarily among anaerobes, but the effects are measured in an in-
crease in stool pH (partly caused by elevated ammonia production)
and in bile or urobilinogen and possibly by a decrease in short chain
fatty acids, especially in butyrate. Epidemiologic and experimental
data implicate this type of dysbiosis in the pathogenesis of colon can-
cer and breast cancer(6). A putrefaction dysbiosis is accompanied by
an increase in fecal concentrations of various bacterial enzymes
which metabolize bile acids to tumor promotors and deconjugate ex-
creted estrogens, raising the plasma estrogen level(6). Putrefaction
dysbiosis is corrected by decreasing dietary fat and flesh, increasing
fiber consumption and feeding Bifidobacteria and Lactobacillus prep-
arations.

Most adverse effects of the indigenous gut flora are caused by the
intense metabolic activity of luminal organisms. The following are
associated with Putrefaction dysbiosis:

1. The enzyme urease, found in Bacteroides, Proteus and Klebsiella
species, and induced in those organisms by a diet high in meat, hy-
drolyzes urea to ammonia, raising stool pH. A relatively high stool
pH is associated with a higher prevalence of colon cancer(7).

2. Bacterial decarboxylation of amino acids yields vasoactive and
neurotoxic amines, including histamine, octopamine, tyramine and
tryptamine; these are absorbed through the portal circulation and
deaminated in the liver. In severe cirrhosis they reach the systemic
circulation and contribute to the encephalopathy and hypotension of
hepatic failure(1).

3. Bacterial tryptophanase degrades tryptophan to carcinogenic phe-
nols, and, like urease, is induced by a high meat diet(8).

4. Bacterial enzymes like beta-glucuronidase hydrolyze conjugated es-
trogens and bile acids. Hepatic conjugation and biliary excretion is an
important mechanism for regulating estrogen levels in the body. Bacte-
rial deconjugation increases the enterohepatic recirculation of estrogen.
A Western diet increases the level of deconjugating enzymes in stool,
lowers estrogen levels in stool and raises estrogen levels in blood and
urine, possibly contributing to the development of breast cancer(6).

5. Beta-glucuronidase and other hydrolytic bacterial enzymes also
deconjugate bile acids.

Deconjugated bile acids are toxic to the colonic epithelium and
cause diarrhea. They or their metabolites appear to be carcinogenic
and are thought to contribute to the development of colon cancer(6,9)
and to ulcerative colitis(10). Gut bacteria also reduce primary bile
acids like cholate and chenodeoxycholate to secondary bile acids like
deoxycholate (DCA) and lithocholate. The secondary bile acids are ab-
sorbed less efficiently than primary bile acids and are more likely to
contribute to colon carcinogenesis. The prevalence of colon cancer is
proportional to stool concentration of DCA.

Not all bacterial enzyme activity is harmful to the host. Fermenta-
tion of soluble flber by Bifidobacteria sp. yields SCFA. Recent interest
has focused on the beneficial role of short-chain fatty acids like buty-
rate in nourishing healthy colonic mucosal cells. Butyrate has been
shown to induce differentiation of neoplastic cells(l1), decreased ab-
sorption of ammonia from the intestine(1), decreased inflammation in
ulcerative colitis(12) and, following absorption, decreased cholesterol
synthesis in the liver(7). Butyrate lowers the stool pH. A relatively
low stool pH is associated with protection against colon cancer(S). The
principal source of colonic butyrate is fermentation of soluble fiber by
colonic anaerobes. Thus, putrefaction dysbiosis results from the inter-
play of bacteria and diet in their effects on health and disease.

Fermentation

This is a condition of carbohydrate intolerance induced by overgrowth
of endogenous bacteria in the stomach, small intestine and cecum.
The causes and effects of small bowel bacterial overgrowth have been
well characterized.

Bacterial overgrowth is promoted by gastric hypochlorhydria, by
stasis due to abnormal motility, strictures, fistulae and surgical blind
loops, by immune deficiency or by malnutrition( 13). Small bowel
parasitosis may also predispose to bacterial overgrowth(4). Some of
the damage resulting from small bowel bacterial overgrowth is pro-
duced by the action of bacterial proteases which degrade pancreatic
and intestinal brush border enzymes causing pancreatic insufficiency,
mucosal damage and malabsorption. In more severe cases the intesti-
nal villi are blunted and broadened and mononuclear cells infiltrate
the lamina propria. Increased fecal nitrogen leads to hypoalbumine-
mia. Bacterial consumption of cobalamin lowers blood levels of vita-
min B12. Bile salt dehydroxylation impairs micelle formation(10).
Endotoxemia resulting from bacterial overgrowth contributes to hep-
atic damage in experimental animals(14).

Gastric bacterial overgrowth increases the risk of systemic infec-
tion. Gastric bacteria convert dietary nitrates to nitrites and nitro-
samines; hence, the increased risk of gastric cancer in individuals
with hypochlorhydria( 15) . Some bacterial infections of the small
bowel increase passive intestinal permeability(16).

Carbohydrate intolerance may be the only symptom of bacterial
overgrowth, making it indistinguishable from intestinal candidosis;
in either case dietary sugars can be fermented to produce endogenous
ethanol(17,18). Chronic exposure of the small bowel to ethanol may
itself impair intestinal permeability(19). Another product of bacterial
fermentation of sugar is D-lactic acid. Although D-lactic acidosis is
usually a complication of short-bowel syndrome or of jejuno-ileal by-
pass surgery (colonic bacteria being the source of acidosis), elevated
levels of D-lactate were found in blood samples of 1.12% of randomly
selected hospitalized patients with no history of gastro-intestinal sur-
gery or disease(20). Small bowel fermentation is a likely cause of
D-lactic acidosis in these patients. British physicians working with
the gut-fermentation syndrome as described by Hunisett et al(18)
have tentatively concluded, based on treatment results, that the ma-
jority of cases are due to yeast overgrowth and about 20% are bacte-
rial in origin. The symptoms include abdominal distension, carbohy-
drate intolerance, fatigue and impaired cognitive function.

Deficiency

Exposure to antibiotics or a diet depleted of soluble fiber may create
an absolute deficiency of normal fecal flora, including Bifidobacteria,
Lactobacillus and E. Coli. Direct evidence of this condition is seen on
stool culture when concentrations of Lactobacillus or E. Coli are re-
duced. Low fecal short chain fatty acids provide presumptive evi-
dence. This condition has been described in patients with irritable
bowel syndrome and food intolerance (see below). Deficiency and pu-
trefaction dysbiosis are complementary conditions which often occur
together and have the same treatment.

Sensitization

Aggravation of abnormal immune responses to components of the
normal indigenous intestinal microflora may contribute to the patho-
genesis of inflammatory bowel disease, spondyloarthropathies, other
connective tissue disease and skin disorders like psoriasis or acne.
The responsible bacterial components include endotoxins, which can
activate the alternative complement pathway and antigens, some of
which may cross react with mammalian antigens. Treatment studies
in ankylosing spondylitis and inflammatory bowel disease suggest
that sensitization may complement fermentation excess and that sim-
ilar treatments may benefit both conditions.

Clinical research has implicated bacterial dysbiosis in a number of
diseases of inflammation within the bowel or involving skin or con-
nective tissue. The published associations are reviewed below:

Atopic Eczema

Ionescu and his colleagues have studied fecal and duodenal flora in
patients with atopic eczema and found evidence of small bowel dys-
biosis and subtle malabsorption phenomena in the majority(21,22).
Treatment with antibiotics or with a natural antibiotic derived from
grapefruit seeds, produced major improvement in the gastro-intesti-
nal symptoms of eczema patients and moderate improvement in se-
verity of eczema(23). One advantage in the use of grapefruit seed ex-
tract over conventional antibiotics lies in its anti-fungal activity. This
agent adds a second therapeutic dimension and eliminates the possi-
bility of secondary candidosis. The minimum effective dose of grape-
fruit seed extract for bacterial dysbiosis is 600 mg a day.

Irritable Bowel Syndrome

Hunter and his colleagues have studied patients with the irritable
bowel syndrome in whom diarrhea, cramps and specific food intol-
erances are major symptoms(24). They have found abnormal fecal
flora to be a consistent finding, with a decrease in the ratio of anaer-
obes to aerobes, apparently due to a deficiency of anaerobic flora
(25,26). Previous exposure to antibiotics, metronidazole in particular,
was associated with the development of this disorder(27).

Inflammatory Bowel Disease

Two decades ago, exaggerated immunologic responses to components
of the normal fecal flora were proposed as possible mechanisms in the
etiology of inflammatory bowel disease(28). Little progress has been
made in confirming or disproving this theory, although bacterial
overgrowth of the jejunum has been found in 30% of patients hospi-
talized for Crohn’s disease, in which it contributes to diarrhea and
malabsorption(29).

The demonstration of increased intestinal permeability in patients
with active Crohn’s disease and in healthy first degree relatives sug-
gests the existence of a pre-existing abnormality that allows an exag-
gerated immune response to normal gut contents to occur(30).

It is interesting to note that elemental diets can induce remission
in Crohn’s disease as effectively as prednisone. The chief bacteriologic
effect of elemental diets is to lower the concentration of Lactobacilli
in stool drastically without altering levels of other bacteria(31). It is
well-known that many patients with Crohn’s disease can be brought
into remission with metronidazole, tetracycline and other antibiotics.
In ulcerative colitis, colonic damage from toxic metabolites of bile
acids has been suggested(9). Alpha-tocopherylquinone, a vitamin E
derivative that antagonizes vitamin K dependent bacterial enzymes
reversed ulcerative colitis dramatically in one subject(32).

Drawing on much broader experience with inflammatory bowel dis-
ease, Gottschall has proposed that gut dysbiosis plays the major
etiologic role, with small and large bowel fermentation being a key
component. She has used a specific carbohydrate diet restricted in
disaccharide sugars and devoid of cereal grains to alter gut flora(33).
Some will undoubtedly argue that Gottschall’s success is due to food
allergen elimination, but the time course of patients’ responses is
more consistent with the authors’ contention that a gradual alter-
ation of gut flora content is the mechanism.

McCann has pioneered a dramatic, experimental treatment for in-
flammatory bowel disease which has induced a rapid remission in 16
out of 20 patients with ulcerative colitis. A two-day course of multi-
ple-broad spectrum antibiotics to “decontaminate” the gut is followed
by administration of defined strains of E. coli, and Lactobacillus ac-
idophillus to produce a “reflorastation” of the colon(34).

Arthritis and Ankylosing Spondylitis

Immunologic responses to gut flora have been advanced by several
authors as important factors in the pathogenesis of inflammatory
joint diseases. It is well-known that reactive arthritis can be acti-
vated by intestinal infections with Yersinia, Salmonella and other
enterobacteria(35). In some cases bacterial antigens have been found
in synovial cells(36,37) and may enter the circulation because of the
increased intestinal permeability associated with the intestinal infec-
tion(l5). Increased intestinal permeability and immune responses to
bacterial debris may cause other types of inflammatory joint disease
as well. but there is little evidence of the frequency with which this
occurs(38-40). Several groups have proposed a specific mechanism by
which Klebsiella pneumoniae may provoke ankylosing spondylitis
(41-43). HLA-B27 is expressed on the lymphocytes and synovial cells
of 97% of patients with ankylosing spondylitis. This antigen cross-
reacts with antigens found on Klebsiella pneumoniae and possibly
other enterobacteria. Patients with ankylosing spondylitis have
higher levels of Klebsiella pneumoniae in their stools than controls
and have higher levels of anti-Klebsiella IgA in plasma than do con-
trols. Patients who are HLA-B27 positive but who do not have an-
kylosing spondylitis do not have Klebsiella in their stools or Kleb-
siella antibodies in their plasma.

Molecular mimicry appears to be the mechanism by which intesti-
nal enterobacteria cause ankylosing spondylitis in genetically suscep-
tible individuals.

Ebringer has successfully treated ankylosing spondylitis with a low
starch diet similar to Gottschall’s regimen for bowel disease. This diet
lowers the concentration of Klebsiella in stool and decreases the titre
of anti-Klebsiella IgA. He has also proposed that rheumatoid ar-
thritis, which is associated with HLA-DR4, involves a similar molecu-
lar mimicry between HLA-DR4 and Proteus mirabilis, as cross-reac-
tive Proteus antibodies are higher in patients with rheumatoid
arthritis than in controls. Abnormal immune responses to compo-
nents of the normal gut flora represents a form of dysbiosis which
suggests novel treatment for inflammatory diseases.

Treatment Approaches

Diet-Putrefaction dysbiosis is usually managed with a diet high in
both soluble and insoluble fiber and low in saturated fat and animal
protein. Dairy products have a variable effect. Fermented dairy foods
like fresh yogurt are occasionally helpful. These dietary changes
work to lower the concentrations of Bacteroides and increase concen-
trations of lactic acid-producing bacteria (Bifidobacteria, Lactobacil-
lus and lactic acid streptococci) in the colon(44,45). Supplementing
the diet with defined sources of fiber can have variable effects on colo-
nic dysbiosis. Insoluble fiber decreases bacterial concentration and
microbial enzyme activity(46,47). Soluble fiber, on the other hand,
tends to elevate bacterial concentration and enzyme activity at the
same time that it raises the levels of beneficial short chain fatty
acids. This disparity may explain the superior effect of insoluble fiber
in the prevention of colon cancer(48-51). Fructose-containing oligosac-
charides, found in vegetables like onion and asparagus, have been
developed as a food supplement for raising stool levels of Bifidobac-
teria and lower stool pH.(52)

In fermentation dysbiosis, by contrast, starch and soluble fiber may
exacerbate the abnormal gut ecology(3,33). When the upper small
bowel is involved, simple sugars are also contra-indicated. A diet free
of cereal grains and added sugar is generally the most helpful. Fruit,
fat and starchy vegetables are tolerated to variable degree in differ-
ent cases. Oligosaccharides found in some vegetables, carrots in par-
ticular, inhibit the binding of enterobacteria to the intestinal mucosa.
Carrot juice and concentrated carrot oligosaccharides have been used
in Europe for bacterial diarrhea for almost a century(53).
BiotherapiesÑAdministration of bacteria indigenous to the healthy
human colon can reverse relapsing Clostridium difficile infection(54).
Lactobacillus administration has long been used in an attempt to im-
prove gut microbial ecology. Regular ingestion of acidophilus milk
lowers stool concentrations of urease-positive organisms and of bacte-
rial enzymes which may contribute to carcinogenesis(55). Fermented
dairy products and Iyophilized Lactobacillus preparations have been
shown to be useful in treating and preventing salmonellosis, shig-
ellosis, antibiotic-induced diarrhea and in inhibiting tumor growth
(56). Problems with Lactobacilli include the failure of organisms to
adhere to the intestinal mucosa or to survive damage from gastric
acid and bile. The acidophilus sweepstakes has led to the search for
newer and better strains for medical uses(57,58).

Bifidobacteria are the predominant lactic acid bacteria of the colon
with a concentration that is 1000 times higher than Lactobacilli. Ad-
ministration of Bifidobacterium brevum to humans and animals re-
duces fecal concentrations of Clostridia and Enterobacter species, am-
monia, and toxigenic bacterial enzymes including beta-glucuronidase
and tryptophanase; urinary indican is also lowered(59). Administra-
tion of defined strains of E. coli and Enterococcus for the purpose of
altering gut flora has been popular in Europe, but documentation of
the health effects is scanty.

Bacillus laterosporus, a novel organism classified as non patho-
genic to humans(60), produces unique metabolites with antibiotic,
anti-tumor and immune modulating activity(61-63). This organism
has been available as a food supplement in the United States for
about 5 years. We have found it to be an effective adjunctive treat-
ment for control of symptoms associated with small bowel dysbiosis in
a number of patients.

Of equal interest, and more thoroughly researched, a yeast, Sac-
charomyces boulardii, has been used in Europe for control of non-
specific diarrhea for several decades. Originally isolated from Indo-
chinese leechee nuts, S. boulardii is grown and packaged as a medica-
tion in France, where it is popularly called, “Yeast Against Yeast”.
Controlled studies have demonstrated its effectiveness in preventing
antibiotic associated diarrhea and Clostridium difficile colitis(64,65).
S. boulardii has also been shown to stimulate production of secretory
IgA in rats(66). Immune enhancing therapy of this type may be con-
traindicated in patients suffering from reactive arthritis and other
diseases in which an exaggerated intestinal immune response is
found.

Antimicrobials

Antibiotic drugs may either cause or help control dysbiosis, depend-
ing upon the drug and the nature of the disorder. Where contamina-
tion of the small bowel by anaerobes is the problem, metronidazole or
tetracyclines may be beneficial. When enterobacterial overgrowth
predominates, ciprofloxacin is usually the drug of choice because it
tends to spare anaerobes. Herbal antibiotics may be preferred because
of their greater margin of safety and the need for prolonged anti-
microbial therapy in bacterial overgrowth syndromes. Citrus seed ex-
tract may be a desirable first line of treatment because of its broad
spectrum of antibacterial, anti-fungal and anti-protozoan effects(23).
The usual dose required is 600 to 1600 mg/day. Animal studies have
shown no toxicity except for intestinal irritation producing diarrhea
at very high doses. The mechanism of action is not known; there is no
evidence of systemic absorption. Bayberry leaf, containing the alka-
loid berberine, appears to be cidal for enterobacteria, yeasts and
amoebae. The control of dysbiotic symptoms usually requires several
grams a day. Artemesia annua has primarily been used for treatment
of protozoan infection(67). The most active ingredient, artemisinin, is
a potent pro-oxidant whose activity is enhanced by polyunsaturated
fats like cod liver oil and antagonized by vitamin E.(68). Artemisinin
is used intravenously in Southeast Asia for the treatment of cerebral
malaria; it has no known side effects except for induction of abortion
when used at high doses in pregnant animals.

The herbal pharmacopeia lists many substances with natural anti-
biotic activity and the potential for herbal treatment of gut dysbiosis
is virtually unlimited. A tannin-rich mixture of herbal concentrates
including extracts of gentiana, sanguinaria and hydrastis has been
marketed under various names. In vitro studies at Great Smokies Di-
agnostic Laboratory have found this mixture to exert more potent ac-
tivity against enterobacteriaceae and Staphylococcus than any of the
common antibiotic drugs tested; its major side effect is nausea pro-
duced by the high tannin content.

Summary and Conclusions

Altered microbial ecology in the gut may produce disease and dys-
function because of the intense metabolic activity and antigenicity of
the bacterial flora. Bacterial enzymes can degrade pancreatic en-
zymes, damage the intestinal brush border, deconjugate and reduce
bile acids and alter the intestinal milieu in numerous ways, some of
which can be easily measured in a properly collected sample of stool.
Bacterial antigens may elicit dysfunctional immune responses which
contribute to autoimmune diseases of the bowel and of connective
tissue. Effective treatment of dysbiosis with diet, antimicrobial sub-
stances and biotherapies must distinguish among patterns of dys-
biosis. The failure of common approaches utilizing fiber and Lacto-
bacilli is a strong indication of small bowel bacterial overgrowth, a
challenging disorder which demands a radically different approach.

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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. 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].

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.

(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.

(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.

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

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

NOTES:

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26. Juhlin, L. and G. Micha:elsson, Fibrin microclot formation in patients with acne. Acta Derm Venereol, 1983. 63(6): p. 538-40.

27. Hamilton, I., et al., Small intestinal permeability in dermatological disease. Q J Med, 1985. 56(221): p. 559-67.

28. Belew, P.W., et al., Endotoxemia in psoriasis [letter]. Arch Dermatol, 1982. 118(3): p. 142-3.

29. Jackson, P.G., et al., Intestinal permeability in patients with eczema and food allergy. Lancet, 1981. 1(8233): p. 1285-6.

30. Scadding, G., et al., Intestinal permeability to 51Cr-labelled ethylenediaminetetraacetate in food-intolerant subjects. Digestion, 1989. 42(2): p. 104-9.

31. Jacobson, P., R. Baker, and M. Lessof, Intestinal permeability in patients with eczema and food allergy. Lancet, 1981. i: p. 1285-1286.

32. F:alth-Magnusson, K., et al., 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). Clin Allergy, 1986. 16(6): p. 543-51.

33. F:alth-Magnusson, K., et al., Gastrointestinal permeability in atopic and non-atopic mothers, assessed with different-sized polyethyleneglycols (PEG 400 and PEG 1000). Clin Allergy, 1985. 15(6): p. 565-70.

34. F:alth-Magnusson, K., et al., Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized polyethyleneglycols (PEG 400 and PEG 1000). Clin Allergy, 1984. 14(3): p. 277-86.

35. Jalonen, T., Identical intestinal permeability changes in children with different clinical manifestations of cow’s milk allergy. J Allergy Clin Immunol, 1991. 88(5): p. 737-42.

36. Barau, E. and C. Dupont, Modifications of intestinal permeability during food provocation procedures in pediatric irritable bowel syndrome. J Pediatr Gastroenterol Nutr, 1990. 11(1): p. 72-7.

37. Paganelli, R., et al., Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration. Ann Allergy, 1990. 64(4): p. 377-80.

38. Batash, S., et al., Intestinal permeability in HIV infection: proper controls are necessary [letter]. Am J Gastroenterol, 1992. 87(5): p. 680.

39. Lim, S.G., et al., Intestinal permeability and function in patients infected with human immunodeficiency virus. Scand J Gastroenterol, 1993. 28(7): p. 573-580

40. Tepper, R.E., et al., Intestinal permeability in patients infected with human immunodeficiency virus. Am J Gastroenterol, 1994. 89: p. 878-882.

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52. Ohri, S.K., et al., The effect of intestinal hypoperfusion on intestinal absorption and permeability during cardiopulmonary bypass. Gastroenterology, 1994. 106(2): p. 318-23.

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102. Sudduth, W.H., The role of bacteria and enterotoxemia in physical addiction to alcohol. Microecology and Therapy, 1989. 18: p. 77-81.

103. Ukabam, S.O. and B.T. Cooper, Small intestinal permeability as an indicator of jejunal mucosal recovery in patients with celiac sprue on a gluten-free diet. J Clin Gastroenterol, 1985. 7(3): p. 232-6.

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108. Hallert, C. and J. Astr:om, Psychic disturbances in adult coeliac disease. II. Psychological findings. Scand J Gastroenterol, 1982. 17(1): p. 21-4.

109. Hallert, C., J. Astr:om, and G. Sedvall, Psychic disturbances in adult coeliac disease. III. Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol, 1982. 17(1): p. 25-8.

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114. Dohan, F.C., et al., Is schizophrenia rare if grain is rare? Biol Psychiatry, 1984. 19(3): p. 385-99.

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116. Wyatt, J., et al., Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet, 1993. 341(8858): p. 1437-9.

117. Vanderhoof, J.A., et al., Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture. Tokai J Exp Clin Med, 1990. 15(6): p. 417-23.

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Virtually all chronic degenerative diseases are caused or aggravated by
digestive problems. After the most extensive study on nutrition ever undertaken
by the government, the U.S. Senate Select Committee on Nutrition and Human
Needs concluded in its 1978 report entitled “Diet and Killer Diseases,”
that the average American diet is responsible for the development of chronic
degenerative diseases such as heart disease, atherosclerosis, cancer, diabetes,
stroke, etc. Many of the most common health complaints revolve around a
20-foot, mucus-lined tube that directly interfaces us with our environment.
This is no mystery: This is the gastro-intestinal tract, affectionately
abbreviated “GI.” The job of the GI is to alchemically transmute
the food we eat into our flesh, blood, actions, thoughts and feelings…
with a little help from our friends the salivary glands, the pancreas,
the liver, and most importantly RAW FOOD — all of which provide (now we’re
getting to the point) ENZYMES.



Enzymes are delicate dynamos. Delicate because they are destroyed by temperatures
over 118 degrees (some by as little as 105 degrees), which means that they
may not survive even light steaming. Dynamos because they are powerful
biochemical catalysts; they speed burning or building reactions in the body
according to need. They are specialized proteins, often with long complicated
names ending in -ase.



The three primary digestive enzymes are protease, lipase and amylase which
digest, respectively, protein, fat (lipids), and carbohydrates (which includes
sugars). Amylase comes from the salivary glands: carbohydrates start digesting
right in our mouth. Have you ever chewed a piece of bread or potato for
an extra moment before swallowing, and tasted how sweet it is? (It is a
good idea to chew our foods thoroughly; literally making juice in our mouths
before swallowing.) Lipase is synthesized principally in the liver and
protease comes from the pancreas.



Although the enzyme-producing organs continue to function over the entire
course of a healthy life, they eventually wear down, especially with the
“standard American diet” (which, in the naturopathic community,
we call SAD.) Dr. Francis M. Pottenger’s nutritional studies have shown
that a regular diet of cooked or canned foods causes the development of
chronic degenerative diseases and premature mortality. Professor Jackson
of the Dept. of Anatomy, University of Minnesota, has shown that rats fed for 135 days on an 80 percent
cooked food diet resulted in an increase pancreatic weight of 20 to 30 percent.
What this means is that the pancreas is forced to work harder with a cooked
food diet. “Although the body can manufacture enzymes, the more you
use your enzyme potential, the faster it is going to run out…” wrote
Dr. Edward Howell, who pioneered research in the benefits of food enzymes.
A youth of 18 may produce amylase levels 30 times greater than those of
an 85 year old person.



Enzymes are what make seeds sprout. Sprouts are, in fact, one of the richest
sources of enzymes. Other excellent sources are papaya, pineapple and the
aspergillus plant. Science cannot duplicate enzymes, because they are the
stuff of life itself. Only raw food has functional “live” enzymes.
Therefore the liver, pancreas, stomach and intestines must come to the
rescue and furnish the requisite digestive enzymes to the individual nourished
solely on a cooked food diet.



This extra activity can be detrimental to health and longevity because it
continually taxes the reserve energy of our organs. Furthermore, cooked
food passes through the digestive tract more slowly than raw food, tends
to ferment, and throws poisons back into the body. Colon cancer is second
only to lung cancer as a killer in America and is related, in various ways,
to eating enzyme-deficient cooked food. Prolonged intestinal toxemia may
manifest the following symptoms: Fatigue, nervousness, gasto-intestinal
discomfort, recurrent infections, skin eruptions, hormonal disturbances,
headaches, arthritis, sciatica, low back pain, allergies, asthma, eye, ear,
nose and throat disorders, cardiac irregularities, pathological changes
in the breasts, and so forth. All of these conditions have been shown to
respond to therapy directed to correcting the bowel toxemia. Of course,
it is important to have fiber in the diet to scrub the colon walls clean,
but even more important are the enzymes which will allow proper digestion
and assimilation of vital nutrients. Cooked food often passes into the
bloodstream as unsplit molecules that are deposited, as waste, in various
parts of the body. If it is a fat molecule we know it as cholesterol plaque;
if calcium, arthritis; if sugar, diabetes. White blood cell count rises
dramatically after ingesting a meal of canned or cooked foods (“digestive
leukocytosis”). Elevated WBCs are correlated to bacterial infection,
inflammation and depressed immunity. Raw foods do not produce this reaction.
All raw foods contain exactly the right enzymes required to split every
last molecule into the basic building blocks of metabolism: Amino acids
(from protein), glucose (from complex carbohydrates) and essential fatty
acids (from unsaturated vegetable fats).



You are what you ate: Eat living foods (at least once daily!).

Sinus infections (sinusitis)

Mild bowel irritations and inflammations

Upper respiratory tract infections

Colds and flu

Hay fever

Urinary tract infections

Eye infections or irritations

Demulcents have these general properties:

• They reduce irritation down the whole length of the bowel.
  
• They reduce the sensitivity of the digestive system to gastric acids.
  
• Help to ease the digestive muscle spasms which cause colic.

Some demulcents also:

• Ease coughing by a soothing of bronchial tension.
  
• Relax painful spasm in the bladder and urinary system, and sometime seven in the uterus.

Herbal Demulcents

Coltsfoot

Comfrey

Corn Silk

Couch Grass

Flaxseed

Iceland moss

Irish Moss

Liquorice

Lungwort

Marshmallow

Mullein

Slippery Elm

Demulcents that are also Anti-Catarrhal : Coltsfoot, Lungwort, Mullein

Demulcents that are also Anti-Inflammatory : Coltsfoot, Comfrey, Liquorice, Lungwort, Marshmallow, Mullein, Slippery Elm



Demulcents that are also Anti-Microbial : Couch Grass

Demulcents that are also Anti-Spasmodic : Coltsfoot, Liquorice, Lungwort, Mullein

Demulcents that are also Astringent : Coltsfoot, Comfrey, Lungwort, Marshmallow, Slippery Elm

Demulcents that are also Carminative :

Demulcents that are also Diaphoretic : Mullein

Demulcents that are also Diuretic : Coltsfoot, Corn Silk, Couch Grass, Marshmallow, Mullein

Demulcents that are also Emmenagogue :

Demulcents that are also Expectorant : Coltsfoot, Comfrey, Irish Moss, Liquorice, Lungwort, Mullein

Demulcents that are also Hepatic :

Demulcents that are also Laxative : Flaxseed, Liquorice

Demulcents that are also Nervine :

Demulcents that are also Tonic : Coltsfoot, Corn Silk, Liquorice, Mullein

Demulcents that are also Vulnerary : Coltsfoot, Comfrey , Lungwort, Marshmallow, Mullein