Dr. Burzynski named these peptides “antineoplaston”s because of their ability to inhibit neoplastic, or cancerous, cell growth. He discovered that cancer patients have a drastic shortage of these compounds in their bodies-blood samples of advanced cancer patients reveal only 2 to 3 percent of the amount typically found in healthy individuals. By simply reintroducing the peptides into the patient’s bloodstream, either orally or intravenously, he brings about tumor shrinkage or complete remission. In many cases, just weeks after the start of treatment, tumors have shrunk in size or disappeared. Most types of cancer reportedly respond to the therapy, which is safe and nontoxic. The natural substances used are well tolerated by the body, even in high doses, without any of the disastrous side effects routinely associated with toxic chemotherapy and radiation.

Since the Burzynski Research Institute (BRI) opened in 1977, Dr. Burzynski has treated some 2,000 cancer patients, most of them in advanced stages. He has saved or prolonged hundreds of lives with his innovative approach. A significant number of persons treated have been in complete remission for five years or more, even though they were pronounced “terminal” or “incurable” by their conventional doctors. However, Dr. Burzynski advises that antineoplaston treatments are not effective against all types of cancer nor for all patients.

A front-page article in the July-August 1990 issue of Oncology News was devoted to antineoplastons, “a completely new type of antitumor agent that is nontoxic and seems to make malignant cancer cells revert to normal.” Dvorit Samid, Ph.D., a Bethesda, Maryland, researcher, was quoted as saying, “Such a dramatic phenomenon is seldom seen…. I am very excited about these findings.” This report on the Ninth International Symposium on Future Trends in Chemotherapy, held in Geneva, Switzerland, presented favorable preclinical and clinical results achieved with antineoplaston therapy by researchers from Japan, Poland, China, and the United States.

A complete remission in a Japanese patient with inoperable metastatic ovarian cancer and complete remissions in American patients with advanced prostate cancer were among the results presented. These types of cancer are very rarely cured by conventional forms of treatment.

Some of the most exciting results obtained with antineoplastons have been with the tumors that usually do not respond to chemotherapy, radiation, or immunotherapy. These include malignant brain tumors (astrocytoma, stages III and IV, and glioblastoma), advanced cancer of the prostate, certain forms of lung cancer, bladder cancer, and even cancer of the pancreas. For example, in a Phase II trial involving astrocytoma, a highly malignant form of brain cancer, twenty patients-nearly all of them in advanced stages of the disease — were treated with antineoplastons. All but one had received and failed prior standard therapies.

Four patients achieved complete remission, and two others, partial remission. Ten other patients showed objective stabilization (less than 50 percent decrease of tumor size). Since the end of this study, in May 1990, some of the ten patients classified as stabilized have achieved complete or partial remission.1

Clinical studies are also underway with patients in Poland. Researchers in Japan, Great Britain, Italy, the United States, and China have reproduced and are expanding Dr. Burzyoski’s preclinical work. In September 1990, the Burzynski Research Institute entered into a letter of intent with Ferment, a major Soviet pharmaceutical firm, to conduct clinical trials with antineoplastons on cancer patients in the Soviet Union.

While Burzynski’s breakthroughs are being eagerly pursued abroad, here in the United States, where he lives and sees patients, the doctor has been the target of an ill-informed, multipronged attack aimed at discrediting him and closing down his clinic. Despite the fact that he has published 150 scientific papers and holds twenty patents for antineoplaston treatment covering sixteen countries, his work has been dismissed as quackery by such interlocking government agencies and private-sector vested-interest groups as the Food and Drug Administration and the American Cancer Society. Close-minded oncologists, when asked by their patients about Dr. Burzynski, have said that he has published nothing. Some insurance companies have sent pleasantly worded form letters denying all payment for his services.

The American Cancer Society in 1983 put Burzynski’s antineoplaston therapy on its Unproven Methods blacklist, where it remains to this day. Yet, as Ralph Moss notes in The Cancer Industry, the ACS’s condemnatory report on the therapy “included data which undercut its own conclusions,” such as the fact that 86 percent of far-advanced cancer patients treated with antineoplastons showed clinical improvement in one 1977 study! Four patients (19 percent) had complete remission, and another four had partial remission. Yet the ACS twisted the facts and said it “does not have evidence that treatment with antineoplaston results in objective benefit.”2

The FDA filed suit against Dr. Burzynski in March 1983 in an attempt to drive him out of business. It ordered Burzynski and his institute to stop all further research, development, manufacture, and use of antineoplastons. A federal judge allowed the doctor to continue his research and treatment within the state of Texas but ruled that he could not ship the drugs across state lines.

In July 1985, FDA agents and federal marshals, armed with an illegal search warrant to look for vague “violations,” raided the Burzynski Research Institute and seized over 200,000 confidential documents, including private medical records. They went through Dr. Burzynski’s personal correspondence and rifled his briefcase. The federal officers loaded eleven of his filing cabinets onto their truck in an outrageous violation of his (and patients’) constitutional and civil liberties. Dr. Burzynski sued the FDA for the return of his records, but all the documents remain in the FDA’s hands to this day.

The Texas State Board of Medical Examiners tried to revoke Burzynski’s medical license in 1988 on hairsplitting technical charges that had no connection whatsoever with the quality of care he provides. Hundreds of letters of support were sent to the board by Burzynski’s patients and their families and friends. The following letter from a Midwestern teenager was typical:

I am 13 years old and I have a 7 year old brother. We love our father very much. Thanks to Dr. Burzynski’s treatment, my father’s tumor has stopped growing. All of the doctors in my home state of Missouri said there was no cure for my father’s disease. Dr. Burzynski gave him a chance for life again. Please don’t take that away from us.

The board’s investigation has been slowed but not stopped.

For five years, the Justice Department has unsuccessfully sought an indictment against Dr. Burzynski on trumped-up charges of mail fraud. This investigation has been centered not on the treatment’s efficacy but on how insurance is billed by the clinic. The charges are not based on any patient’s complaint nor on harm caused to any patient. BRI and Aetna Life Insurance Company have sued each other; the outcome is pending.

To the American medical monopoly, Dr. Burzynski and his therapy are a threat in at least three ways. First, if his theory about a biochemical defense system separate from the immune system is correct, the biology textbooks will have to be rewritten. His theory is revolutionary in its implications. Second, although he is an alternative healer, Burzynski plays by the rules, publishing his findings openly and widely in the peer-reviewed medical literature, which makes it much harder to smear him as a quack. Third, and most important, his safe, nontoxic cancer treatment, with its tremendous promise, is perceived as a threat by the mega-billion-dollar cancer business with its vested monetary interests in toxic chemotherapy, radiation, and surgery. Orthodox doctors and the huge drug companies would not welcome a safe, relatively inexpensive cancer cure- such as naturally occurring peptides, an herbal brew, or something similar-that can’t be marketed to reap superprofits.

At present, antineoplaston therapy is not cheap. The monthly minimum cost of outpatient treatment is between $3,000 and $5,000, excluding the expense of room and board in Houston, transportation, and so forth. The minimum length of treatment time is averaging from four months to one year. The costs are spelled out in detail in the Burzynski Clinic’s patient brochure. A number of insurance companies accept antineoplaston treatment for full or partial reimbursement.

The treatment costs reflect the enormous expenses involved in developing and manufacturing the drugs, which are produced by BRI without the advantages enjoyed by the big pharmaceutical companies. However, if antineoplastons ever gain wide acceptance and are mass-produced by a big pharmaceutical company, the cost to the patient would drop drastically.

Ten-year-old Ryan Werthwein was diagnosed by doctors in August 1989 with advanced (Stage IV) thalamic glioblastoma, a brain tumor with the highest grade of malignancy. Under conventional care, persons with this type of cancer usually don’t live longer than six to nine months after diagnosis. This cancer is considered incurable.

Orthodox doctors told Ryan’s parents that the boy, an identical twin from Marlboro, New Jersey, had six months to a year to live. If Ryan took a highly toxic experimental drug, the doctors said, he might survive a year, just possibly a year and a half, but in a progressively debilitated condition. Ryan underwent radiation therapy for five weeks starting in early October, but it proved ineffective. The tumor remained the same size, as indicated by a Magnetic Resonance Imaging (MRI) scan of the brain in January 1990. “The radiation burnt out most of Ryan’s pituitary gland, stunted his growth, and hurt his mental functioning,” according to Sharon Werthwein, the boy’s mother. “We were never told about radiation’s possible long-term effects.”

After reading up extensively on alternative therapies, Ryan’s parents decided to forego chemotherapy and take their son to Houston for treatment by Dr. Burzynski. “The doctors really beat us up over not doing chemo. We were discouraged at every turn from pursuing a safe, nontoxic alternative. They also told us Burzynski was a quack,” recalls Sharon. “The American Cancer Society said they have an arrangement with the Hilton to keep rooms available for cancer patients’ families, but when we mentioned Dr. Burzynski’s name, they said to ‘forget it.’ The Corporate Angel Network, which boasts in TV ads how it flies young cancer patients around the country for free, refused to fly our son because the National Cancer Institute won’t let them fly Burzynski’s patients. The system is a disgrace.”

Ryan’s treatment with antineoplastons began in mid-April 1990. One month after the intravenous infusions were started, there was a major breakdown of the tumor mass, and from then on, it steadily shrank as the therapy continued. “It felt as if a miracle had occurred,” says Sharon. An MRI scan of the brain on May 15-after four weeks of treatment-showed only barely visible tumor remnants. On November 1, 1990, Ryan displayed complete remission. Subsequent MRI scans have shown him to be cancer-free.

“When I called the radiologist to tell him the good news, he said, ‘I thought you were calling to tell me your son had passed away,'” says Sharon. “In utter disbelief, he begged me to come in the next day with my son’s brain scan. After inspecting it, he admitted that he had never seen anything like this before but refused to discuss his earlier negative evaluation of Dr. Burzynski.”

Ryan continues to receive antineoplaston treatment, but the dosage is gradually being reduced. He wears a miniature infusion pump, carried in a waist pack, that injects antineoplastons through a catheter in his chest twenty-four hours a day. There is no pain or discomfort. The ambulatory pump, similar to the one used by diabetics, is reloaded with medicine every two to three days. A patient can inconspicuously carry it in a moderately sized shoulder bag or waist pack. Patients can function and walk about with minimum inconvenience.

Ryan’s physical growth and metabolism have slowed. At the age of thirteen, he is over three inches shorter than his identical twin brother, which the Werthweins attribute to the radiation therapy. “The thing that attracted us to Dr. Burzynski’s approach,” explains Sharon, “is that it is safe and nontoxic, without the horrendous damage and pain that chemotherapy and radiation cause. We figured, ‘Our boy is dying. What have we got to lose by trying this method?’ It is criminal that the American medical system would attempt to suppress Dr. Burzynski’s therapy, which has saved our son’s life. It is wrong that we can only get this treatment for our son in Texas, rather than right here where we live.”

Dr. Burzynski reports that he continues to see very encouraging results in the majority of his patients with advanced, high-grade malignant brain tumors.

Some of Dr. Burzynski’s patients receive the antineoplastons orally, through capsules. For others, the treatment is administered intravenously, through a catheter. The insertion of a catheter is a simple procedure, performed by a qualified medical doctor outside the clinic.

Another of Dr. Burzynski’s patients was a thirty-six-year-old female diagnosed by the University of California Medical Center with advanced (Stage IV) astrocytoma of the brain stem. The patient was initially treated with radiation therapy but showed clear, debilitating progression of the disease before starting on an antineoplaston protocol. She was given oral doses of Antineoplaston A10 (one of the specific peptide compounds) as well as intravenous injections of Antineoplaston AS2-1. She did not show objective response to the treatment, however, and was switched to Antineoplaston A10 and AS2-1 infusions. After six months on this regimen, she was documented to be in complete remission, and she continues to be cancer free three years later.3

There’s a telling irony in the saga of a scientist fleeing Poland for the United States in search of freedom to do his work, only to encounter harassment and repression by the government and medical establishment. At age twenty-five, Stanislaw Burzynski graduated from the prestigious Lublin Medical Academy in Poland, ranked first in his class of 250. The next year, in 1968, he received a Ph.D. in biochemistry, becoming one of the youngest people in Europe ever to receive both advanced degrees. It was in 1967, at age twenty-four, that Burzynski discovered the cancer-growth-inhibiting properties of peptides.

When Burzynski refused to join the communist party in Poland, his position became precarious. He emigrated to the United States in 1970, becoming an assistant professor at Baylor College of Medicine in Houston. A research grant from the National Cancer Institute allowed him to continue his investigation of peptides part-time.

Over the next few years, Burzynski isolated 119 peptides and classified them according to activity. He elaborated on his original finding that “messenger” peptides bond to potential cancer cells, feeding them the complex information they need to revert to normal and perform their intended function. Without this corrective biochemical defense system, asserts Burzynski, we would soon succumb to the cancer-causing forces that continually trigger abnormal cell development, such as carcinogenic chemicals, radiation, and viruses.

Burzynski’s work on peptides convinced him that cancer is “a disease of information processing.” Some peptides spur cellular growth, others inhibit it, but they all accomplish their mission by sending messages the body can obey. The peptides in the bloodstream, which he named antineoplastons, are said to correct the DNA’s chemical program inside the cell and force the cell toward normal development.

Dr. Burzynski discovered that antineoplastons exhibit three di~stinct modes of action. In the first mode, the antineoplastons inhibit the incorporation of glutamine (an amino acid) into the protein of cancerous cells. In the second mode of action, the antineoplastons intercalate (insert) themselves into the double-helix strand of DNA.

Since carcinogens also do this, the antineoplastons are believed to work because they pre-emptively take up the carcinogen’s “parking spot” on the DNA strand. This mechanism is not new; some conventional anticancer drugs act in precisely this manner, but they also bind with normal cells and are highly toxic. In the third mode of action, the antineoplastons inhibit methylation (introduction of a methyl group) in the DNA and RNA of cancer cells, thus inducing malignant cells to differentiate and enter a normal cell cycle.4

At first, Burzynski derived the antineoplaston compounds from blood serum. Then he discovered that the body eliminates these peptides in the urine. Today, most antineoplastons are synthesized from off-the-shelf chemicals, but some of them are still derived from purified human urine. Critics have twisted these facts to paint Burzynski’s therapy as bizarre. In reality, the investigation of urinary peptides and amino acids in human urine has been pursued by researchers for over half a century. As Dr. Burzynski observed, “Urine is not really waste material, but probably the most complex chemical mixture in the human body, and therefore it can deliver us virtually any information about the body. So from the cybernetic point of view it is just a treasure of information. Blood is not such a complex mixture. It contains fewer chemicals.”5 Far from being bizarre, Burzynski’s method of isolating antineoplastons falls squarely within mainstream science.

Antineoplastons, being species-specific, are not generally effective in experiments on laboratory animals. Because of this, Dr. Burzynski received permission to do clinical trials on cancer patients at Houston’s Twelve Oaks Hospital. The results were extremely impressive, with the antineoplastons having a pronounced effect on cancers unresponsive to chemotherapy and radiation. But, just as the doctor was proving the efficacy of antineoplastons on human patients, the hospital withdrew its permission for him to do further tests, the National Cancer Institute got cold feet and cancelled his funding, and the American Cancer Society refused him research money.

So, with entrepreneurial spirit, an undaunted Dr. Burzynski quit his job at Baylor University in 1977 and struck out on his own, establishing his own laboratory so that he could manufacture antineoplastons and treat patients himself. His only savings was $5,000, and he was forced to turn to bank loans to keep the operation alive. Today, the Burzynski Research Institute has three facilities in Houston, including a large pharmaceutical plant, and employs a staff of doctors, engineers, and lab technicians.

In 1983, Burzynski submitted an Investigational New Drug (IND) Application, which took the foot-dragging FDA six years to approve. As a result of the approval, the doctor is currently seeking funding to do a Phase II trial on the effects of Antineoplaston A10 on patients with advanced breast cancer, to be conducted at an institute independent of his clinic.

Perhaps the most important preclinical study on antineoplastons, according to Dr. Burzynski, was done by the pathology department of the United States Department of Defense in Bethesda, Maryland, in 1989. Researchers there demonstrated that using Antineoplaston AS2-1 in tissue culture changes cancer cells into normal cells after approximately two to three days. These “corrected” cells behave completely like normal cells until they die, unless the medicine is removed from the culture medium too soon.6

“This means that when we are treating a patient who has cancer . . . we have to maintain a certain consistent concentration of antineoplastons in their body, in their blood,” comments Dr. Burzynski. “If we slow down too soon, then we have to start from scratch, because the cell will begin to multiply again and simply go toward the cancerous way of life.”

Antineoplastons appear to be remarkably effective in the early diagnosis and prevention of cancer. Researchers at the Medical College of Georgia in Augusta demonstrated that Antineoplaston A10 significantly delayed the appearance of inborn tumors in mice.7 Low doses of synthetic Antineoplaston A10 administered orally can prevent lung, breast, and liver cancer in animals, according to research carried out at the University of Kurume Medical School in Japan and the Burzynski Research Institute. Antineoplastons show great promise as part of a preventive program against cancer in humans. Seemingly healthy individuals who have low levels of antineoplastons, such as smokers, would be prime candidates for that type of program. The possibilities of Burzynski’s “new medicine” appear endless since, in addition to cancer, errors in cell programming can lead to such diverse disorders as benign tumors, certain skin diseases, AIDS (acquired immune deficiency syndrome), genital warts, and Parkinson’s disease.

All patients at the Burzynski Clinic are treated on an outpatient basis. The initial patient response to treatment can be evaluated by standard medical tests, usually within the first three to six weeks of care. While patients receive treatment, clinical evaluations are made, including tumor measurements, radiologic studies, and a total laboratory profile. Most patients show virtually no side effects; a small percentage experience just minor adverse reactions such as skin rashes, slightly changed blood pressure, chills, or fever. In contrast to toxic chemotherapy and radiotherapy, antineoplaston therapy can actually create beneficial side effects, including increases in white- and red-bloodcell counts and decreases in blood cholesterol.

According to the clinic, the treatment does not interfere with surgery, radiation, nor various forms of conventional chemotherapy or immunotherapy. In fact, for some types of cancer, antineoplastons are used together with a small dose of chemotherapy. Such combination treatments are usually free of chemo’s adverse reactions because the dose of chemotherapy given is very small. In addition, the depression of bone marrow that occurs under chemotherapy is offset by the antineoplastons, which actually stimulate bone-marrow function.

In addition to the successes against brain tumors, the clinic reports its most favorable results are obtained against lymphomas, such as non-Hodgkin’s lymphoma; prostate cancer; certain forms of breast cancer; and bladder cancer. The clinic claims an objective response in treating advanced cancer of the pancreas, with two patients in remission for three years. Certain types of cancer do not respond well to antineoplaston therapy. For instance, the clinic does not accept patients with childhood leukemia or testicular cancer.

A small number of AIDS patients have been treated at the Burzynski Clinic. Most of them reportedly had marked improvement in their white-blood-cell counts, with their T4 cells (the white blood cells particularly affected by AIDS) increasing after the first four weeks of treatment. Most AIDS patients take Antineoplaston AS2-1 orally, in capsule form. According to Dr. Burzynski, “Antineoplaston AS2-1 will block the ‘AIDS program’ which is in the DNA of the cell. The cell will undergo specialization and function normally. The virus will not be able to multiply in a cell which is not dividing, and when the cell dies, the virus will die also. Hopefully, this will be the main benefit for the patient.”

While scientists in countries such as Japan, Poland, and the Commonwealth of Independent States (formerly the Soviet Union) actively pursue antineoplaston research, the American medical establishment has been dragging its heels. At the time of this writing, the National Cancer Institute finally agreed to conduct four independent Phase II trials of antineoplaston therapy on patients with brain tumors.

Dr. Burzynski maintains a calm, single-minded perseverance in the face of opposition. With philosophical detachment, he once said, “Most medical breakthroughs have happened because there was some lack of suppression by the supervisors of people doing some innovative work. For instance, the introduction of insulin happened after experiments were performed by Dr. Banting in the absence of the head of his laboratory. He went for a vacation to Europe, and this allowed Dr. Banting to have some freedom to do the experiments….

“That they leave you alone-this is the best you can hope for, yes. Louis Pasteur’s discovery was suppressed for about 22 years, and the reason why it was finally accepted was because Louis Pasteur was allowed to do a final experiment to indicate the effectiveness of his vaccinations. The experiment was constructed in a way that his adversaries thought would never succeed, and they set it up this way to prove that the discovery was not working. But they made an error. They allowed a certain degree of freedom. They allowed him to do the experiment, hoping that it would fail-but it succeeded.”8

1. S.R. Burzynski, E. Kubove, and B. Burzynski, “Phase II Clinical Trials of Antineoplaston A10 and AS2-1 Infusions in Astrocytoma,” 17th International Congress of Chemotherapy, Berlin, Germany, 1991.

2. Ralph W. Moss, The Cancer Industry (New York: Paragon House, 1989), pp. 307-308.

3. Burzynski et al., op. cit.

4. S.R. Burzynski, M.D., Ph.D., “The Body Itself Has a Treatment for Cancer,” lecture presented at the 1990 World Research Foundation Congress, Los Angeles, 7 October 1990, published in Health Consciousness,June 1991, pp. 31-32.

5. Avis Lang, “The Disease of Information Processing: An Interview With Stanislaw R. Burzynski, Townsend Letter for Doctors, June 1989, p. 294.

6. Dvorit Samid, Lin Ti Sherman, and Donata Rimoldi, “Induction of Phenotypic Reversion and Terminal Differentiation in Tumor Cells by Antineoplaston AS2-1,” abstract, Ninth International Symposium on Future Trends in Chemotherapy, Geneva, 26-28 March 1990.

7. T.G. Muldoon, J.A. Copland, A.F. Lehner, and L.B. Hendry, “Inhibition of Spontaneous Mouse Mammary Tumour Development by Antineoplaston A10,” Drugs Under Experimental and Clinical Research, vol. 13 (supp. I), 1987.

8. Lang, op. cit., p. 292.

Burzynski Clinic

6221 Corporate Drive

Houston, TX 77036

Phone: 713-777-8233

For further information on antineoplaston therapy and details on treatment.

Reading Material

Gary Null’s Complete Guide to Healing Your Body Naturally, by Gary Null .

The Cancer Industry: UnraveUing the Politics, by Ralph W. Moss.

Burzynski Clinic, written and published by the Burzynski Clinic (see above for address and phone number). Patient brochure.

From Options: The Alternative Cancer Therapy Book by Richard Walters, © 1992. Published by Avery Publishing, New York. For personal use only; neither the digital nor printed copy may be copied or sold. Reproduced by permission.

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.

References

l. Mentioned in Brown JP. Role of gut bacterial flora in nutrition and health: a review of recent advances in bacteriological techniques, metabolism and factors affecting flora composition. CRC Rev Food Sci Nutr 1977 8:229-336.

2. Haenel H, Bendig J. Intestinal flora in health and disease. Prog Food Nutr Sci
1975, 1:21-64.

3. Berghouse L, Hon S, Hill M, et al. Comparison between the bacterial and oligosaccharide content of ileostomy effluent in subjects taking diets rich in refined or unrefined carbohydrate. Gut 1984; 25:1071-1077.

4. Galland L. Effects of intestinal microbes on systemic immunity. Post Viral Fatigue

Syndrome, Mowbray P, Jenkins R eds. John Wiley & Sons, London, 1991; 405430.

5. Newmark HL, Lupton JR. Determinants and consequences of colonic luminal pH: implications for colon cancer. Nutr and Cancer 1990; 14:161-173.
6. Goldin BR. The metabolism of the intestinal microflora and its relationship to di-
etary tat, colon and breast cancer. Dietary Fat and Cancer New York, Alan R. Liss
1986 655-685.

7. Malhotra SL. Fecal urobilinogen levels and pH of stools. J Royal Soc Med 1982;
75:710.

8. Chung K-T, Fulk GE, Slein MW. Tryptophanase of fecal flora as a possible factor in the etiology of colon cancer. J Natl Can Inst 1975, 54:1073-1078.

9. Hill MJ, Melviulle DM, LennardÇJones JE, Neale K, Ritchie JK. Faecal bile acids, dysplasia, and carcinoma in ulcerative colitis. Lancet 1987; 2:185-186.

10. Bennet JD. Ulcerative colitis: the result of an altered bacterial metabolism of bile
acids or cholesterol. Med Hypoth 1986, 20:125-132.

11. Effects of short-chain fatty acids on a human colon carcinoma cell line. Nutr Rev
(United States) 1988; 46(1):11-12.

12. Breuer Rl. Rectal irrigation with short-chain fatty acids. Dig Dis Sci 1991;
2:185-187.

13. Kistler LA, Gianella RA. Relationship of intestinal bacteria to malabsorption.
Pract Gastroenterol 1980; 4:24-44.

14. Lichtman SN, Keku J, Schwab JH, Sartor RB. Hepatic injury associated with
small bowel bacterial overgrowth in rats is prevented by metronidazole and tetra-
cycline. Gastroenterol 1991; 100:513-519.

15. du Moulin GC, Hedley-White J. The stomach as a bacterial reservoir: clinical significance. IM: Internal Medicine for the Specialist 1982; 3:47-55.

16. Serrander R, Magnusson K-E, Kihlstrom E, Sundqvist T. Acute yersinia infections in man increase intestinal permeability for low-molecular weight polyethylene glycols (PEG 400). Scand J Inf Dis 1986, 18:409-412.

17. Bode JC, Rust S, Bode C. The effect of cimetidine treatment on ethanol formation in the human stomach. 9and J Gastroenterol 1984; 19:853-856.

18. Hunnisett A, Howard J, Davies S. Gut fermentation (or the auto-brewery) syn-
drome: a new clinical test with initial observations and discussion of clinical and
biochemical implications. J Nutr Med 1990; 1:33-38.

19. Sudduth WH. The role of bacteria and enterotoxemia in physical addiction to alcohol. Microecology and Therapy 1989; 18: 77-81.

20. Thurn JR, Pierpont GL, Ludvigsen CW, Eckfeldt JH. D-lactate encephalopathy.
Am J Med 1985; 79:717-721.

21. Ionescu G, Kiehl R, Ona L, Schuler R. Abnormal fecal microflora and malabsorption phenomena in atopic eczema patients. J Adv Med 1990; 3:71-89.

22. Ionescu G, Kiehl R, Wichmann-Kunz F, Leimbeck R. Immunobiological significance of fungal and bacterial infections in atopic eczema. J Adv Med 1990; 3:47-58.

23. Ionescu G, Kiehl R, Wichmann-Kunz F, Williams C, et al. Oral citrus seed extract in atopic eezema: In vitro and in vivo studies on intestinaˆ microflora. J Orthomoˆ Med 1990, 5:155-161.

24. Alun Jones V, Shorthouse M, McLaughlin P, et al. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet 1980 2:1115-1117.

25. Bayhss CE, Bradley HK, Alun Jones V, Hunter JO. Some aspects of colonic microblal actlvlty in irritable bowel syndrome associated with food intolerance. Annalidell Istituto Superiore di Sanita 1986, 22:959-964.

26. Hunter JO, Alun Jones V. Studies on the pathogenesis of irritable bowel svndrome
produced by food intolerance. Read NW, ed, The Irritable Bowel Syndro;ne, New
York, Grune and Stratton, 1985; 185-190.

27. Alun Jones V, Wilson AJ, Hunter JO, Robinson RE. The aetiological role of antibilotgi8c4pr5o/phYlalxli)ssw2ith hysterectomy in irritable bowel syndrome J Ob and Gyn

28. Shorter RG, Huizenga KA, Spencer BJ. A working hypothesis for the etiology and pathogenesis of nonspecific inflammatory bowel disease. Digest Dis 1972;

29. Beeken WL. Remedial defects in Crohn disease. Arch Int Med 1975, 135:686-690.

30. Hollander D, Vadheim C, Brettholz E, et al. Increased intestinal permeabilitv in
patients with Crohn’s disease and their relatives. Ann Int Med 1986, 105 883-885

31. Giaffer MH, Holsworth CD. Effects of an elemental diet on the the faecal ‡lora of patients with Crohn’s disease. 9and J Gastroenterol 1989; 24(suppl): S148.

32. Bennett JD Use of a-tocopherylquinone in the treatment of ulcerative colitis. Gut

33. Gottschall E. Food and the Gut Reaction. Kirkton, Ontario, The Kirkton Press
1986.

34. McCann M. J Allergy Clin Immunol, 1993 (In Press).

35. Inman RD. Reactive arthritis, Reiter’s syndrome, and enteric pathogens. Infections in The Rheumatic Diseases. In: Espinoza L, Goldenberg D, Arnett F, Alarcon G eds. Orlando, FL Grune & Stratton; 1988: 273-280.

36. Gransfors KF Jalkanen S, von Essen R, et al. Yersinia antigens in synovial-fluid
cells from patients with reactive arthritis. N Engl J Med 1989 320:216-221.

37. Gransfors K, Jalkanen S, Lindberg AA, et al. Salmonella iipopolysaccaride in
synovlal cells from patients with reactive arthritis. Lancet 1990, 1: 685-688.

38. Fox A. Role of bacterial debris in inflammatory diseases of the joint and eye
APMIS 1990; 98:957-968.

39. Phillips PE. How do bacteria cause chronic arthritis? J Rheumatol 1989; 16:
1017-1019.

40. Rooney PJ, Jenkins RT, Buchanan WW. A short review of the relationship be-
tween intestinal permeability and inflammatory joint disease. Clin and Exp Rheu-
amatol 1990; 8:75-83.

41. Ebringer A, Cox N, Abuljadayel I, et al. Klebsiella antibodies in ankylosing spondylitis and proteus antibodies in rheumatoid arthritis. Brit J of Rheumatol 1988
27(suppl II): 72-85.

42. McGuignan LE, Prendergast JK, Geczy AF, et al. Significance of nonpathogenic
cross reactive bowel flora in patients with ankylosing spondylitis. Ann Rheum Dis
1986; 45:577-571.

43. Husby G, Tsuchiya N, Schwinmmbeck PL, et al. Cross-reactive epitope with Klebslella pneumoniae nitrogenase in articular tissue of HLA-B27 + patients with ankylosing spondylitis. Arth Rheum 1989, 32:437-445.

44. Malhotra SL. Faecal urobilinogen levels and pH of stools in population groups with different incidence of cancer of the colon, and their possible role in its aetiology. J Royal Soc Med 1982, 75:709-714

45. Walker ARP, Walker BF, Walker AJ. Faecal pH, dietary fiber intake, and proneness to colon cancer in four South Afncan populations. Brit J Canc 1986; 53:489-495.

46. Rowland IR. Factors affecting metabolic activity of the intestinal microflora. Drug Metabol Rev 1988; 19:243-261.

47. Rowland IR, Mallett AK. Dietary fiber and the gut microflora -their effects on
toxicity. In: Chambers PL, Gehring P, Sakai F, eds, Amsterdam. New Concepts
and Developments in Toxicology, 1986: 125-138.

48. Freudenheim J, Graham S, Horvath P. Risks associated with source of flber and
fiber components in cancer of the colon and rectum. Canc Res 1990; 50:3295-3300.

49. DeCosse JJ, Miller HH, Lesser ML. Effect of wheat fiber and vltamins C and E on rectal polyps in patients with familial adenomatous polyps. J Natl Canc Inst 1989; 81:1290-1297.

50. Alberts D, Einspahr J, Rees-McGee S. Effects of dietary wheat bran fiber on rectal epithelial cell proliferation in patients with resection for colorectal cancers. J Natl Canc Inst 1990; 82:1280-1285.

51. Heitman DW, Cameron IL. Reduction of colon cancer risk by dietary cellulose supplementation. J Natl Canc Inst 1990; 82:1154-1155.

52. Mitsuoka T, Hidaka H, Eida T. Effect of fructo-oligosaccharides on intestinal microflora. Die Nahrung 1987; 31:427436.

53. Guggenbichler JP, Allerberger F, Hofstotter H, Dierich MP. Oral therapy for acute diarrhea. N Eng J Med 1991; 324:1672-1673.

54. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhea in six patients. Lancet 1989; 1:1156-1160.
55. Ayebo AD, Angelo IA and Shahani KM. Effect of ingesting acidophilus milk upon fecal flora and enzyme activity in humans. Milchwissenschaft 1980; 35:730-733.
56. Gorbach SL. Lactic acid bacteria and human health. Ann Med 1990; 22:37-41.

57. Siitonen S, Vapaatalo H, Salminen S, et al. Effect of Lactobaclllus GG yogurt in prevention of antibiotic associated diarrhoea. Ann Med 1990; 22:57-59.

58. Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travelers’ diarrhoea by Lactobacillus GG. Ann Med 1990; 22:53-56.

59. Mitsuoka T. Bifidobacteria and their role in human health. J Ind Microbiol 1990; 6:263-268.

60. Yabbara KF, Juffali F, Matossian RM. Bacillus laterosporus endopthalmitis. Arch Ophthalmol 1977; 95:2187-2189.

61. Okube M, Inoue K, Umetani N, et al. Lupus nephropathy in New Zealand Fl hybrid mice treated by ( – )15-deoxyspergualin. Kidney Intl 1988; 34:467-473.

62. Umezawa K, Takeuchi T. Spergualin: a new antitumor antibiotic. Biomed Pharmacotherapy 1987; 41:227-232.

63. Shoji J, Sakazaki R, Wakisaka Y, et al. Isolation of a new antibiotic, lat-
erosporamine. Studies on antibiotics from the genus Bacillus Xlll. J Antiblotlcs (Tokyo) 1976; 29:390-393.

64. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospectlve study. Gastroenterol 1989; 96:981-988.

65. Castex F, Corthier G, Jouvert S, et al. Prevention of Clostridium difflcile-induced experimental pseudomembranous colitis by Saccharomyces boulardii: a scanning electron microscopic and microbiological study. J Gen Microbiol 1990; 136:1085-1089.

66. Buts J-P, Bernasconi P, Vaerman J-P, Dive C. Stimulation of secretory IgA and secretory component of immunoglobulins sn small mtestme of rats treated withSaccharomyces boulardii. Dig Dis 9i 1990: 35:251-256.

67. Klayman DL. Qinghaosu (Artemisinin): an antimalarial drug from China. Science 1985, 228.1049-1055.

68. Levander OA, Ager A, Morris VC, May RG. Qinghaosu, dietary vitamin E, selenium and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoelii. Am J Clin Nutr 1989; 50:346-352.

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:

1. Crissinger, K.D., P.R. Kvietys, and D.N. Granger, Pathophysiology of gastrointestinal mucosal permeability. J Intern Med Suppl, 1990. 732: p. 145-54.

2. Anderson, K.E., Dietary Regulation of Cytochrome P450. Ann. Rev. Nutr., 1991. 11: p. 141-167.

3. Paine, A.J., Excited states of oxygen in biology: their possible involvement in cytochrome P450 linked oxidations as well as in the induction of the P450 system by many diverse compounds. Biochem. Pharmacol., 1978. 27: p. 1805-1813.

4. Braganza, J.M., et al., Lipid-peroxidation (free-radical-oxidation) products in bile from patients with pancreatic disease. Lancet, 1983. ii: p. 375-378.

5. Braganza, J.M., Pancreatic disease: a casualty of hepatic “detoxification”? Lancet, 1983. ii: p. 1000-1002.

6. Deitch, E.A., The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch. Surgery, 1990. 125: p. 403-404.

7. Hazenberg, M.P., et al., Are intestinal bacteria involved in the etiology of rheumatoid arthritis? Review article. Apmis, 1992. 100(1): p. 1-9.

8. Peters, T.J. and I. Bjarnason, Uses and abuses of intestinal permeability measurements. Can. J. Gastroenterol., 1988. 2: p. 127-132.

9. Rooney, P.J., R.T. Jenkins, and W.W. Buchanan, A short review of the relationship between intestinal permeability and inflammatory joint disease [see comments]. Clin Exp Rheumatol, 1990. 8(1): p. 75-83.

10. Walker, W.A., Antigen absorption from the small intestine and gastrointestinal disease. Pediatr Clin North Am, 1975. 22(4): p. 731-46.

11. Bloembergen, P., et al., Endotoxin-induced auto-immunity in mice. I. Time and dose dependence of production and serum levels of antibodies against bromelain-treated mouse erythrocytes and circulating immune complexes. Int Arch Allergy Appl Immunol, 1987. 84(3): p. 291-7.

12. Bloembergen, P., et al., Endotoxin-induced auto-immunity in mice. II. Reactivity of LPS-hyporesponsive and C5-deficient animals. Int Arch Allergy Appl Immunol, 1988. 86(4): p. 370-4.

13. Bloembergen, P., et al., Endotoxin-induced auto-immunity in mice. III. Comparison of different endotoxin preparations. Int Arch Allergy Appl Immunol, 1990. 92(2): p. 124-30.

14. Katz, K.D., et al., Intestinal permeability in patients with Crohn’s disease and their healthy relatives [see comments]. Gastroenterology, 1989. 97(4): p. 927-31.

15. Pearson, A.D., et al., Intestinal permeability in children with Crohn’s disease and coeliac disease. Br Med J, 1982. 285(6334): p. 20-1.

16. Pironi, L., et al., Relationship between intestinal permeability to [51Cr]EDTA and inflammatory activity in asymptomatic patients with Crohn’s disease. Dig Dis Sci, 1990. 35(5): p. 582-8.

17. Munkholm, P., et al., Intestinal permeability in patients with Crohn’s disease and ulcerative colitis and their first degree relatives. Gut, 1994. 35(1): p. 68-72.

18. Hollander, D., et al., Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med, 1986. 105(6): p. 883-5.

19. Teahon, K., et al., Intestinal permeability in patients with Crohn’s disease and their first degree relatives. Gut, 1992. 33(3): p. 320-3.

20. Jenkins, R.T., et al., Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral nonsteroidal anti-inflammatory drug therapy? Br J Rheumatol, 1987. 26(2): p. 103-7.

21. Mielants, H., Reflections on the link between intestinal permeability and inflammatory joint disease [letter; comment]. Clin Exp Rheumatol, 1990. 8(5): p. 523-4.

22. Morris, A.J., et al., Increased intestinal permeability in ankylosing spondylitis–primary lesion or drug effect? [see comments]. Gut, 1991. 32(12): p. 1470-2.

23. Smith, M.D., R.A. Gibson, and P.M. Brooks, Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis. J Rheumatol, 1985. 12(2): p. 299-305.

24. Sk:oldstam, L. and K.E. Magnusson, Fasting, intestinal permeability, and rheumatoid arthritis. Rheum Dis Clin North Am, 1991. 17(2): p. 363-71.

25. Juhlin, L. and C. Vahlquist, The influence of treatment on fibrin microclot generation in psoriasis. Br J Dermatol, 1983. 108(1): p. 33-7.

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.

41. Lichtman, S.N., et al., Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology, 1991. 100(2): p. 513-9.

42. Mack, D.R., et al., Correlation of intestinal lactulose permeability with exocrine pancreatic dysfunction. J. Pediatr., 1992. 120: p. 696-701.

43. Lahesmaa-Rantala, R., et al., Intestinal permeability in patients with yersinia triggered reactive arthritis. Ann Rheum Dis, 1991. 50(2): p. 91-4.

44. Serrander, R., K.E. Magnusson, and T. Sundqvist, Acute infections with Giardia lamblia and rotavirus decrease intestinal permeability to low-molecular weight polyethylene glycols (PEG 400). Scand J Infect Dis, 1984. 16(4): p. 339-44.

45. Serrander, R., et al., Acute yersinia infections in man increase intestinal permeability for low-molecular weight polyethylene glycols (PEG 400). Scand J Infect Dis, 1986. 18(5): p. 409-13.

46. Lim, S.G., et al., Intestinal permeability and function in patients infected with human immunodeficiency virus. A comparison with coeliac disease. Scand J Gastroenterol, 1993. 28(7): p. 573-80.

47. Bjarnason, I., R. Wise, and T. Peters, The leaky gut of alcoholism: Possible route of entry for toxic compounds. Lancet, 1984. i: p. 79-82.

48. Worthington, B.S., L. Meserole, and J.A. Syrotuck, Effect of daily ethanol ingestion on intestinal permeability to macromolecules. Am J Dig Dis, 1978. 23(1): p. 23-32.

49. Bjarnason, I., et al., Effect of non-steroidal anti-inflammatory drugs on the human small intestine. Drugs, 1986. 1: p. 35-41.

50. Rooney, P.J. and R.T. Jenkins, Nonsteroidal antiinflammatory drugs (NSAID’s) and the bowel mucosa: changes in intestinal permeability may not be due to changes in prostaglandins [letter]. Clin Exp Rheumatol, 1990. 8(3): p. 328-9.

51. Ohri, S.K., et al., Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability. Ann Thorac Surg, 1993. 55(5): p. 1080-6.

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.

53. Grisham, M.B., et al., Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability. Inflammation, 1990. 14(5): p. 531-42.

54. Bjarnason, I., et al., Intestinal permeability to 51Cr-EDTA in rats with experimentally induced enteropathy. Gut, 1985. 26(6): p. 579-85.

55. Lifschitz, C.H. and D.H. Mahoney, Low-dose methotrexate-induced changes in intestinal permeability determined by polyethylene glycol polymers. J Pediatr Gastroenterol Nutr, 1989. 9(3): p. 301-6.

56. Berg, R.D., The translocation of the normal flora bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs. Microecology Therapy, 1981. 11: p. 27-34.


57. Andr:e, C., [Food allergy. Objective diagnosis and test of therapeutic efficacy by measuring intestinal permeability]. Presse Med, 1986. 15(3): p. 105-8.

58. Andr:e, C., F. Andr:e, and L. Colin, Effect of allergen ingestion challenge with and without cromoglycate cover on intestinal permeability in atopic dermatitis, urticaria and other symptoms of food allergy. Allergy, 1989. 9: p. 47-51.

59. Andre, C., et al., Measurement of intestinal permeability to mannitol and lactulose as a means of diagnosing food allergy and evaluating therapeutic effectiveness of disodium cromoglycate. Ann Allergy, 1987. 59(5 Pt 2): p. 127-30.

60. Barau, E. and C. Dupont, Allergy to cow’s milk proteins in mother’s milk or in hydrolyzed cow’s milk infant formulas as assessed by intestinal permeability measurements. Allergy, 1994. 49(4): p. 295-8.

61. Doe, W.F., An overview of intestinal immunity and malabsorption. Am J Med, 1979. 67(6): p. 1077-84.

62. Williamson, R.C., Intestinal adaptation (first of two parts). Structural, functional and cytokinetic changes. N Engl J Med, 1978. 298(25): p. 1393-402.

63. Williamson, R.C., Intestinal adaptation (second of two parts). Mechanisms of control. N Engl J Med, 1978. 298(26): p. 1444-50.

64. Lunn, P.G., C.A. Northrop-Clewes, and R.M. Downes, Recent developments in the nutritional management of diarrhoea. 2. Chronic diarrhoea and malnutrition in The Gambia: studies on intestinal permeability. Trans R Soc Trop Med Hyg, 1991. 85(1): p. 8-11.

65. Behrens, R.H., et al., Factors affecting the integrity of the intestinal mucosa of Gambian children. Am J Clin Nutr, 1987. 45(6): p. 1433-41.

66. Galland, L. and S. Barrie, Intestinal dysbiosis and the causes of disease. J. Advancement Med., 1993. 6: p. 67-82.

67. Avakian, H., et al., Ankylosing spondylitis, HLA-B27 and Klebsiella. II. Cross-reactivity studies with human tissue typing sera. Br J Exp Pathol, 1980. 61(1): p. 92-6.

68. Ebringer, R., et al., Ankylosing spondylitis: klebsiella and HL-A B27. Rheumatol Rehabil, 1977. 16(3): p. 190-6.

69. Ebringer, A. and M. Ghuloom, Ankylosing spondylitis, HLA-B27, and klebsiella: cross reactivity and antibody studies [letter]. Ann Rheum Dis, 1986. 45(8): p. 703-4.

70. Ebringer, A., The relationship between Klebsiella infection and ankylosing spondylitis. Baillieres Clin Rheumatol, 1989. 3(2): p. 321-38.

71. Geczy, A.F., et al., Cross-reactivity of anti-Klebsiella K43 BTS 1 serum and lymphocytes of patients with ankylosing spondylitis: antipodean curiosity? [letter]. Lancet, 1985. 1(8438): p. 1169.

72. Geczy, A.F., et al., HLA-B27, molecular mimicry, and ankylosing spondylitis: popular misconceptions. Ann Rheum Dis, 1987. 46(2): p. 171-2.

73. Husby, G., et al., Cross-reactive epitope with Klebsiella pneumoniae nitrogenase in articular tissue of HLA-B27+ patients with ankylosing spondylitis. Arthritis Rheum, 1989. 32(4): p. 437-45.

74. Ilowite, N.T., et al., The rheumatoid factor cross-reactive idiotype in juvenile rheumatoid arthritis: role of the CD5-positive B cell. Clin Immunol Immunopathol, 1993. 67(3 Pt 2): p. S74-82.

75. Khalafpour, S., et al., Antibodies to Klebsiella and Proteus microorganisms in ankylosing spondylitis and rheumatoid arthritis patients measured by ELISA. Br J Rheumatol, 1988. 2: p. 86-9.

76. Phillips, P.E., Evidence implicating infectious agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Clin. Exper. Rheumatol., 1988. 6: p. 87-94.

77. Ramakrishnan, T.P., et al., The major rheumatoid factor crossreactive idiotype and IgA rheumatoid factor in juvenile rheumatoid arthritis. J Rheumatol, 1991. 18(7): p. 1068-72.

78. Sullivan, J.S., et al., Cross-reacting bacterial determinants in ankylosing spondylitis. Am J Med, 1988. 85(6A): p. 54-5.

79. Trull, A.K., et al., IgA antibodies to Klebsiella pneumoniae in ankylosing spondylitis. Scand J Rheumatol, 1983. 12(3): p. 249-53.

80. Welsh, J., et al., Ankylosing spondylitis, HLA-B27 and Klebsiella. I. Cross-reactivity studies with rabbit antisera. Br J Exp Pathol, 1980. 61(1): p. 85-91.

81. Yu, D.T., S.Y. Choo, and T. Schaack, Molecular mimicry in HLA-B27-related arthritis [see comments]. Ann Intern Med, 1989. 111(7): p. 581-91.

82. Katz, K.D. and D. Hollander, Intestinal mucosal permeability and rheumatological diseases. Baillieres Clin Rheumatol, 1989. 3(2): p. 271-84.

83. Davies, G.R., M.E. Wilkie, and D.S. Rampton, Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci, 1993. 38(3): p. 417-25.

84. Bjarnason, I., et al., Effect of prostaglandin on indomethacin-induced increased intestinal permeability in man. Scand J Gastroenterol Suppl, 1989. 164: p. 97-102.

85. Bjarnason, I., et al., Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci, 1989. 34(3): p. 407-11.

86. Bjarnason, I., et al., Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enteropathy. Gut, 1992. 33: p. 1204-1208.

87. O’Dwyer, S.T., et al., A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg, 1988. 123(12): p. 1459-64.

88. Severijnen, A.J., et al., Intestinal flora of patients with rheumatoid arthritis: induction of chronic arthritis in rats by cell wall fragments of Eubacterium aerofaciens strain. Br J Rheumatol, 1990. 29: p. 433-439.

89. Dearlove, M., et al., The effect of non-steroidal anti-inflammatory drugs of faecal flora and bacterial antibody levels in rheumatoid arthritis. Br J Rheumatol, 1992. 31: p. 443-447.

90. Alarcon, G.S. and I.S. Mikhail, Antimicrobials in the treatment of rheumatoid arthritis and other arthritides: a clinical perspective. Am. J. Med. Sci., 1994. 309: p. 201-209.

91. Brown, The puzzling problem of the rheumatic diseases. Maryland State Med. J., 1856. 2: p. 88-109.

92. Caperton, E.M., et al., Ceftriaxone therapy of chronic inflammatory arthritis. A double-blind placebo controlled trial. Arch. Intern. Med., 1990. 150: p. 1677-1682.

93. Brown, T.M., et al., Antimycoplasma approach to the mechanism and the control of rheumatoid disease. Inflammatory Diseases anbd Copper. edited by J.R.J. Sorenson., 1982. Humana Press, Clifton, N.J.

94. Porter, D., et al., Prospective trial comparing the use of sulphasalazine and auranofin as second line drugs in patients with rheumatoid arthritis. Ann Rheum Dis, 1992. 51(4): p. 461-4.

95. Porter, D.R. and H.A. Capell, The use of sulphasalazine as a disease modifying antirheumatic drug. Baillieres Clin Rheumatol, 1990. 4(3): p. 535-51.

96. Pybus, P.K., Metronidazole in rheumatoid arthritis. S. African Med. J., 1982. (February 20): p. 261-262.

97. Tilley, B.C., et al., Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. Ann Int Med, 1995. 122(2): p. 81-89.

98. Wojtulewski, J.A., P.J. Gow, and J. Waller, Clotrimazole in rheumtoid arthritis. Ann Rheum Dis, 1980. 39: p. 469-472.

99. Kloppenburg, M., et al., Antibiotics as disease modifiers in arthritis. Clin. Exp. Rheumatol., 1993. 11 Suppl 8: p. S113-S115.

100. Peltonen, R., et al., Changes of faecal flora in rheumatoid arthritis during fasting and one-year vegetarian diet. Br J Rheumatol, 1994. 33: p. 638-643.

101. Whitcomb, D.C. and G.D. Block, Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA, 1994. 272(23): p. 1845-1850.

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.

104. Cobden, I., J. Rothwell, and A.T. Axon, Intestinal permeability and screening tests for coeliac disease. Gut, 1980. 21(6): p. 512-8.

105. Hamilton, I., et al., Intestinal permeability in coeliac disease: the response to gluten withdrawal and single-dose gluten challenge. Gut, 1982. 23(3): p. 202-10.

106. Mulder, C.J., et al., Coeliac disease. Diagnostic and therapeutic pitfalls. Scand J Gastroenterol Suppl, 1993. 200: p. 42-7.

107. Hallert, C. and T. Derefeldt, Psychic disturbances in adult coeliac disease. I. Clinical observations. Scand J Gastroenterol, 1982. 17(1): p. 17-9.

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.

110. Hallert, C., J. Astr:om, and A. Walan, Reversal of psychopathology in adult coeliac disease with the aid of pyridoxine (vitamin B6). Scand J Gastroenterol, 1983. 18(2): p. 299-304.

111. Singh, M.M. and S.R. Kay, Wheat gluten as a pathogenic factor in schizophrenia. Science, 1976. 191(4225): p. 401-2.

112. Storms, L.H., J.M. Clopton, and C. Wright, Effects of gluten on schizophrenics. Arch Gen Psychiatry, 1982. 39(3): p. 323-7.

113. Wood, N.C., et al., Abnormal intestinal permeability. An aetiological factor in chronic psychiatric disorders? Br J Psychiatry, 1987. 150: p. 853-6.

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

115. O’Farrelly, C., et al., Association between villous atrophy in rheumatoid arthritis and a rheumatoid factor and gliadin-specific IgG. Lancet, 1988. 2(8615): p. 819-22.

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.

118. Gupte, S., Use of berberine in treatment of giardiasis. Am J Dis Child, 1975. 129(7): p. 866.

119. Rabbani, G.H., et al., Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis, 1987. 155(5): p. 979-84.

120. Subbaiah, T.V. and A.H. Amin, Effect of berberine sulphate on Entamoeba histolytica. Nature, 1967. 215(100): p. 527-8.

121. Buchanan, H.M., et al., Is diet important in rheumatoid arthritis? [see comments]. Br J Rheumatol, 1991. 30(2): p. 125-34.

122. Darlington, L.G. and N.W. Ramsey, Is diet important in rheumatoid arthritis? [letter; comment]. Br J Rheumatol, 1991. 30(4): p. 315-6.

123. Darlington, L.G. and N.W. Ramsey, Review of dietary therapy for rheumatoid arthritis. Br J Rheumatol, 1993. 6: p. 507-14.

124. Prudden, J.F. and L.L. Balassa, The biological activity of bovine cartilage preparations. Sem Arthritis Rheumatism, 1974. 3(4): p. 287-321.

125. Sperling, R.I., Dietary omega-3 fatty acids: effects on lipid mediators of inflammation and rheumatoid arthritis. Rheum Dis Clin North Am, 1991. 17(2): p. 373-89.

126. Bjarnason, I., et al., Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut, 1991. 32(3): p. 275-7.

127. Kirsch, M., Bacterial overgrowth. Am. J. Gastroenterol., 1990. 85: p. 231-237.

128. Stockbrugger, R.W. and U. Armbrecht, Bacterial overgrowth in the upper gastrointestinal tract and possible consequences: report of a workshop in Brussels, Belgium, 9-10 February, 1990. Microb. Ecol. Health Dis., 1991. 4: p. i-vii.

129. Brandt, J., B. L.H., and A. Wagle, Production of vitamin B12 analogues in patients with small-bowel bacterial overgrowth. Ann. Int. Med., 1977. 87: p. 546-551.

130. Giannella, R.A., S.A. Broitman, and N. Zamcheck, Competition between bacteria and intrinsic factor for vitamin B 12 : implications for vitamin B 12 malabsorption in intestinal bacterial overgrowth. Gastroenterology, 1972. 62(2): p. 255-60.

131. Playford, R.J., et al., Effect of luminal growth factor preservation on intestinal growth [see comments]. Lancet, 1993. 341(8849): p. 843-8.

132. Surawicz, C.M., et al., Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol, 1989. 84(10): p. 1285-7.

133. Surawicz, C.M., et al., Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology, 1989. 96(4): p. 981-8.

134. Buts, J.-P., et al., Stimulation of secretory IgA and secretory component of immunoglobulins in small intestine of rats treated with Saccharomyces boulardii. 1990.

135. Eibl, M.M., et al., Prophylaxis of necrotizing enterocolitis by oral IgA-IgG: review of a clinical study in low birth weight infants and discussion of the pathogenic role of infection. J Clin Immunol, 1990. 10(6 Suppl): p. 77S-79S.

136. Siitonen, S., et al., Effect of Lactobacillus GG yoghurt in prevention of antibiotic associated diarrhoea. Ann Med, 1990. 22(1): p. 57-9.

137. Salminen, E., et al., Preservation of intestinal; integrity during radiotherapy using live Lactobacillus acidophilus cultures. Clin Radiol, 1988. 39: p. 435-437.

138. Oksanen, P.J., et al., Prevention of travellers’ diarrhoea by Lactobacillus GG. Ann Med, 1990. 22(1): p. 53-6.

139. Gorbach, S.L., T.W. Chang, and B. Goldin, Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG [letter]. Lancet, 1987. 2(8574): p. 1519.

140. Klimberg, V.S., et al., Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg, 1990. 125(8): p. 1040-5.

141. Souba, W.W., The gut-a key metabolic organ following surgical stress:Benefits of glutamine supplementation. Contem Surg, 1989. 35(5A): p. 5-13.

142. Souba, W.W., Glutamine: a key substrate for the splanchnic bed,. Annu. Rev. Nutr., 1991. 11: p. 285-308.

143. van der Hulst, R.R., et al., Glutamine and the preservation of gut integrity. Lancet, 1993. 341(8857): p. 1363-5.

144. Hagen, T.M., et al., Fate of dietary glutathione: disposition in the gastrointestinal tract. A,. J. Physiol., 1990. 259: p. G530-G535.

145. Cody, V., et al., ed. Plant Flavonoids in Biology and Medicine II. Biochemical, Cellular and Medicinal Properties. Progress in Clinical and Biological Research, Vol. 280. 1988, Aland R. liss, Inc.: New York. 481.

146. Vanderhoof, J.A., et al., Effect of dietary menhaden oil on normal growth and development and on ameliorating mucosal injury in rats. Am J Clin Nutr, 1991. 54(2): p. 346-50.

147. Stark, J.M. and S.K. Jackson, Sensitivity to endotoxin is induced by increased membrane fatty-acid unsaturation and oxidant stress. J Med Microbiol, 1990. 32(4): p. 217-21.

148. Eisenhans, B. and W.F. Caspary, Differential changes in the urinary excretion of two orally administered polyethylene glycol markers (PEG 900 and PEG 4000) in rats after feeding various carbohydrate gelling agents. J Nutr, 1989. 119: p. 380-387.

149. Gyory, C.P. and G.W. Chang, Effects of bran, lignin and deoxycholic acid on the permeability of the rat cecum and colon. J Nutr, 1983. 113: p. 2300-2307.

150. Shiau, S.Y. and G.W. Chang, Effects of certain dietary fibers on apparent permeability of the rat intestine. J Nutr, 1986. 116(2): p. 223-32.

151. Spaeth, G., et al., Food without fiber promotes bacterial translocation from the gut. Surgery, 1990. 108(2): p. 240-6.

152. Fukushi, T., Studies on edible rice bran oils. Part 3. Antioxidant effects of oryzanol. Rep Hokaido Inst Pub Health, 1966. 16: p. 111.

153. Yagi, K. and N. Ohishi, Action of ferulic acid and its derivatives as anti-oxidants. J Nutr Sci Vitaminol, 1979. 205: p. 127-135.

Like cortisone, testosterone and estrogen, DHEA is a steroid hormone. The original precursor of all steroid hormones in the body is cholesterol. We sometimes think of cholesterol and hormones as being bad; but, they are absolutely essential for life and health. The key point is that the hormones need to be in balance. Hormonal imbalances may be caused by genetic or inherited tendencies, nutritional deficiencies, toxic exposures, infections, aging and stress of all kinds.

DHEA or DHEA Sulfate blood levels can be measured easily to determine if there is a deficiency of this hormone. Frequently, this hormone is low in patients with rheumatoid arthritis, cancer, ulcerative colitis, allergies, chronic fatigue, multiple sclerosis, lupus erythematosus and AIDS. When levels are below optimal levels, DHEA may be prescribed by a physician. At the present time, DHEA is not available commercially in most pharmacies, but is available from compounding pharmacies, which compound or make up and then fill prescriptions that are written by doctors.

What is the evidence for the value of DHEA in various conditions? In one study published in the New England Journal of Medicine, men with apparently healthy hearts and low DHEA levels had a 3.3 times greater chance of dying of heart disease during the next 12 years when compared to men with normal DHEA levels.

Both animal and human studies indicate that low DHEA levels predispose to breast cancer. DHEA may be of value in preventing and even treating cancer–especially breast cancer. Dr. Hans Nieper in Germany has used DHEA in many of his cancer patients for years.

Autoimmune diseases are a result of the body’s immune system attacking itself. Rheumatoid arthritis, lupus, ulcerative colitis, diabetes mellitus, multiple sclerosis and many other diseases involve autoimmune problems. Animal and human studies indicate that DHEA can be very helpful in all of these conditions.

Many of our multiple sclerosis patients with fatigue and patients with chronic fatigue and allergies frequently show significant improvement when given DHEA. DHEA generally goes down as a person ages. Supplementation with DHEA may retard the aging process. In addition to its own activity, DHEA can be converted to both testosterone and estrogen. It appears to have bone strengthening qualities by retarding bone resorption and stimulating bone growth.

In summary, natural DHEA appears to be potentially valuable as a therapeutic agent.