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.