The pathogenetic significance of intestinal Candida colonization – A systematic review from an interdisciplinary and environmental medical point of view

Int. J. Hyg. Environ. Health 205, 257 ± 268 (2002) ¹ Urban & Fischer Verlag http: // www.urbanfischer.de/journals/intjhyg

International Journal of Hygiene and Environmental Health

Review The pathogenetic significance of intestinal Candida colonization ± A systematic review from an interdisciplinary and environmental medical point of view Michael Lacoura, Thomas Zundera, Roman Huberb, Anna Sanderc, Franz Daschnera, Uwe Franka a b c

Institute of Environmental Medicine and Hospital Epidemiology, Freiburg University Hospital, Freiburg, Germany Department of Internal Medicine II, Freiburg University Hospital, Freiburg, Germany Institute of Medical Microbiology and Hygiene, Freiburg University Hospital, Freiburg, Germany

Received September 24, 2001 ¥ Revision received February 8, 2002 ¥ Accepted February 12, 2002

Abstract The etiological significance of intestinal Candida colonization continues to be controversial. This is a systematic review to determine the pathogenetic significance of intestinal Candida colonization. The search was essentially performed from 1990 to 12/7/2000 in Medline and the Cochrane-Library. The data source was restricted to articles in English and German. Selection criteria covered the topics ™Epidemiology∫, ™Infectious Diseases∫, ™CandidaSyndrome∫ and ™Therapy∫ and were essentially confined to in-vivo examination of immunocompetent adults. Two reviewers extracted independently data using predefined criteria. In total, 96 citations that proved suitable for use in the systematic review were found. Depending on the localization in the gastrointestinal tract, the recovery technique employed, and transport times, Candida colonization is frequently detected in healthy, immunocompetent adults (prevalence: 4 ± 88%). None of the studies available so far furnish any evidence that nutritional factors, food additives, pollutants, anti-ovulants, other types of medication or diabetes mellitus might be predisposing factors for intestinal Candida colonization. However, therapeutic studies point to the possibility of Candida playing a role in antibiotic-associated diarrhea. On the other hand, antibiotics seem to favor bacterial dysbiosis, and this, like the direct side effects of drugs, offers a more plausible explanation for diarrhea or gastrointestinal symptoms. The role of intestinal colonization by Candida in Candida-associated vulvovaginitis and IgE-mediated disorders remains contradictory. Nevertheless, neither epidemiological nor therapeutic studies provide evidence for the existence of the so-called ™Candida-syndrome∫ or ™Candida-hypersensitivity-syndrome∫. At present, there are no proven treatment indications for antifungal ™bowel decontamination∫. Key words: Yeasts ± Candida ± mycoses ± Candidiasis ± ™Candida-syndrome∫ ± ™Candidahypersensitivity-syndrome∫

Corresponding author: Dr. U. Frank, Institute of Environmental Medicine and Hospital Epidemiology, Freiburg University Hospital, Hugstetterstr. 55, D-79106 Freiburg, Germany. Phone: ‡ 49 761 270 5471, Fax: ‡ 49 761 270 5485, E-mail: [email protected]

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Introduction The history of the ™Candida-Syndrome∫, i. e. the ™Candida-hypersensitivity- syndrome∫ goes back to a publication in 1977 in the journal ™Orthomolecular Psychiatry∫ by C.O. Truss. The article describes tissue injury induced by Candida albicans with resultant mental and neurological manifestations (Truss, 1985). Thereafter, Truss and other protagonists of a ™Candida-associated symptoms complex∫ attributed such afflictions as bloating, indigestion, flatulence, diarrhea, constipation, alcohol and food intolerance, bulimia, overweight, hypersensitivity to ™chemical∫ odors, shortness of breath, heart complaints, urethritis, cystitis, recurrent vaginal fungal infections, premenstrual tension and perimenstrual symptoms, arthritis, myalgia, acne, migraine, chronic fatigue, depression, anxiety, lack of self-confidence, impaired ability to cope and lethargy to an overgrowth of Candida spp. in the gut (Truss, 1985). In this connection, the administration of antibiotics, corticosteroids, anti-ovulants and other types of medication, as well as certain nutritional factors, such as a high-sugar diet and alcohol, pollutants, especially mercury, but also preservatives and food colorings were considered decisive for the development of an intestinal dysbiosis (Truss, 1985; Peters and Zimmermann, 1996; Heizmann and Nolting, 1999). Truss and other protagonists of the ™Candida-(hypersensitivity)syndrome∫ believe that Candida spp. overgrowth leads to an appreciable formation of gas, to intestinal alcohol production by fermentation and the production of toxins, which impair mucosal barrier defense. In their opinion the immune system is thrown off balance and this, coupled with multiple allergies, leads to the complaints described above (Peters and Zimmermann, 1996). Since then, a number of media reports have been published, and the myth of fungi invading the gut has been propagated. In 1986, the American Academy of Allergy and Immunology and in 1992 the American Medical Association devoted themselves to the issue and concluded that the concept of the ™Candida-syndrome∫, i. e. the ™Candida-hypersensitivity-syndrome∫ is speculative and devoid of proof (Executive Committee of the American Academy of Allergy and Immunology, 1986; Council on Scientific Affairs, American Medical Association, 1992). Meanwhile, numerous articles have appeared, which, written from the viewpoint of different specialty fields, are devoted to the possible pathogenetic importance of intestinal Candida colonization (Levine et al., 1995; Wedding et al., 1995; Denning, 1995; Bernhardt, 1996; Knoke,

1996; Rˆsch, 1996; Sander, 1997; Kreisel, 1999). While these authors consistently dispute the existence of a ™Candida-syndrome∫ or a ™Candidahypersensitivity-syndrome∫, they do not entirely rule out the possibility of Candida-associated diarrhea. The current search of the literature has been undertaken to elucidate open questions in an interdisciplinary and systematic fashion.

Materials and methods A systematic search of the literature was conducted in the Cochrane Library under the keyword: ™candida∫ (505 hits) and in Medline from 1990 (for fewer than 100 hits the search was started from 1966 ± otherwise, there were no restrictions) to 12/7/2000 under the keywords ™candida∫ AND ™syndrome∫ OR ™hypersensitivity syndrome∫ (490 hits) and the following more specific keywords. Epidemiology 1. How frequently is intestinal Candida colonization found in healthy persons? Key words: candida AND colonization OR colonisation OR gut colonization OR gut colonisation OR gut flora OR intestinal flora (587 hits), OR incidence OR prevalence (1544 hits). 2. How often are Candida spp. detected in the bowels of humans following antibacterial therapy? Key words: candida AND diarrh(o)ea OR gastroenteritis OR enteritis OR enterocolitis OR colitis (142 hits). 3. Can nutritional factors, food additives, pollutants, anti-ovulants and other types of medication favor intestinal colonization by Candida? Key words: candida AND xenobiotic(s) OR pollutant(s) OR hazardous pollutant(s) OR hazardous substance(s) OR mercury OR amalgam OR food additive(s) (170 hits), OR colonization AND nutrition OR food OR sugar OR medicament(s) (115 hits), OR colonisation AND nutrition OR food OR sugar OR medicament(s) (14 hits). 4. Is diabetes mellitus a predisposing factor for intestinal colonization by Candida? Key words: candida AND diabetes AND colonization OR colonisation (25 hits), OR diabetes mellitus AND colonization OR colonisation (21 hits). 5. Is there a correlation between intestinal colonization by Candida and the symptoms and complaints in humans described above? Key words: candida AND complaint(s) (83 hits), OR gastrointestinal complaint(s) OR bloating OR indigestion OR reflux (o)esophagitis OR cramping OR abdominal cramping OR meteorism OR flatulence OR Roemheld`s syndrome OR diarrh(o)ea OR irritable bowel disease OR irritable bowel syndrome OR food intolerance OR food allergy OR food sensitivity(ies) OR food hypersensitivity(ies) OR nutrition allergy OR alcohol intolerance OR alcohol allergy

Pathogenetic significance of Candida colonization OR alcohol sensitivity(ies) OR alcohol hypersensitivity(ies) OR morbid appetite OR bulimia OR sitomania OR cynorexia OR hyperorexia OR hypoglyc(a)emia OR dumping syndrome OR perianal pruritus (664 hits), OR asthma OR asthma bronchiale OR atopia OR conjunctivitis OR rhinitis OR atopic conjunctivitis OR atopic rhinitis OR atopic dermatitis OR urticaria OR acne (162 hits), OR arthralgia(s) OR arthritis OR parainfectious arthritis OR reactive arthritis OR rheumatism OR myalgia(s) OR fibromyalgia (102 hits), OR perimenstrual tension OR dysmenorrh(o)ea OR gyn(a)ecological complaint(s) (8 hits), OR fatigue OR chronic fatigue OR chronic fatigue syndrome OR CFS OR chemical odor(s) OR multiple chemical sensitivity(ies) OR MCS OR cephalgia OR migraine OR vertigo (30 hits), OR mental function(s) OR mental status OR mental disorder(s) OR cognitive function(s) OR cognitive impairment(s) OR cognitive disturbance(s) OR behavioral disturbance(s) OR behavioural disorder(s) OR psychiatric disease(s) OR psychosomatic disease(s) OR depression(s) OR lethargy OR anxiety OR self confidence OR coping (150 hits), OR urethritis AND intestine OR intestinal tract OR gut (1 hit), OR cystitis AND intestine OR intestinal tract OR gut (no hits), OR urinary tract infection(s) AND intestine OR intestinal tract OR gut (6 hits), OR vaginal candidosis AND intestine OR intestinal tract OR gut (34 hits), OR genital candidosis AND intestine OR intestinal tract OR gut (7 hits), OR perianal candidosis OR perianal mycosis (40 hits). Infectious diseases 1. Do intestinal Candida infections exist in immunocompetent subjects? Key words: see Epidemiology. 2. Is there evidence of translocation of Candida spp. from the bowel of immunocompetent subjects? Key words: candida AND translocation (66 hits), OR septic(a)emia AND Escherichia coli (80 hits), OR sepsis AND Escherichia coli (102 hits), OR blood stream infection(s) AND Escherichia coli (2 hits). 3. Do invasive or systemic Candida infections occur in immunocompetent subjects, in whom the intestinal tract acts as a reservoir of pathogens? Key words: candida AND infection(s) AND immunocompetence OR immunocompetent host (72 hits), OR systemic infection(s) AND immunocompetence OR immunocompetent host (11 hits), OR invasive infection(s) AND immunocompetence OR immunocompetent host (6 hits). ªCandida-syndromeº 1. Can intestinal Candida colonization impair gut barrier defense? Key words: candida AND barrier AND intestine OR intestinal tract OR gut (7 hits), OR gut barrier OR intestinal barrier OR enteric barrier OR enteral barrier (8 hits).

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2. Are mycotoxins released by Candida spp., which lead to an irritable bowel or which may be absorbed by the bowel and cause systemic disturbances? Key words: candida AND mycotoxin(s) (145 hits). 3. Can intestinal Candida colonization lead to gas formation and intestinal alcohol production by fermentation and cause an increase in symptoms? Key words: candida AND intestine AND gas OR alcohol OR fermentation (13 hits), OR intestinal tract AND gas OR alcohol OR fermentation (12 hits), OR gut AND gas OR alcohol OR fermentation (6 hits), OR intestinal gas OR intestinal gas formation OR intestinal fermentation OR enteral gas OR enteral gas formation OR enteral fermentation OR flatulence OR meteorism (11 hits). 4. Can Candida overgrowth in the gut cause malabsorption or malassimilation syndrome in immunocompetent subjects? Key words: candida AND malabsorption OR malassimilation (35 hits). 5. Can colonization by Candida in humans lead to bile acid-induced diarrhea or steatorrhea through disturbed bile acid deconjugation? Key words: candida AND bile acid deconjugation (3 hits). 6. Are there Candida-induced endocrinological disorders in humans? Key words: candida AND endocrinology OR endocrinological disease(s) OR endocrinological dysfunction(s) OR endocrinological disorder(s) OR hypothyroidism OR hypoadrenalism (13 hits). 7. Can Candida colonization of the human gut lead to clinically relevant immunomodulation or allergies? Key words: See epidemiology AND candida AND immunomodulation OR immunostimulation OR immunosuppression OR malt (395 hits), OR syndrome(s) AND immunity OR cellular immunity OR humeral immunity (257 hits), OR hypersensitivity syndrome AND immunity OR cellular immunity OR humeral immunity (44 hits). Therapy 1. Is eradication of Candida spp. with antifungals (e. g. nystatin) or alternative methods (e. g. antifungal diet) possible? Key words: candida AND eradication OR antifungal diet (103 hits), OR intestine AND nystatin OR diet (30 hits), OR intestinal tract AND nystatin OR diet (30 hits), OR gut AND nystatin OR diet (13 hits). 2. Does this type of treatment improve the symptoms associated with the so-called ™Candida-syndrome∫ or ™Candida-hypersensitivity-syndrome∫? Key words: see Epidemiology. The literature search in the databases was supplemented by a hand-search based on the reference-list given in seven earlier reviews (M¸ller, 1993; Denning, 1995; Levine et al., 1995; Knoke, 1996, 1999; Rˆsch, 1996; Kreisel, 1999). In addition, German-language journals on environmental medicine were screened (™Umweltmedizin in

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Forschung und Praxis∫; ™Zeitschrift f¸r Umweltmedizin∫) and the ™Deutsches ærzteblatt∫, ™Versicherungsmedizin∫, ™Zeitschrift f¸r Rechtsmedizin∫; these are not available in Medline. Likewise books of Heizmann and Nolting (1999) and Truss (1985) were used for the review. Two reviewers independently screened, extracted and interpreted data using the following predefined criteria: 1. Screening the headings and abstracts to the abovementioned questions and hypotheses for each individual question belonging to each subject (™Epidemiology∫, ™Infectious diseases∫, ™Candida-Syndrome∫, ™Therapy∫) found in the specified Medlinesearch. Each question was treated as a separate investigation. Screening-results were compared with the screening-results of the general search in The Cochrane Library and were supplemented if necessary. 2. If the contents of the abstract corresponded to the questions asked above, the studies and reviews were evaluated on the basis of the original (primary) literature. In particular, special attention was paid to possible methodological weaknesses in the study (e. g. lack of controls). 3. The literature search was essentially confined to invivo examination of immunocompetent adults. In those cases where in-vivo examinations in immunocompetent adults had not been carried out, the studies were rounded off by the examination of animal models; in-vitro trials and clinical studies on neonates or children were partly taken into consideration in the sections ™Epidemiology∫ and ™Candida-Syndrome∫. 4. The literature search was confined to articles in English and German. There were no restrictions on the publication-type or the study-quality. 5. In cases of discrepancies in data selection between the two reviewers consensus opinion was reached by them in discussion. In cases of discrepancies in data extraction and interpretation consensus was sought by the employment of an independent supervisor. 6. Extraction and interpretation of data were also monitored and if need be modified by representatives from different specialized fields (hygiene and environmental medicine, microbiology, internal medicine, gastroenterology, allergology and methodology).

Results Altogether, 96 citations were found that proved suitable for use in the systematic review. Eightythree articles were found in the database search (see reference list); thirteen additional articles were found in the hand-search (Brabander et al., 1957; Kozinn and Taschdjian, 1962; Sappington et al., 1963; Knoke et al., 1981; Petitpierre et al., 1985; Executive Committee of the American Academy of Allergy and Immunology, 1986; Giuliano et al., 1987; Friedel and Kohler, 1988; Renfro et al., 1989; Parsons et al., 1993; Wedding et al., 1995; Peters

and Zimmermann, 1996; Muss et al., 2000). The following number of citations were reviewed for the individual topics under study: ™Epidemiology∫: 35 articles, ™Infectious diseases∫: 12 articles, ™Candida-syndrome∫: 37 articles and ™Therapy∫: 18 articles. Seven articles proved suitable for use in more than one topic. As the specified Medline searchstrategy was sensitive but not specific to the questions and hypotheses described above, the following citations had to be excluded: ™Epidemiology∫: 4007 abstracts, ™Infectious diseases∫: 327 abstracts, ™Candida-syndrome∫: 912 abstracts, ™Therapy∫: 158 abstracts. Since the selection-criteria were complex the reasons for excluding literature cannot be presented here in detail. However, in summary it may be said that the excluded citations did not deal with the predefined questions as described above, but mainly dealt with animal models, in-vitro examinations, laboratory methods, neonates or children, immunosuppressed or deficient adults, infectious diseases other than gut-associated infections in immunocompromised hosts or antimicrobial chemotherapy other than antifungals to eradicate Candida spp. in the gut. Duplicates and 3 citations in Italian or Spanish were also excluded (Serrano, 1975; Proto et al., 1992; Ramirez Moreno et al., 2000).

Review of the literature and Discussion Epidemiology The minimum detection limit for Candida spp. in stool cultured quantitatively and enriched in liquid media is about 102 cfu/ml (M¸ller, 1993). Despite the lack of investigations into different ethnical populations, the frequency of colonization by Candida spp. ( 102 cfu/ml) in healthy persons ranges from 4 to 88 % depending on the site in the gastrointestinal tract, the recovery technique employed, and transport times (M¸ller, 1993). This confirms the statement by Knoke, who points out that the incidence of gastrointestinal Candida colonization is between 23% and 76%. Man does not seem to be an exception in respect of these high colonization rates, as 80% of all reptile guts may be colonized by yeasts (Knoke, 1999). The most frequently identified organisms are C. albicans. Provided proper microbiological techniques are used, the fecal yeast counts in the small and large bowel of healthy persons is, as a rule, no higher than 104 cfu/ml (M¸ller, 1993; Bernhardt and Knoke, 1997). Antibacterial therapy leads to an overgrowth of yeasts in the gut because of their

Pathogenetic significance of Candida colonization

selective growth advantages (Giuliano et al., 1987). In contrast, other predisposing factors discussed in the literature such as nutritional factors, food additives, pollutants (especially mercury), anti-ovulants and other types of medication may not have demonstrable influence on Candida colonization of the gastrointestinal tract (Peters and Zimmermann, 1996; Muss et al., 2000). Although epithelial adhesion of Candida spp. was shown to be enhanced by dietary carbohydrates and 17-beta-estradiol in-vitro, clinical significance is not confirmed as yet (Zhang et al., 2000; Pizzo et al., 2000). In a study conducted by Weig et al. (1999), 28 healthy volunteers received dietary supplementation with refined carbohydrates. No correlation was found between refined carbohydrate uptake and fecal C. albicans counts. Schmidt et al. (1997) studied two groups of 60 healthy female volunteers in terms of vaginal colonization rates and intake of anti-ovulants. Women taking anti-ovulants showed no increase in the rate of colonization by Candida spp. In a study by de Olveira et al. (1993), prevalence of C. albicans in vaginal fluid of 1004 asymptomatic Portuguese women was even lower in the group taking oral contraceptives. In contrast case-control studies by Geiger and Foxman (1996), Spinillo et al. (1993) and Reed et al. (2000) found oral contraceptive use and nutritional habits (low milk ingestion, but no high intake of dietary carbohydrates) as independent risk factors for Candida vulvovaginitis. Unfortunately, all these studies did not cover intestinal colonization rates. No other relevant epidemiological investigations of factors possibly influencing Candida colonization of the intestines have been published. Furthermore, no studies on the possible influence of diabetes mellitus on intestinal Candida colonization are available. Although the saliva of diabetics may show raised values in correlation with blood sugar, and buccal cells from patients with diabetes mellitus showed an increase in adhesion of C. albicans in vitro compared with those collected from non-diabetic controls, there is no evidence that diabetes mellitus presents a significant risk factor for oropharyngeal colonization by Candida spp. in vivo (Darwazeh et al., 1990, 1991; Dorocka-Bobkowska et al., 1996; Hedderwick et al., 1998; Willis et al., 1999). The possible associations between intestinal colonization and complaints postulated by protagonists of the ™Candida-syndrome∫ have been inadequately investigated. Most studies explore the possibility of Candida-induced diarrhea after administration of antibiotics (Levine et al., 1995). Only one study investigates the colonization-rate of Candida in

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patients with diarrhea without predisposing factors (Talwar et al., 1990). In this study, the prevalence of Candida spp. was 54.8%, but, unfortunately, no comparison with a healthy control group was made, which would have been necessary for a proper interpretation of the results. Furthermore, a study of Chaudhury et al. (1996) on 978 diarrhea stool specimens in which Candida spp. was detected as being the sole pathogen in 15.3% is of no significance for clarifying the pathogenetic role of yeasts in the gut, because a control group is missing. All in all, there is no epidemiologically proven association between epigastric complaints and Candida colonization of the gastrointestinal tract. However, there is evidence of impaired healing of gastric ulcers being induced by Candida (ZwolinskaWcislo et al., 1998). There is no doubt that Candida spp. may be a causal factor for perianal eczemas, vulvovaginitis and other genital infections (Pirone et al., 1992; David et al., 1997). However, the relationship between these Candida infections and intestinal Candida colonization is unclear. An investigation by Silverman et al. (1989) revealed no difference in the fecal microflora of 20 patients with pruritus ani and 20 asymptomatic matched controls, but the study failed to provide evidence for Candida infection as a basis for pruritus ani. Two other studies found only a partial phenotypic or genotypic correlation between intestinal Candida spp. and vaginal yeasts in women with vulvovaginitis (Poirier et al., 1990; Mendling et al., 1998). In another study, neither a single biotype nor genotype was associated with recurrent vaginitis and a particular body site (cervix, anus and throat) (Mercure et al., 1993). Another study found an increased prevalence of rectal Candida carriage in several hundred women with vaginal candidiasis compared to healthy controls (Fong, 1994). However, the prevalence of rectal Candida carriage in patients during symptomatic vaginitis is not significantly higher than during asymptomatic periods and results in exudates of cervical smear tests do not differ significantly in women with and without inflammatory changes (Parsons et al., 1993; Fong, 1994). Another study was conducted to investigate the role of fecal C. albicans in the pathogenesis of irritable bowel syndrome (Middleton et al., 1992). C. albicans was discovered in stool samples of only three of 38 patients with irritable bowel syndrome who had previously received antibiotics. C. albicans was not found in any stool samples of the controls. Thus, an epidemiological relationship between dysfunction of the intestinal tract and C. albicans could not be established. Another often cited study tried to

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clarify the possible association of chronic fatigue syndrome (CFS) with candidal bowel colonization (Renfro et al., 1989). Of 100 patients investigated, eight believed to be suffering from a ™Candidahypersensitivity-syndrome∫ (so called ™yeast connection∫). As regards the history of their disease, physical examination and laboratory tests, these patients showed no differences to the remaining 92 patients without a ™yeast connection∫. However, the study is unsuitable for clarification of the pathogenetic significance of intestinal Candida colonization, since the patients were grouped according to their own theories about their illness rather than on the basis of medical judgment. In this context, a study by Mawle et al. (1995) on 26 CFS patients and 50 healthy controls is more revealing. No differences were found between the two groups with respect to serological testing for Candida spp. No other relevant epidemiological studies on the possible relationship between symptoms and complaints associated with the so-called ™Candida-syndrome∫ or ™Candida-hypersensitivity-syndrome∫ and intestinal colonization by Candida were found. Infectious diseases To diagnose intestinal Candida infection, it is necessary to carry out an endoscopic examination and a tissue biopsy, since a stool examination for yeasts does not even quite reflect histopathological changes (Wedding et al., 1995; Knoke, 1996). Relevant studies or case reports are only available on hematooncologic or pediatric patients, but not on immunocompetent adults (Kozinn and Taschdjian, 1962; Knoke et al., 1981; Prescott et al., 1992; Bond et al., 2000). On the other hand, even in the case of immunosupressed patients with invasive Candida infection there is no known association with diarrhea. So far, there is no clear evidence of intestinal translocation of Candida spp. i. e. of invasive candidal infections occurring in immunocompetent adults. A prospective study by MacFie et al. (1999) compared cultures from nasogastric aspirates, mesenteric lymph nodes taken at laparatomy from 279 surgical patients, and cultures from subsequent septic foci. Bacterial, but not fungal translocation, was found in 21% of the patients. However, there are a few case reports on fungal translocation in infants receiving long-term parenteral nutrition following surgical procedures (Pierro et al., 1996; MacFie et al., 1999). A study by Goff et al. (1995) reports on 34 HIVnegative patients infected with Candida spp. Unfortunately, the study does not indicate the type of infection involved and whether individual persons

were without predisposing factors for Candida infection. Calvo Romero et al. (1998) report a case of septic Candida arthritis in an immunocompetent patient who did not have predisposing risk factors. Since there is no mention in the report of preceding arthrocentesis having been performed, pathogenetically, therefore, haematogenic dissemination and transitory fungemia must be assumed (Silveira et al., 1993). In a population-based epidemiological assessment of invasive mycoses by Rees et al. (1998), in which a total of 1619 patients from the San Francisco bay area were investigated, no predisposing factors were found or mentioned in 2 to 8% of the patients with invasive Candida infection. Therefore, invasive intestinal Candida infection also occurring in immunocompetent people cannot be ruled out entirely. ªCandida-syndromeº To date there is no data that supports the hypothesis that intestinal colonization by Candida spp. impairs the functions of the gut barrier in humans. In an invitro assay by Diebel et al. (1999), translocation of E. coli was significantly augmented in the presence of Candida adhering to epithelial cells. In another invitro assay, Reid et al. (1995) demonstrated the ability of lactobacilli to influence the adhesion of C. albicans to fibers and epithelial cells. This finding was confirmed in a mouse model using heat-killed lactobacilli (Wagner et al., 2000). Nevertheless, a review of the literature furnished no data indicating increased translocation or sepsis rates for E.coli in patients with intestinal Candida colonization. Mycotoxins do not seem to participate significantly in the pathogenesis of Candida infections (Vartivarian, 1992). The immunosuppressive effects of gliotoxin, a toxin produced by C. albicans, have been recognized (Shah et al., 1998). In vitro, gliotoxin inhibits macrophage functions against C. albicans and E. coli. So far, there are no reasons for assuming that gliotoxin, or any other undefined mycotoxin of C. albicans, may cause localized irritation of the intestinal wall or have other systemic toxic effects in humans. Relevant endogenous ethanol-production seems to be possible only in a few rare instances (Japanese subjects with very serious yeast infections) (Logan and Jones, 2000). Despite this, there is no evidence of relevant alcohol production or gas formation by intestinal yeasts. Appreciable gas formation in the large bowel takes place as a result of polymer carbohydrate breakdown in vegetable and other bulk fibers by anaerobes, which are found in large quantities of 1012 ±1014 cfu/g stool (Rˆsch, 1996).

Pathogenetic significance of Candida colonization

According to a calculation by Bernhardt (1996), Candida spp. merely have a 0.005% share in intestinal gas production. The same applies to endogenous alcohol production by Candida spp. in the bowel (Geertinger et al., 1982; Rˆsch, 1996). A review of the literature revealed no studies indicating either a relationship between intestinal Candida colonization and a malabsorption or malassimilation syndrome, or that Candida spp. in the bowel has the ability to deconjugate bile acids in humans (Hˆgenauer et al., 1998). Neither has there been any suggestion that there might be an association between intestinal Candida colonization and endocrinologic disorders, although the co-incidence of hypoparathyroidism, hypoadrenalism, hypothyroidism, and chronic mucocutaneous candidiasis has been described and put down to an autosomal recessive or autosomal dominant inherited disorder (Coleman and Hay, 1997). Some animal models and in-vitro trials indicate that Candida spp. may depress the functions of T cells, NK cells and monocytes/macrophages or lead to an increase in the apoptosis of normal neutrophils (Cater, 1995; Shah et al., 1998; d'Ostiani et al., 2000; Rotstein et al., 2000). As cell-mediated immunity is an important host defense mechanism against Candida infections, these findings may be interpreted as natural defense mechanisms, which allow Candida spp. to avoid the cell-mediated immunity of the host (Fidel and Sobel, 1994). However, in an investigation by Nawrot et al. (2000), there was indication of distinct suppression of cell-mediated immune response in patients suffering from recurrent vulvovaginal candidiasis; but whether these findings are the consequence of, or a reason for recurrent vulvovaginitis is a subject to be discussed (Fidel and Sobel, 1996; Nawrot et al., 2000). In another study by Talluri et al. (1990) the serum levels of the Th2 cytokines were found to be high in hospitalized patients with persistent candiduria and occult candidemia when compared with matched patients with no clinical or laboratory evidence of urinary or hematogenous fungal infection. However, these findings are not representative of immunocompetent adult patients, as these patients had relevant risk factors for the development of candiduria. Other studies show that yeast wall may activate immunostimulating effects (Tokunaka et al., 2000). However, at present, there is no data on the systemic effects of intestinal Candida colonization on the cellular immune system (Cater, 1995). Humoral factors such as the production of Candida specific IgA antibodies and antibodies of subclasses IgA1 and IgA2 are not impaired, even in patients infected with HIV (Coogan et al., 1994).

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However, a connection between intestinal Candida colonization and various chronic disorders in the presence of IgE-mediated type I hypersensitivity to Candida spp. cannot be excluded. In an early study, Petitpierre et al. (1985) found evidence of an association between chronic abdominal symptoms and IgE-mediated hypersensitivity to food in nine out of 12 atopic individuals (versus zero in 12 non-atopic persons). This possible association is important in so far as IgE-mediated type I hypersensitivity to C. albicans has been suggested in connection with patients suffering from atopic dermatitis, bronchial asthma and allergic rhinitis, and allergic symptoms can be triggered by conjunctival and inhalative provocation with acid protease produced by C. albicans (Savolainen et al., 1990; Akiyama et al., 1994, 1996; Nermes et al., 1994; Matsumura et al., 1997; Savolainen et al., 1998; Scalabrin et al., 1999; Kimura et al., 2000). However, these findings are contradicted by other investigations that have been unable to confirm an association between IgEmediated type I hypersensitivity to C. albicans and atopic dermatitis or urticaria, or which show a cross reactivity between C. albicans and Pityrosporum ovale or P. orbiculare, or Saccharomyces cerevisiae (Doekes and van Ieperen-van Dijk, 1993; Kortekangas-Savolainen et al., 1993; Huang et al., 1995; Seebacher, 1999). Unfortunately, a study by Middleton et al. (1992) on the role of fecal C. albicans in the pathogenesis of irritable bowel syndrome did not investigate the possible presence of Candida specific IgE-antibodies. Moreover, it is still not known whether allergic disorders such allergic conjunctivitis or rhinitis, bronchial asthma, atopic dermatitis and urticaria can be triggered by intestinal Candida colonization in the presence of IgE-mediated hypersensitivity to Candida spp. Convincing evidence of a correlation between yeasts in stool and atopic dermatitis as compared to healthy controls has to be furnished (Buslau et al., 1990; Henseler, 1995). A study by Moraes (1998) points to a correlation between recurrent vaginal candidiasis and allergic rhinitis, while Henseler and Tausch (1997) found an indication of a correlation between Candida colonization of the skin and atopic dermatitis or urticaria. In theory, therefore, such an association could also apply to intestinal Candida colonization. Therapy According to M¸ller (1993) and Rˆsch (1996), the eradication of yeasts in the bowel is impossible. As long as antifungals (nystatin, amphotericin B, fluconazole) are being administered, fecal counts in stool may drop below the minimum detection limit

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of 102 cfu/ml. However, as a rule, four to five days after medication is withdrawn, yeasts are again detectable in stool specimens. The concept of the low-carbohydrate- or carbohydrate-free, so called ™anti fungal diet∫ is questionable, since mono-, diand oligosaccharides are completely absorbed in the proximal sections of the small bowel and are therefore not available to Candida spp. in the colon (Rˆsch, 1996; Kreisel, 1999). As expected, in a study conducted by Weig et al. (1999) on 28 healthy subjects, a high-sugar diet was found to have no effect on intestinal Candida colonization. The effect of antifungal therapy on complaints associated with the ™Candida-syndrome∫ has been evaluated in many studies, however, most of these explore treatment of so called ™Candida induced diarrhea∫. Levine et al. discussed this topic at length in a systematic review published in 1995. From 1957 to 1991, seven therapeutic studies (5 ± 50 cases) were carried out with nystatin. They were conducted as observational studies (without controls) and supplemented by three single case reports. One study had a matched pair design (Danna et al., 1991). Most of the studies and all the single case reports state antibiotic therapy to be a predisposing factor. Only one study investigated adult patients who obviously had no predisposing risk factors (Brabander et al., 1957). With the exception of two studies, all treatments were 100% successful (symptomatic and mycological response). Since then no further studies have been carried out on ™Candida-induced diarrhea∫. An evaluation of the available therapeutic studies must take into account that the absence of a control group does not allow any conclusion that treatment was successful. It is possible that the discontinuation of antibacterial treatment alone might lead to the resolution of diarrhea, as reported by Danna et al. (1991), and that diarrhea is a direct side effect of antibiotics (Martinez and Marcos, 1991; Hˆgenauer et al., 1998; Levy, 2000). A preceding antibacterial therapy may also favor bacterial dysbiosis and the suppression of normal bacterial flora in the colon, and this would offer a more plausible explanation for diarrhea or gastrointestinal symptoms than an intestinal infection or overgrowth by Candida spp. Furthermore, diarrhea caused, for example, by enteropathogenic viruses, which usually resolves spontaneously, was not (completely) ruled out in the studies. A study by Sappington et al. (1963), however, is interesting: Twenty-five patients with prolonged, possibly Candida-induced diarrhea, with a mean duration of 15.5 months were investigated. Six of these patients had received prior antibacterial therapy. Otherwise, no predisposing risk factors were indicated. Eighteen of

the 25 patients responded promptly after two to three days of therapy with nystatin. Since spontaneous resolution of the diarrhea was unlikely in this study, and the patients were not at the time undergoing antibacterial therapy that had subsequently been withdrawn, the therapeutic success of nystatin suggests itself. However, the study did not include a control group and, as yet, the results have not been corroborated by a further study. Likewise, caution is called for in the evaluation of a multi-center study in which 94% of the 1325 patients investigated, suffering from flatulence, showed symptomatic improvement under oral antifungal therapy (Friedel and Kohler, 1988). It is true that a large number of cases were investigated and 53.3% of the patients had shown symptoms for longer than four weeks, but no controls were used for comparison. Since mean duration of treatment was 18 days, symptoms may in fact have improved spontaneously. Evaluation of therapeutic success was not standardized, e. g. by the use of a visual analogous or rating scale, but was assessed on the basis of the clinical subjective judgment of the attending physicians. In another comparative multicenter study, 258 patients with vulvovaginal candidiasis were either treated with vaginal suppositories (nystatin or clotrimazol) alone, or with a combination of vaginal suppositories and oral nystatin for ™bowel decontamination∫ (Nystatin Multicenter Study Group, 1986). With respect to symptomatic and mycological response rates, the combination therapy proved to be superior to treatment with vaginal suppositories alone. In a study by Spinillo et al. (1992) on women with vaginal candidiasis, however, treatment of candidal colonization of the intestinal tract did not influence the relapse rate. This finding was confirmed in a literature-review by Denning (1995). In another study, 42 premenopausal patients with persistent or recurrent vaginal candidiasis, who at the same time had symptoms attributed to the socalled ™Candida-hypersensitivity-syndrome∫ (such as tiredness, premenstrual tension, gastrointestinal symptoms and depression), were given three active treatment regimens (oral and vaginal nystatin, oral nystatin and vaginal placebo and oral placebo and vaginal nystatin) or oral and vaginal placebo regimen (Dismukes et al., 1990). The three active regimens were more effective than placebo in relieving vaginal symptoms, but nystatin did not reduce symptoms associated with the so-called ™Candidahypersensitivity-syndrome∫. In two dermatological studies, clinical course, total serum IgE and serum IgE antibody level against C. albicans were investigated in patients with atopic dermatitis or urticaria (Back et al., 1995; Morita

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et al., 1999). When the patients who showed evidence of IgE-mediated hypersensitivity to C. albicans received antifungal drugs (e. g. ketocanozole), active scores and serum IgE levels decreased significantly. Since these studies were merely observational studies and lacked a control group for comparison, it is impossible to draw any conclusions about the therapeutic effectiveness of antifungal therapy. In other words, as yet, there are no proven therapeutic indications for antifungal ™bowel decontamination∫.

Conclusion Intestinal colonization by Candida is frequently detected in healthy, immunocompetent adults. The role of Candida colonization in antibiotic-associated diarrhea or IgE-mediated disorders remains contradictory. At present, there are no proven treatment indications for antifungal ™bowel decontamination∫. Acknowledgements. We wish to thank the Karl and Veronica Carstens-Foundation, Essen, Germany for their support of this literature review. We also wish to thank Dr. Markus Dettenkofer, Institute of Environmental Medicine and Hospital Epidemiology, Freiburg University Hospital, Freiburg, Germany, and Dr. Andres Busse, Department of Dermatology, Freiburg University Hospital, Freiburg, Germany for critically reviewing the article.

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