Yeasts in the Gut: from Commensals to Infectious Agents Jürgen Schulze, Ulrich Sonnenborn
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MEDICINE REVIEW ARTICLE Yeasts in the Gut: From Commensals to Infectious Agents Jürgen Schulze, Ulrich Sonnenborn SUMMARY hree decades ago, on the basis of case reports, the American physician C. O. Truss (e1–e3) Background: Controversy still surrounds the question T proposed the hypothesis that an unhealthy lifestyle whether yeasts found in the gut are causally related to and increased intake of drugs, modified foods, and disease, constitute a health hazard, or require treatment. pollutants could lead to overgrowth of Candida Methods: The authors present the state of knowledge in this species in the intestine. This would generally reduce area on the basis of a selective review of articles retrieved the defenses of the host organism and trigger a multi- by a PubMed search from 2005 onward. The therapeutic organ Candida-associated complex of symptoms recommendations follow the current na tional and (“Candida hypersensitivity syndrome”). Since then, international guidelines. this topic has been repeatedly and vigorously dis- Results: Yeasts, mainly Candida species, are present in the cussed by experts and laymen. In 1996, C. Seebacher gut of about 70% of healthy adults. Mucocutaneous Candida even claimed that “mycophobia” was spreading. infections are due either to impaired host defenses or to Many of the publications supporting Truss’s hypoth- altered gene expression in formerly commensal strains. esis are not to be taken seriously. Abnormal condi- The expression of virulence factors enables yeasts to form tions and severe diseases have often been uncritically biofilms, destroy tissues, and escape the immunological linked to the mere detection of fungi in the gut, lead- attacks of the host. Yeast infections of the intestinal mucosa ing to the initiation of antimycotic therapy. This pro- are of uncertain clinical significance, and their possible voked justifiably critical publications during the connection to irritable bowel syndrome, while plausible, 1990s, although some of these were exaggeratedly remains unproved. Yeast colonization can trigger allergic polemical (for example, e4). An objective scientific reactions. Mucosal yeast infections are treated with discussion on intestinal Candida colonization, with topically active polyene antimycotic drugs. The adjuvant evaluation according to criteria of environmental administration of probiotics is justified on the basis of medicine, was started in 2004, under the manage- positive results from controlled clinical trials. ment of the Robert Koch Institute (1). Nevertheless, Conclusion: The eradication of intestinal yeasts is advised some questions remain open. only for certain clearly defined indications. Since then, microbiological, molecular biological, and experimental clinical studies have succeeded in Key words: gastrointestinal mycosis, candidiasis, clarifying additional facts, so that it appears to be yeast infection, pathogenesis, treatment appropriate to re-evaluate the clinical importance of yeasts in the gut. Methods The report of the Commission on Methods and Quality Assurance in Environmental Medicine (Kommission “Methoden und Qualitätssicherung in der Umwelt- medizin”) on the Pathogenetic Significance of Candida Colonization of the Intestine appeared in 2004 (1). In order to identify later relevant literature, the database PubMed was searched and evaluated from 2005. The following search terms (MeSH) were used as selection criteria in the preparation of the present review article: “Candida/pathogenicity,” “fungi/pathogenicity/viru- lence factors,” “Candida/clinical trials, humans,” Cite this as: Dtsch Arztebl Int 2009; 106(51–51): 837–42 “mycoses/microbiology/drug therapy AND gastrointes- DOI: 10.3238/arztebl.2009.0837 tinal tract OR urogenital system.” Publications on molds were not considered. Therapeutic statements are Nuthetal, Alice-Bloch-Straße: PD Dr. rer. nat. Schulze in accordance with national and international guide- Ardeypharm GmbH, Herdecke: Dr. rer. nat. Sonnenborn lines. Deutsches Ärzteblatt International | Dtsch Arztebl Int 2009; 106(51–52): 837–42 837 MEDICINE TABLE 1 gastrointestinal microflora (3, 4, 5). They are then guests which cause no damage. For example, oral and Information on microorganism groups and counts in different sections of the esophageal candidiasis is only manifest when CD4+ gastrointestinal tract Th1 lymphocytes deficiency and reduced formation of Microorganisms Stomach Jejunum Ileum Colon proinflammatory cytokines (IL-12, INF-gamma) Aerobic and facultatively anaerobic microorganism groups prevent effective defense against fungi (6, e6). Candida infections may arise as a consequence of Enterobacteria 0–102 0–103 102–106 104–1010 3 4 2 6 5 10 ● disturbances in the host’s defense systems, includ- Enterococci 0–10 0–10 10 –10 10 –10 2 3 2 5 4 7 Staphylococci 0–10 0–10 10 –10 10 –10 ing the physiological intestinal microflora, the 3 4 2 5 6 10 Lactobacilli 0–10 0–10 10 –10 10 –10 2 2 2 3 2 6 gut-associated immune system and the mucosa Fungi 0–10 0–10 10 –10 10 –10 itself (4, 5, 7, e7); Anaerobic microorganism groups ● changes in gene expression in previously Bacteroides spp. rare 0–102 103–107 1010–1012 commensal Candida strains, including activation Bifidobacteria rare 0–103 103–105 108–1012 of virulence genes (8, e7–e9). Anaerobic streptococci rare 0–103 102–104 108–1011 Clostridia rare rare 102–104 106–1011 Eubacteria rare rare rare 109–1012 Janus-headed Candida Candida spp. are yeasts which are normally present as (Essential microorganism groups compiled as in [2]. individual cells and which predominantly replicate Figures in colony forming units (CFU) per mL or per g intestinal content. asexually by budding. The expression “yeast fungus” is pleonastic, as yeasts belong to the kingdom of the fungi. Candida albicans is a diploid polymorphic yeast with eight pairs of chromosomes. It can also replicate Intestinal microflora and fungi under anaerobic conditions, as found in the human Already at birth, microbial colonization starts in the colon (e8). Almost 200 Candida species are known, gastrointestinal tract, which has previously been sterile. although few are important for man. The most impor - Intestinal microflora—now also known as microbio- tant of these are C. albicans, C. glabrata, C. krusei, C. ta—is established in successive stages and consists of dubliniensis, C. tropicalis, C. parapsilosis, C. guillier- numerous types of microorganism. More than 99% of mondii, and C. lusitaniae (3, 4, e10). One reason that this microbiota consists of bacterial and archaeal this list is short is that about two thirds of Candida species (2). In addition, Candida yeasts are detectable species are incapable of growing at 37oC (e10). in 96% of neonates by the end of the first month of life Molecular genetic studies have shown that there is (e5). The constitutional development process is much greater variety in individual Candida flora (e11). complete after 3 to 5 years and each individual then has Candida yeasts are classified as opportunistic an individual microflora compatible with his/her pathogens, meaning that they are pathogens only under immune system. The special anatomical and physio- specific conditions (4, e7). Overgrowth of yeasts is logical features of the individual compartments of the normally inhibited by both specific (immune system) mouth, stomach and intestine offer disparate ecological and non-specific defense systems (intestinal flora, niches and they are colonized with site-specific peristalsis, intestinal enzymes, defensins, and others). microbe communities (2). Changes in the qualitative or quantitative composi- Table 1 contains groups of important microorgan- tion of the bacterial flora in the gastrointestinal isms detected by culture. The concentration ranges tract—for example, after administration of antibiotics given for the individual counts of life microbes indicate (9)—or a deficiency in specific parameters of the host’s the great individual variability in the microflora of immune system evidently enhance the virulence of adults. The findings also show that fungi are detectable opportunistic Candida strains through gene regulation in all gastrointestinal sections of about 70% of healthy mechanisms (10, e7, e12). Their damaging activities adults (1). Most of these are members of the Candida can manifest at two different levels: genus. Normally 101 to 103 fungal cells per g stool are ● Superficial infections of the skin, mucus found, which is much lower than the corresponding membranes, or epithelia (skin or mucosal values for bacteria – 1011 to 1012 bacteria per g stool. mycoses, Candida vaginoses) Fungi of other genera are occasionally detected in ● Invasive penetration into deeper tissue layers, stool. Although these may be pathogens of the respi - distribution in blood and dissemination in various ratory tract or skin, they are thought to be only transient organs (invasive or systemic mycoses or candi- in the digestive tract. Examples include Aspergillus, doses). Mucor, Cryptococcus, Rhodotorula, and Trichosporon. Even though Candida species are relatively often Pathogenicity factors of Candida strains detected in stool, it is unclear whether these fungi are Pathogenic yeasts bear genes coding for specific patho- physiological and (useful) intestinal symbionts. As long genicity factors and for other properties important for as the site-specific microbial communities are intact the infection process (10, 11, e7). These primarily and the innate immune system is functioning, Candida include adhesion factors,