We examined whether Candida albicans gut colonization aggravates immune diseases in mice. Chronic and latent C. albicans gut colonization was established by the intragastric inoculation of C. albicans in mice fed as part of a purified diet. Allergic diarrhea was induced by repetitive intragastric administration of ovalbumin in sensitized BALB/c mice. Contact hypersensitivity was evaluated by measuring ear swelling after topical application of 2, 4-dinitrofluorobenzene in NC/Nga mice. Arthritis was induced by intradermal injection of bovine type-II collagen emulsified with complete Freund's adjuvant in DBA/1J mice. C. albicans gut colonization increased the incidence of allergic diarrhea, which was accompanied by gut hyperpermeability, as well as increased infiltration of inflammatory cells in the colon. Contact hypersensitivity was also exacerbated by C. albicans gut colonization, as demonstrated by increased swelling, myeloperoxidase activity, and proinflammatory cytokines in ear auricles. Furthermore, C. albicans gut colonization promoted limb joint inflammation in collagen-induced arthritis, in an animal model of rheumatoid arthritis. These findings suggest that C. albicans gut colonization in mice aggravates inflammation in allergic and autoimmune diseases, not only in the gut but also in the extra-gut tissues and underscores the necessity of investigating the pathogenic role of C. albicans gut colonization in immune diseases in humans.

We previously observed that gut colonization by Candida albicans promoted serum antibody response to orally administered ovalbumin in mice. We therefore postulated that C. albicans affects oral tolerance induction. The present study tested this idea. BALB/c mice were intragastrically administered with either C. albicans (1 × 107) or vehicle, and the colonization was confirmed by weekly fecal cultures. Mice were further divided into two subgroups and intragastrically administered with either ovalbumin (20 mg) or vehicle for five consecutive days. Thereafter, all mice were intraperitoneally immunized with ovalbumin in alum. In mice without C. albicans inoculation, ovalbumin feeding prior to immunization significantly suppressed the increase in ovalbumin-specific IgE, IgG1 and IgG2a in sera, suggesting oral tolerance induction. In C. albicans-inoculated mice, however, the antibody levels were the same between ovalbumin- and vehicle-fed mice. In contrast, ovalbumin feeding significantly suppressed cellular immune responses, as evidenced by reduced proliferation of splenocytes restimulated by ovalbumin ex vivo, in both C. albicans-inoculated and uninoculated mice. Ex vivo supplementation with neither heat-killed C. albicans nor the culture supernatant of C. albicans enhanced the production of ovalbumin-specific IgG1 in splenocytes restimulated by the antigen. These results suggest that gut colonization by C. albicans inhibits the induction of humoral immune tolerance to dietary antigen in mice, whereas C. albicans may not directly promote antibody production. We therefore propose that C. albicans gut colonization could be a risk factor for triggering food allergy in susceptible individuals.