Gastrointestinal Colonization of Candida Albicans Increases Serum (1→3)-β-D-Glucan, without Candidemia, and Worsens Cecal Ligation and Puncture Sepsis in Murine Model

Abstract

The role of intestinal Candida albicans in bacterial sepsis, in the absence of candidemia, was investigated in murine models. Live C albicans or normal saline solution (NSS) was administered orally once, followed by 5 days of daily oral antibiotic-mixtures (ATB). Cecal ligation and puncture (CLP) was then performed to induce sepsis.Fecal Candida was detected by culture only in models with Candida administration. Oral Candida administration with/without ATB enhanced gut-pathogenic bacteria as determined by microbiome analysis. Despite negative candidemia, serum (1→3)-β-D-glucan (BG) was higher in CLP with Candida preconditioning models than in CLP-controls (NSS-preconditioning) at 6 and/or 18 h post-CLP. Blood bacterial burdens were not increased with Candida administration.Additionally, CLP with high-dose Candida (10 colony forming units) induced higher levels of fecal Candida, serum BG, serum IL-6, and mortality than the lowest dose (100 colony forming units). Interestingly, fluconazole attenuated fecal Candida and improved survival in mice with live-Candida administration, but not in the CLP-controls. Heat-killed Candida preparations or their supernatants reduced bone marrow-derived macrophage killing activity in vitro but enhanced cytokine production.In conclusion, intestinal abundance of fungi and/or fungal-molecules was associated with increased bacterial sepsis severity, perhaps through cytokine storm induction and/or decreased macrophage killing activity. These observations suggest that further investigation of the potential role of intestinal fungal burdens in sepsis is warranted.