Oral administration of live- or heat-killed Candida albicans worsened cecal ligation and puncture sepsis in a murine model possibly due to an increased serum (1→3)-β-D-glucan

Abstract

Candida albicans is the most common fungus in the human intestinal microbiota but not in mice. To make a murine sepsis model more closely resemble human sepsis and to explore the role of intestinal C. albicans, in the absence of candidemia, in bacterial sepsis, live- or heat-killed C. albicans was orally administered to mice at 3h prior to cecal ligation and puncture (CLP). A higher mortality rate of CLP was demonstrated with Candida-administration (live- or heat-killed) prior to CLP. Fecal Candida presented only in experiments with live-Candida administration. Despite the absence of candidemia, serum (1→3)-β-D-glucan (BG) was higher in CLP with Candida-administration than CLP-controls (normal saline administration) at 6h and/or 18h post-CLP. Interestingly, fluconazole attenuated the fecal Candida burden and improved survival in mice with live-Candida administration, but not CLP-control. Microbiota analysis revealed increased Bacteroides spp. and reduced Lactobacillus spp. in feces after Candida administration. Additionally, synergy in the elicitation of cytokine production from bone marrow-derived macrophages, in vitro, was demonstrated by co-exposure to heat-killed E. coli and BG. In conclusion, intestinal abundance of fungi and/or fungal-molecules was associated with increased bacterial sepsis-severity, perhaps through enhanced cytokine elicitation induced by synergistic responses to molecules from gut-derived bacteria and fungi. Conversely, reducing intestinal fungal burdens decreased serum BG and attenuated sepsis in our model.

Factors associated with the development of septic shock in patients with candidemia: a post hoc analysis from two prospective cohorts

“…Our data suggest that, apart from older age, the only variable associated with septic shock in candidemic patient was an intra-abdominal origin of the infection. This result supports recent experimental observations that intestinal abundance of Candida may be associated with an increased sepsis severity, perhaps through cytokine storm induction and/or decreased macrophage killing activity [29][30][31]. The fact that patients with other source of the infection (i.e., CVC or urinary tract) received a similar rate of adequate source control of candidemia (43.4% vs 40.5%, p = 0.86) and even a lower rate of adequate antifungal treatment (38.1% vs 61.5%, p = 0.008) is further consistent with this intriguing explanation.…”

Candida Administration Worsens Cecal Ligation and Puncture-Induced Sepsis in Obese Mice Through Gut Dysbiosis Enhanced Systemic Inflammation, Impact of Pathogen-Associated Molecules From Gut Translocation and Saturated Fatty Acid

“…In addition, intestinal C. albicans is a source of BG in gut contents. In addition, BG from gut translocation amplifies the inflammatory property of LPS through the synergy of Dectin-1 and Toll-like receptor (TLR)-4 which are receptors of BG and LPS, respectively, in sepsis and several inflammatory models (19)(20)(21)(22)(23)(24).…”

Additional Candida albicans administration enhances the severity of dextran sulfate solution induced colitis mouse model through leaky gut-enhanced systemic inflammation and gut-dysbiosis but attenuated by Lactobacillus rhamnosus L34

“…4 Besides increased bacterial dysbiosis, enhanced gut fungi in patients with IBD are also wellknown [4][5][6] which could be beneficial or detrimental to the host. 7,8 In addition, intestinal barrier disruption (leaky-gut) in IBD as demonstrated by the spontaneous elevation of Gram-negative bacteria, endotoxin (LPS; a bacterial cell-wall component) and (1→3)-β-D-glucan (BG; a fungal cell-wall component), without systemic infection, in patients and in animal models are mentioned. [9][10][11][12] The presentation of BG in serum of patients with active IBD 12 implies the impact of gut Candida and leaky-gut upon IBD.…”