Remodeling of the Candida glabrata cell wall in the gastrointestinal tract affects the gut microbiota and the immune response

Abstract

The gastrointestinal (GI) microbiota acts a natural barrier to the proliferation of opportunistic pathogens. Candida glabrata is an opportunistic yeast pathogen that has adapted to colonize all segments of the human GI tract. We observed an increase in Escherichia coli, Enterococcus faecalis, and Bacteroides vulgatus populations, and a decrease in Lactobacillus johnsonii, Bacteroides thetaiotaomicron, and Bifidobacterium animalis in mice with DSS-induced colitis. This reduction was more pronounced for L. johnsonii during C. glabrata overgrowth. In addition, C. glabrata overgrowth increased mouse mortality and inflammatory parameters, and modulated the expression of intestinal receptors and signaling pathways. The C. glabrata cell wall underwent various changes during the course of C. glabrata colonization, and showed a significant increase in chitin. C. glabrata deficient in chitin synthase-3 induced fewer inflammatory parameters than the parental strain during intestinal inflammation. Oral administration of chitin attenuated the impact of colitis, and reduced the number of aerobic bacteria and C. glabrata overgrowth, while chitinase-3-like protein-1 increased. This study provides evidence that inflammation of the gut alters the microbial balance and leads to C. glabrata cell wall remodeling through an increase in chitin, which is involved in promoting persistence of C. glabrata in the gut.

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

“…While one study reported that an increase in chitin led to incomplete killing C. glabrata by caspofungin [43], another reported that there were no significant increases in chitin production upon caspofungin exposure in vitro [50]. A more recent study noted an increase in C. glabrata chitin levels upon murine GI tract colonization [51]. We have shown that treatment of colonized mice with a combination of caspofungin and the chitin synthase inhibitor Nikkomycin Z, caused an increase in killing of C. glabrata within the murine GI tract and a decrease of dissemination upon immunosuppression [30].…”

Epithelial-microbial diplomacy: escalating border tensions drive inflammation in inflammatory bowel disease

“…As mentioned above, B. vulgatus also increased pro-inflammatory cytokine production in Nod2-deficient mice. 153 The capacity of pathobionts to drive a pro-inflammatory response does not appear to be uniformly dependent on the presence of a host defect in innate immunity as E. faecalis activates NF-κB, p38 MAPK, and ERK1/2 pro-inflammatory signaling via TLR2 resulting in induction of IL-6 and IP-10 secretion in wild-type murine IECs. 154 AIEC secretion of outer membrane vesicles leads to activation of the host ER stress response protein Gp96.…”

Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata

“…While one study reported that an increase in chitin led to incomplete killing of C. glabrata by caspofungin [ 45 ], another reported that there were no significant increases in chitin production upon caspofungin exposure in vitro [ 52 ]. A more recent study noted an increase in C. glabrata chitin levels upon murine GI tract colonization [ 53 ]. We have shown that treatment of colonized mice with a combination of caspofungin and the chitin synthase inhibitor Nikkomycin Z caused an increase in killing of C. glabrata within the murine GI tract and a decrease of dissemination upon immunosuppression [ 30 ].…”