Candida Intestinal Domination Precedes Fungal Infections Bloodstream in Allogeneic Hematopoietic Cell Transplant Patients

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are at high risk of developing invasive bloodstream infections during the period of neutropenia prior to engraftment, even with prophylactic administration of antibacterial and antifungal drugs. Previous studies have demonstrated that disruption of the diversity and stability of commensal intestinal bacteria facilitates intestinal domination by pathobionts, a process that is associated with subsequent bacteremia. The relationship and dynamics of intestinal fungal communities (i.e., mycobiota) and the development of fungemia during allo-HCT remains unknown. In this study, we identified 8 allo-HCT patients that developed fungemia and participated in a prospective collection of fecal samples between 2014 and 2017 at MSKCC. All 8 patients developed Candida species fungemia (6 C. parasilopsis, 1 C. albicans, 1 C. lusitaniae). Using quantitative PCR to analyze fungal 18S rDNA, we found a temporal expansion of total intestinal fungi that coincided with the onset of fungemia (Figure A). We then analyzed the composition of the mycobiota by sequencing the internal transcribed spacer 1 (ITS1) region of the fungal rDNA, and found a significant loss of diversity of gut fungal flora (Figure B). Moreover, in seven of the eight cases, we observed intestinal dominance of the specific Candida species that was associated with fungemia, prior to the identification of positive blood cultures. Through whole genome sequencing of the fecal and the bloodstream fungal isolates, we further confirmed that the bloodstream fungal strain was the same clone as the one that had robustly colonized in the gut. Taken together, our results indicate that Candida intestinal domination precedes Candida bloodstream infection. Thus, monitoring the dynamics and composition of the mycobiota may facilitate identification of patients at-risk for this life-threatening complication and enable improved strategies for prophylactic or therapeutic gain.