High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis

The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi(1,2). Although the composition of bacterial constituents has been linked to immune homeostasis and infectious susceptibility(3-7), the role of non-bacterial constituents and cross-kingdom microbial interactions in these processes is poorly understood(2,8). Fungi represent a major cause of infectious morbidity and mortality in immunocompromised individuals, although the relationship of intestinal fungi (that is, the mycobiota) with fungal bloodstream infections remains undefined(9). We integrated an optimized bioinformatics pipeline with high-resolution mycobiota sequencing and comparative genomic analyses of fecal and blood specimens from recipients of allogeneic hematopoietic cell transplant. Patients with Candida bloodstream infection experienced a prior marked intestinal expansion of pathogenic Candida species; this expansion consisted of a complex dynamic between multiple species and subspecies with a stochastic translocation pattern into the bloodstream. The intestinal expansion of pathogenic Candida spp. was associated with a substantial loss in bacterial burden and diversity, particularly in the anaerobes. Thus, simultaneous analysis of intestinal fungi and bacteria identifies dysbiosis states across kingdoms that may promote fungal translocation and facilitate invasive disease. These findings support microbiota-driven approaches to identify patients at risk of fungal bloodstream infections for pre-emptive therapeutic intervention. Expansion of pathogenic Candida species coupled with bacterial dysbiosis in the gut precedes Candida bloodstream infections in hematopoietic cell transplant recipients.