High-resolution mycobiota analysis reveals dynamic intestinal translocation prior to invasive candidiasis

The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi(1,2). While the composition of bacterial constituents has been linked to immune homeostasis and to infectious susceptibility(3–7), the role of non-bacterial constituents and of cross-kingdom microbial interactions in these processes is poorly understood(2,8). Fungi represent a major cause of infectious morbidity and mortality in immune-compromised individuals, though the relationship of intestinal fungi (i.e., the mycobiota) with fungal bloodstream infections (BSI) 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 (allo-HCT). Patients with Candida BSI 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 species was associated with a significant 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 for fungal BSI for pre-emptive therapeutic intervention.