The gut as a source of infection for fungal pathogens: increased fecal Candida albicans precedes onset of Candida late-onset sepsis in very preterm infants.

BACKGROUND The skin-to-blood route is traditionally considered the main pathway in Candida late-onset sepsis (LOS) development in preterm infants. However, emerging evidence suggests that the gut also serves as a source of infection. We aimed to characterize fecal mycobiota and microbiota profiles preceding onset of Candida LOS to assess the role of the preterm gut microbiome in disease development. METHODS In this multicenter, case-control study, very preterm infants (<30 weeks of gestation) with Candida LOS were included. Each case was matched to non-affected controls by gestational and postnatal age, hospital site, and/or cumulative antibiotic exposure prior to day of LOS onset (t=0). Fecal samples collected at t=0 and the five preceding days were analyzed using ITS1 and 16S RNA sequencing. Microbial amplicon yields, composition, and inter-kingdom correlations were assessed. RESULTS Of 2,397 screened infants, fecal samples were available for 8/19 infants with Candida LOS. In these 8 cases, the ITS/16S amplicon yield ratio was increased (p<0.001) and the relative abundance of fecal Candida albicans correlated positively with fungal amplicon yield (ρ=0.71, padj=0.005), suggesting increased absolute abundance up to five days before onset. Additionally, bacterial yields were significantly lower (p=0.02) and α-diversity was significantly decreased (p=0.012), compared to the controls. CONCLUSIONS Increased fecal C. albicans preceded Candida LOS onset, implicating the preterm gut as a potential source of infection. Reduced bacterial yields and diversity suggest ecological alterations that may facilitate Candida pathogenicity in the preterm gut. These findings support further research into gut-derived Candida LOS and potential for microbiota-targeted prevention strategies.