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.