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

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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: This multicenter case-control study included very preterm infants (<30 weeks of gestation) with Candida LOS. Each case was matched to nonaffected 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 5 preceding days were analyzed by ITS1 and 16S RNA sequencing. Microbial amplicon yields, composition, and interkingdom correlations were assessed. RESULTS: Of 2397 screened infants, fecal samples were available for 8 of 19 infants with Candida LOS. In these 8 cases, the ITS/16S amplicon yield ratio was increased (P < .001), and the relative abundance of fecal Candida albicans correlated positively with fungal amplicon yield (ρ = 0.71, adjusted P = .005), suggesting increased absolute abundance up to 5 days before onset. Additionally, bacterial yields were significantly lower (P = .02) and α-diversity significantly decreased (P = .012) when 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 the potential for microbiota-targeted prevention strategies.