Profound pathogen-specific alterations in intestinal microbiota composition precede late onset sepsis in preterm infants: A longitudinal multicenter case-control study.

BACKGROUND The role of intestinal microbiota in the pathogenesis of late onset sepsis (LOS) in preterm infants is largely unexplored, but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis with causative bacteria that are isolated later in blood culture. METHODS In this multicenter case-control study preterm infants born under 30 weeks of gestation were included. Fecal samples collected from the five days preceding LOS diagnosis, were analyzed by a molecular microbiota detection technique. LOS cases were subdivided into three groups: Gram-negative, Gram-positive and Coagulase negative Staphylococci (CoNS). RESULTS Totally, 40 LOS cases and 40 matched controls were included. In Gram-negative LOS, the causative pathogen could be identified in at least one of the fecal samples collected three days prior LOS onset in all cases, whereas in all matched controls this pathogen was absent (p-value 0.015). The abundance of these pathogens increased from three days towards clinical onset. In Gram-negative and -positive LOS (except CoNS) combined, the causative pathogen could be identified in at least one fecal sample collected three days prior to LOS onset in 92% of the fecal samples of cases, whereas these pathogens were present in 33% of the control samples (p-value 0.004). Overall, LOS (expect CoNS) could be predicted one day prior clinical onset with an AUC of 0.78. CONCLUSIONS Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as early non-invasive biomarker.