Profound Pathogen-Specific Alterations in Intestinal Microbiota Composition Precede Late-Onset Sepsis in Preterm Infants: A Longitudinal, Multicenter, Case-Control Study

S.E. El Hassani*, H.J. Niemarkt, D.J.C. Berkhout, C.F.W. Peeters, C.V. Hulzebos, A.H. van Kaam, B.W. Kramer, R.A. van Lingen, F. Jenken, W.P. de Boode, M.A. Benninga, A.E. Budding, M.M. van Weissenbruch, N.K.H. de Boer, T.G.J. de Meij

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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. This multicenter case-control study included preterm infants born under 30 weeks of gestation. Fecal samples collected from the 5 days preceding LOS diagnosis were analyzed using a molecular microbiota detection technique. LOS cases were subdivided into 3 groups: gram-negative, gram-positive, and coagulase-negative Staphylococci (CoNS).Results. Forty LOS cases and 40 matched controls were included. In gram-negative LOS, the causative pathogen could be identified in at least 1 of the fecal samples collected 3 days prior to LOS onset in all cases, whereas in all matched controls, this pathogen was absent (P =.015). The abundance of these pathogens increased from 3 days before clinical onset. In gram-negative and gram-positive LOS (except CoNS) combined, the causative pathogen could be identified in at least 1 fecal sample collected 3 days prior to LOS onset in 92% of the fecal samples, whereas these pathogens were present in 33% of the control samples (P =.004). Overall, LOS (expect CoNS) could be predicted 1 day prior to clinical onset with an area under the curve of 0.78.Conclusions. Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as an early noninvasive biomarker.
Original languageEnglish
Pages (from-to)E224-E232
Number of pages9
JournalClinical Infectious Diseases
Issue number1
Publication statusPublished - 1 Jul 2021


  • gram-negative sepsis
  • gut-derived sepsis
  • microbiota
  • dysbiosis
  • RISK
  • GUT

Cite this