Preterm birth yields survivors with heightened susceptibility to long-term neurological deficits, with severity being linked to gestational age. The mechanisms behind neurodevelopmental impairment remain elusive, although research underscores the role of the gut microbiome in regulating the gut-brain axis. In this prospective observational cohort study (PROPEL-study follow-up) we evaluated whether modulation of the gut microbiota by Limosilactobacillus reuteri supplementation to 105 extremely preterm infants with extremely low birth weight (EPT-ELBW), as well as their microbiota development during the first month of life, are associated with neurodevelopment at two years of age. The gut microbiota was characterized with 16S amplicon sequencing, and neurodevelopment was assessed with clinical examination and the Bayley-III score. Our results indicate that specific microbiota composition constellations are associated with impaired neurodevelopment, as indicated by alpha- and beta-diversity being discriminative for neurodevelopment, but not a single bacterium, with increased bacterial diversity being associated to normal neurodevelopment. Microbial maturation over the first month of life was also discriminative for neurodevelopment, where higher abundance of E. coli and Enterococcus in relation to Enterobacter was associated to impaired neurodevelopment. In conclusion, the dynamics of gut microbiota maturation during early of life may have an impact on neurodevelopment in EPT-ELBW infants.

TA has received honoraria for lectures and a grant for the present trial from Biogaia AB. The other authors have indicated they have no potential conflict of interest to disclose.

NCT01603368

The study was supported by grants from the Swedish Research Council (grant number 921.2014-7060), the Swedish Society for Medical Research, the Swedish Society of Medicine, the Research Council for the South-East Sweden, ALF Grants, Region Ostergotland, the Ekhaga Foundation, and BioGaia AB. BioGaia AB also provided the study product at no cost.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Committee for Human Research in Linkoping gave ethical approval for this work. Dnr 2012/28-31, 2016/503-32, 2019-04975

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors