Synbiotic supplementation leads to gut microbiome communities with functional capacity linked to better brain white matter development in preterm infants.

Anna Voulgari-Kokota, Els Janson, Ineke Heikamp de Jong, Jan Knol, Ruurd van Elburg, Niek E van der Aa, Lisa M Hortensius, Jeroen Dudink, Caroline G M de Theije, Lidewij Schipper, Marta Kozior, Monique van de Lagemaat, Floris Groenendaal, Frank van Bel, Annemieke Wildt-Grootendorst, Sandra Drost-Verhoef, Annelies Hennink, Charlie C Obihara, Jacqueline L A M van Hillegersberg-Schilder, Carin M Dassel, Johanna H Oudshoorn, Clemens B Meijssen, Inge P de Boer, Károly E Illy, Nathalie Claessens, Max A Viergever, Ivana Isgum, Sudarshan Shetty, Harm Wopereis, Manon Benders, Clara Belzer

Journal: Gut microbes 2026;18(1):2743949

PMID: 42841652

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Abstract

Preterm birth, a major cause of brain injury, is often linked to dysregulated gut microbiome development. This association underscores microbial metabolic function as a modifiable target to support neurodevelopment. In this secondary analysis of data derived from a randomized controlled trial (Trial Registration: ISRCTN96620855), we tested whether daily nutritional supplementation with Bifidobacterium breve M-16V, short- and long-chain oligosaccharides, and L-glutamine could steer the gut microbiome of very and extremely preterm infants toward communities that support brain maturation. The gut microbiome was profiled with longitudinal shotgun metagenomics at nine time points during the intervention, which started at 48-72 h after birth and continued until 36 weeks postmenstrual age. Additionally, MRI scans were conducted when infants reached term-equivalent age to evaluate brain maturation. Supplementation promoted the early establishment of Bifidobacterium-rich communities in the test group, with enhanced capacity for amino acid biosynthesis and pyruvate fermentation towards acetate and lactate production. Integration of microbiome data with brain developmental markers post hoc showed that the same functions were markedly reduced in infants with delayed white-matter myelination. By integrating microbiome functional capacity profiling and evaluation of brain maturation via MRI, this study demonstrated that early microbial modulation could influence brain development, positioning the preterm gut microbiome as a clinically actionable target.

Address: Laboratory of Microbiology, Wageningen University & Research, Wageningen, The Netherlands.; Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.; Danone Research & Innovation, Utrecht, The Netherlands.; Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands.; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Utrecht, The Netherlands.; Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Pediatrics, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands.; Department of Pediatrics, Sint Antonius Hospital, Nieuwegein, The Netherlands.; Department of Pediatrics, Deventer Hospital, Deventer, The Netherlands.; Department of Pediatrics, Gelre Hospital, Apeldoorn, The Netherlands.; Department of Pediatrics, Meander Medical Centre, Amersfoort, The Netherlands.; Department of Pediatrics, Diakonessenhuis, Utrecht, The Netherlands.; Department of Pediatrics, Hospital Rivierenland, Tiel, The Netherlands.; Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.; Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.; Department of Biomedical Engineering & Physics, Amsterdam University Medical Center, Amsterdam, The Netherlands.; Informatics Institute, University of Amsterdam, Amsterdam, The Netherlands.; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands.

DOI: 10.1080/19490976.2026.2743949

MeSH Terms: Humans, Infant, Newborn, Infant, Premature, White Matter, Brain, Gastrointestinal Microbiome, Synbiotics, Dietary Supplements, Male, Bifidobacterium breve, Glutamine, Female, Oligosaccharides, Neurodevelopment, Magnetic Resonance Imaging, Infant