NapBiome: Targeting Gut Microbiota and Sleep Rhythm to Improve Developmental and Behavioral Outcomes in Early Childhood

Overview

The gut-brain axis plays a crucial role in the regulation and development of psychological and physical processes. The first year of life is a critical period for the development of the gut microbiome, which parallels important milestones in establishing sleep rhythm and neurodevelopment. Growing evidence suggests that the gut microbiome influences sleep, cognition, and early neurodevelopment. For term and preterm-born infants, difficulties in sleep regulation can have major consequences on infants' health, attachment between infants and their caregivers, and can even lead to life-threatening consequences such as shaken-baby syndrome. Preterm born infants are at even higher risk for sleep and neurodevelopmental problems. Although neonatal care has improved over recent decades, preterm birth rates continue to rise and lead to a wide range of neurodevelopmental disabilities that are unaddressed with current therapies. Given the importance of sleep and the gut microbiome for brain maturation, neurodevelopment, and behavior, identifying effective interventions within the gut-brain axis at the beginning of life is likely to have long-term implications for health and development of at-risk infants. The aims of this project are to I) demonstrate the association between the gut microbiome, sleep patterns and health outcomes in children up to two years of age; and II) to leverage gut microbiome-brain-sleep interactions to develop new intervention strategies for at-risk infants. The investigators hypothesize that the establishment of a healthy gut microbiome during early life is crucial for both short- and long-term child health outcomes, as dysbiosis can harm sleep regulation, brain maturation, and neurobehavioral development. The investigators predict that the administration of synbiotics improves microbiota establishment, sleep rhythm, and neurodevelopmental outcomes. This project integrates a randomized controlled trial (RCT), ex vivo, and in silico experiments with I) key technology platforms for computational modeling to capture the ontogenic norms of gut microbiota; II) neuronal and actimetry-based quantification of multidimensional aspects of infant sleep; III) breath metabolomics (exhalomics) of host and microbiome metabolism; and IV) high-throughput ex vivo models for investigating host-microbiome interactions. Outcomes include I) an understanding of age-normative microbiome composition, its variation (circadian, inter-individual), and the factors that influence the microbiome's plasticity throughout infancy; II) actionable knowledge of microbial species and metabolism that can be targeted to modify sleep regulation and improve neurodevelopmental outcomes, especially in at-risk infants (e.g., preterm-born); III) microbial and metabolic biomarkers with diagnostic potential for later regulatory and behavioral problems; and IV) an open-source analytical "toolbox" for microbial multi-omics that can be immediately applied in other areas of microbiome-host research. To achieve these goals, our strategy combines multiple disciplines focusing on factors that exert the greatest influence on health during infancy: the gut microbiome, sleep regulation, and neurodevelopment. The impact of this project is substantial and globally relevant, as it advances possible treatment options for supporting neurodevelopmental health in preterm- and term-born infants, explores novel translational approaches for addressing regulatory difficulties, and provides key information for tailored prophylactic synbiotics and possible development of "post-biotics". Further, the study supports the investigation of biomarkers for neurodevelopment and advances early prevention of developmental and mental illnesses.

Interventions

• Dietary supplement Synbiotic
  The capsule contains Lactobacillus helveticus R0052, Bifidobacterium infantis R0033, and Bifidobacterium bifidum R0071 (3 billion bacteria per capsule), as well as zinc oxide, potato starch fructooligosaccharides, coating agent, methyl hydroxypropyl cellulose, anti-caking agent and magnesium stearat
• Dietary supplement Placebo
  The capsule contains zinc oxide, coating agent, methyl hydroxypropyl cellulose, anti-caking agent and magnesium stearat

Primary outcome measures

• Sleep-wake behavior [Time frame: up to two years of age]
• Neuronal connectivity [Time frame: up to two years of age]
• Neurobehavioral development [Time frame: up to two years of age]
• Behavior [Time frame: up to two years of age]
• Gut microbiota [Time frame: up to two years of age]
• Stool metabolome [Time frame: up to two years of age]
• Breath metabolome [Time frame: up to two years of age]

Secondary outcome measures (6)

• Eczema [Time frame: up to two years of age]
• Food allergy [Time frame: up to two years of age]
• Rates of infection [Time frame: up to two years of age]
• Breast milk microbiota [Time frame: up to two years of age]
• Nasal microbiota [Time frame: up to two years of age]
• Oral microbiota [Time frame: up to two years of age]

Eligibility criteria

Inclusion criteria

Preterm-arm:

• neonates born between a gestational age of 34 0/7 to 36 6/7 weeks
• partially breast-fed at the time of inclusion

Term-arm

• neonates born at a gestational age of ≥ 37 0/7 weeks Infants need to be
• partially breast-fed at the time of inclusion

Exclusion criteria

Infants who

• receive probiotics outside the trial design
• have a birth weight < 1500 g
• were prenatally drug-exposed (cannabis, cocaine, heroin, opiates, and alcohol)
• have suspected or confirmed immunodeficiency
• have an underlying disease (excluding transient conditions such as alimentation problems, hyperbilirubinemia, hypoglycaemia, anemia, respiratory distress syndrome or apnea-bradycardia syndrome), congenital malformations, central nervous system disease or injury or congenital infections

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Switzerland · 2 centers

• Hopital cantonal Fribourg — Fribourg
• Cantonal Hospital — Lucerne

Publications

• Zimmermann P, Kurth S, Giannoukos S, Stocker M, Bokulich NA. NapBiome trial: Targeting gut microbiota to improve sleep rhythm and developmental and behavioural outcomes in early childhood in a birth cohort in Switzerland - a study protocol. BMJ Open. 2025 Mar 3;15(3):e092938. doi: 10.1136/bmjopen-2024-092938. PMID 40032396

Identifiers

NCT: NCT06396689 · 123

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗