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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Neurobehavioral Manifestations; Sleep Problem
• Intervention / Treatment: Dietary supplement: Synbiotic; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 380
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Petra Zimmermann, MD, PhD; Phone Number: +412063060000; Email: petra.zimmermann@unifr.ch

Study Locations

• Switzerland
  • Fribourg, Switzerland, 1700
    • Hopital cantonal Fribourg
  • Lucerne, Switzerland, 6000
    • Cantonal Hospital
    • Contact: Martin Stocker, MD; Phone Number: +4141 205 32 31; Email: martin.stocker@luks.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Preterm-born infants assigned to "synbiotics" (PRET-SYN)	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
Placebo Comparator: Preterm-born infants to "placebo" (PRET-PLC)	Dietary supplement: Placebo; The capsule contains zinc oxide, coating agent, methyl hydroxypropyl cellulose, anti-caking agent and magnesium stearat
Active Comparator: Term-born infants to "synbiotics" (TERM-SYN)	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
Placebo Comparator: Term-born infants to "placebo" (TERM-PLC)	Dietary supplement: Placebo; The capsule contains zinc oxide, coating agent, methyl hydroxypropyl cellulose, anti-caking agent and magnesium stearat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuronal connectivity	High-density EEG during sleep	up to two years of age
Behavior	Infant Behavior Questionnaire	up to two years of age
Sleep-wake behavior	Brief Infant Sleep Questionnaire BISQ, actinometry and sleep-wake diary	up to two years of age
Neurobehavioral development	Bayley Scales of Infant Development	up to two years of age
Gut microbiota	Composition of stool microbiota	up to two years of age
Stool metabolome	Composition of stool metabolites	up to two years of age
Breath metabolome	Composition of breath metabolites	up to two years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eczema	SCORing Atopic Dermatitis scoring system (SCORAD)	up to two years of age
Food allergy	Skin prick test	up to two years of age
Rates of infection	Number of episodes	up to two years of age
Breast milk microbiota	Composition investigated trough shotgun metagenomic sequencing	up to two years of age
Nasal microbiota	Composition investigated trough shotgun metagenomic sequencing	up to two years of age
Oral microbiota	Composition investigated trough shotgun metagenomic sequencing	up to two years of age

Collaborators and Investigators

• Sponsor: Petra Zimmermann
• Collaborators: Swiss Federal Institute of Technology in Zurich (ETHZ); University of Luzern

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): February 28, 2029
• Study Completion (Estimated): February 28, 2029

Study Registration Dates

• First Submitted: April 10, 2024
• First Submitted That Met QC Criteria: April 29, 2024
• First Posted (Actual): May 2, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 17, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: probiotics; microbiome; infant; gut; development; metagenomics; brain-gut; synbiotics; metabolics; pre-term
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Dyssomnias; Parasomnias; Neurobehavioral Manifestations
• Other Study ID Numbers: 123 (Giresun University Scientific Research Project)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No