GI Tract Biomarkers in Infants With Different Diets

Longitudinal, Prospective Comparison of the Gastrointestinal Tract of Breastfed and Formula Fed Infants Via Fecal Analysis of the Microbiome, Intestinal Epithelial Cell Expression of Gut Hormones, and Fecal Analysis of the Metabolome

Childhood obesity is increasing with more than one-third of adolescents currently overweight and one in five with obesity. The lifelong incidence of obesity-related morbidities is also increasing with childhood obesity. It is not yet known how obesity develops in an individual, specifically in early childhood. Further, it is unclear what mechanistic role a child's earliest nutrition or changing intestinal flora has in the etiology of obesity. Very young children are developing appetite and satiety patterns early in life. Nutrition and gut microbial flora have impact on how these processes unfold, but specific mechanisms are not yet well understood. The investigators hypothesize that formula-fed infants with changes in their microbial flora are more likely to have altered carbohydrate metabolism, evidenced by greater imbalances of fatty acid production, and are more likely to have accelerated growth trajectory due to satiety disruption. The investigators further hypothesize that altered carbohydrate metabolism, e.g. imbalances of short- and long-chain fatty acid levels in the gut, stimulate cellular stress and affect specific gut hormones. This study will compare the microbiome of the intestinal microbial flora in two groups of infants, one breast fed and the other formula fed, using longitudinally collected fecal samples from both groups. Samples will be subjected to shotgun metagenomic analysis and simultaneous metabolomic analysis. A bioinformatics approach will elucidate key differences among and between sample groups, and will further analyze bacterial gene expression levels related to carbohydrate metabolism. This study will compare the expression of human proteins involved in cellular stress response and gut peptide signaling by applying quantitative Reverse Transcriptase-Polymerase Chain Reaction to human messenger RNA isolated from the longitudinally collected samples from both groups. Finally, this study will monitor the trajectory of growth and feeding over the first 2 years of life. The project's focus on the influence of different early feeding types, microbial flora changes, and altered carbohydrate metabolism leading to disruption of gut-brain signaling will provide critical data for host:microbiome interactions and translational therapeutic targets.

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity, Childhood

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours Children's Hospital - Delaware

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 3 months (Child)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Infants who are either exclusively breast feeding or exclusively formula feeding are eligible to enroll if meeting other criteria.

Description

Inclusion Criteria:

• Otherwise healthy, male or female term infants
• Exclusively breast or formula feeding
• Never been exposed to oral or intravenous antibiotics or probiotics

Exclusion Criteria:

• Maternal antibiotic use while breast-feeding
• Infant or maternal use of probiotics
• Current or recent (<14 days) gastrointestinal infection (viral, bacterial, or fungal)
• Gastrointestinal mucosal disease, or significant constipation
• Consuming formula that is not standard cow's milk formula
• Infants on acid suppression medications or infants receiving high-density formula (>20 calories/ounce) may be enrolled and will be analyzed separately

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Breast Feeding; Infants who, when enrolled, are exclusively breast feeding.
Formula Feeding; Infants who, when enrolled, are exclusively formula feeding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome	Metagenomic analysis of microbial organisms in infant's feces	Enrollment
Microbiome	Metagenomic analysis of microbial organisms in infant's feces	6 months
Microbiome	Metagenomic analysis of microbial organisms in infant's feces	12 months
Microbiome	Metagenomic analysis of microbial organisms in infant's feces	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolome	Metabolic products present in infant's feces	Enrollment
Metabolome	Metabolic products present in infant's feces	6 months
Metabolome	Metabolic products present in infant's feces	12 months
Metabolome	Metabolic products present in infant's feces	18 months
Gut hormone gene expression	Transcriptional output of human epithelial cells in infant's feces	Enrollment
Gut hormone gene expression	Transcriptional output of human epithelial cells in infant's feces	6 months
Gut hormone gene expression	Transcriptional output of human epithelial cells in infant's feces	12 months
Gut hormone gene expression	Transcriptional output of human epithelial cells in infant's feces	18 months

Collaborators and Investigators

• Sponsor: Nemours Children's Clinic
• Collaborators: University of Delaware
• Investigators: Principal Investigator: Matthew Di Guglielmo, MD PhD, Nemours

Publications and helpful links

General Publications

• Di Guglielmo MD, Franke KR, Robbins A, Crowgey EL. Impact of Early Feeding: Metagenomics Analysis of the Infant Gut Microbiome. Front Cell Infect Microbiol. 2022 Mar 4;12:816601. doi: 10.3389/fcimb.2022.816601. eCollection 2022.
• Di Guglielmo MD, Franke K, Cox C, Crowgey EL. Whole genome metagenomic analysis of the gut microbiome of differently fed infants identifies differences in microbial composition and functional genes, including an absent CRISPR/Cas9 gene in the formula-fed cohort. Hum Microb J. 2019 Jun;12:100057. doi: 10.1016/j.humic.2019.100057. Epub 2019 May 25.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2016
• Primary Completion (Actual): July 31, 2021
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: November 16, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 23, 2018

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Microbiome; Hormone; Satiety; Metabolome; Gut-brain axis
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Pediatric Obesity
• Other Study ID Numbers: 822736

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will release deidentified metagenomic sequencing data from each participant to either database of Genotypes and Phenotypes (dbGaP) or Sequence Read Archive (SRA).
• IPD Sharing Time Frame: At the conclusion of the study
• IPD Sharing Access Criteria: To be determined
• IPD Sharing Supporting Information Type: SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No