A Phase II Trial to Prevent Linear Growth Stunting and Malnutrition in Impoverished Children from a Low-Income Country by Treating Small Intestine Bacterial Overgrowth

/ABSTRACT Stunting affects 23.8% of children under age 5 and is associated with poor neurodevelopment and early death. Small intestine bacterial overgrowth (SIBO) in impoverished children living in unsanitary environments in low-income countries is associated with intestinal inflammation and stunting. This project will build upon our preliminary data showing that SIBO predicts future stunting. Our objectives are to determine if treating SIBO in Bangladeshi infants under ideal conditions (i.e. frequent screening and treatment of all episodes) improves growth and to determine the structure and function of the enteric dysbiosis that children with SIBO have. Further, we will determine how this aberrant microbiome affects human metabolism to cause stunting and malnutrition. To this end, we have 3 aims. Aim 1 is to conduct a Phase IIa trial to determine the optimal antibiotic regimen to treat SIBO in Bangladeshi toddlers. In this treatment optimization trial, we will test three antibiotic regimens (amoxicillin-clavulanate, metronidazole, and trimethoprim-sulfamethoxazole + metronidazole) given for 14 days for their efficacy in reversing a positive glucose-hydrogen breath test, the most commonly used SIBO diagnostic. Aim 2 is a treatment efficacy study in which we will conduct an assessor blinded passively controlled Phase IIb trial to test if a package intervention of frequent SIBO testing and treatment of all positive tests improves growth and enteric inflammation over the first 18 months of life. Children will be enrolled at birth and randomized to an active or control arm. All children will be breath tested for SIBO every 6 weeks. Children in the active arm will receive the optimal antibiotic regimen chosen in the Phase IIa trial for 14 days in response to each positive test. Children in the control arm will not be treated. Our primary outcome is length-for-age Z score at 18 months. Aim 3 will define the relationship between the enteric lactate-H2-butyrate economy seen in SIBO and host metabolism. Preliminary data indicates that a positive breath test is associated with increased enteric Lactobacillus species (lactate producers), decreased butyrate producers, and an excess of enteric hydrogen. However, the details of the interactions between these commensal populations are poorly understood. We will conduct two sets of comparisons between 1) SIBO positive and SIBO negative children and; 2) between SIBO positive children before and after treatment, all enrolled in the Phase IIb trial. We will compare fecal metagenomics and metatranscriptomics as well as serum metabolomics to understand the structure and function of the SIBO dysbiosis and how it leads to alterations in growth and development. This work seeks to utilize a novel treatment strategy for malnutrition by targeting antimicrobial therapy only to the subset of malnourished children with SIBO. It also seeks to further our understanding of the mechanisms by which the SIBO microbiome influences growth and development. Project Number: 1R01HD113733-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jeffrey Donowitz | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $499,076 | Activity Code: R01 | Study Section: Etiology, Diagnostic, Intervention and Treatment of Infectious Diseases Study Section[EDIT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11373301A1