The Macronutrient Composition of Infant Formula Produces Differences in Gut Microbiota Maturation That Associate with Weight Gain Velocity and Weight Status

This proof-of-principle study analyzed fecal samples from 30 infants who participated in a randomized controlled trial on the effects of the macronutrient composition of infant formula on growth and energy balance. In that study, infants randomized to be fed cow milk formula (CMF) had faster weight-gain velocity during the first 4 months and higher weight-for-length Z scores up to 11.5 months than those randomized to an isocaloric extensive protein hydrolysate formula (EHF). Here we examined associations among infant formula composition, gut microbial composition and maturation, and children’s weight status. Fecal samples collected before and monthly up to 4.5 months after randomization were analyzed by shotgun metagenomic sequencing and targeted metabolomics. The EHF group had faster maturation of gut microbiota than the CMF group, and increased alpha diversity driven by Clostridia taxa. Abundance of Ruminococcus gnavus distinguished the two groups after exclusive feeding of the assigned formula for 3 months. Abundance of Clostridia at 3–4 months negatively correlated with prior weight-gain velocity and body weight phenotypes when they became toddlers. Macronutrient differences between the formulas likely led to the observed divergence in gut microbiota composition that was associated with differences in transient rapid weight gain, a well-established predictor of childhood obesity and other comorbidities.