Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome

Increased maternal body mass index (BMI) is a robust risk factor for later pediatric obesity. Accumulating evidence suggests that human milk (HM) may attenuate the transfer of obesity from mother to offspring, potentially through its effects on early development of the infant microbiome. Our objective was to identify early differences in intestinal microbiota in a cohort of breastfeeding infants born to obese compared with normal-weight (NW) mothers. We also investigated relations between HM hormones (leptin and insulin) and both the taxonomic and functional potentials of the infant microbiome. Clinical data and infant stool and fasting HM samples were collected from 18 NW [prepregnancy BMI (in kg/m(2)) 30.0) mothers and their exclusively breastfed infants at 2 wk postpartum. Infant body composition at 2 wk was determined by air-displacement plethysmography. Infant gastrointestinal microbes were estimated by using 16S amplicon and whole-genome sequencing. HM insulin and leptin were determined by ELISA; short-chain fatty acids (SCFAs) were measured in stool samples by using gas chromatography. Power was set at 80%. Infants born to obese mothers were exposed to 2-fold higher HM insulin and leptin concentrations (P < 0.01) and showed a significant reduction in the early pioneering bacteria Gammaproteobacteria (P = 0.03) and exhibited a trend for elevated total SCFA content (P < 0.06). Independent of maternal prepregnancy BMI, HM insulin was positively associated with both microbial taxonomic diversity (P = 0.03) and Gammaproteobacteria (e.g., Enterobacteriaceae; P = 0.04) and was negatively associated with Lactobacillales (e.g., Streptococcaceae; P = 0.05). Metagenomic analysis showed that HM leptin and insulin were associated with decreased bacterial proteases, which are implicated in intestinal permeability, and reduced concentrations of pyruvate kinase, a biomarker of pediatric gastrointestinal inflammation. Our results indicate that, although maternal obesity may adversely affect the early infant intestinal microbiome, HM insulin and leptin are independently associated with beneficial microbial metabolic pathways predicted to increase intestinal barrier function and reduce intestinal inflammation. This trial was registered at clinicaltrials.gov as NCT01693406.