title: Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Clinical data and infant stool and fasting HM samples were collected from 18 NW [prepregnancy BMI (in kg/m(2)) <24.0] and 12 obese (prepregnancy BMI >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%.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sections of Neonatology.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Lemas
authors.affiliation: Nutrition, and.
authors.forename: Bridget E
authors.initials: BE
authors.lastname: Young
authors.affiliation: Clinical Genetics and Metabolism, Department of Pediatrics;
authors.forename: Peter R
authors.initials: PR
authors.lastname: Baker
authors.affiliation: Sections of Neonatology.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Tomczik
authors.affiliation: Sections of Neonatology.
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Soderborg
authors.affiliation: Divisions of Endocrinology, Metabolism, and Diabetes and College of Nursing;
authors.forename: Teri L
authors.initials: TL
authors.lastname: Hernandez
authors.affiliation: Sections of Neonatology.
authors.forename: Becky A
authors.initials: BA
authors.lastname: de la Houssaye
authors.affiliation: Infectious Diseases, Department of Medicine;
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.affiliation: Divisions of Endocrinology, Metabolism, and Diabetes and.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rudolph
authors.affiliation: Infectious Diseases, Department of Medicine;
authors.forename: Diana
authors.initials: D
authors.lastname: Ir
authors.affiliation: Nutrition, and.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Patinkin
authors.affiliation: Nutrition, and.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Krebs
authors.affiliation: Human Medical Genetics and Genomics Program; and Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO; and.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Santorico
authors.affiliation: Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Weir
authors.affiliation: Divisions of Endocrinology, Metabolism, and Diabetes and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO;
authors.forename: Linda A
authors.initials: LA
authors.lastname: Barbour
authors.affiliation: Infectious Diseases, Department of Medicine;
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Frank
authors.affiliation: Sections of Neonatology, Divisions of Endocrinology, Metabolism, and Diabetes and jed.friedman@ucdenver.edu.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001823:Body Composition; D015992:Body Mass Index; D001942:Breast Feeding; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005232:Fatty Acids, Volatile / Q000032:analysis; D005243:Feces / Q000737:chemistry; D005260:Female; D020563:Gammaproteobacteria / Q000302:isolation & purification; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007223:Infant; D007328:Insulin / Q000032:analysis*; D056546:Lactobacillales / Q000302:isolation & purification; D020738:Leptin / Q000032:analysis*; D016014:Linear Models; D008297:Male; D008895:Milk, Human / Q000737:chemistry*; D015999:Multivariate Analysis; D009765:Obesity / Q000097:blood / Q000517:prevention & control; D010991:Plethysmography; D011770:Pyruvate Kinase / Q000097:blood; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D005232:Fatty Acids, Volatile; D007328:Insulin; D020738:Leptin; D011770:Pyruvate Kinase
keywords: Gammaproteobacteria; breastfed; maternal obesity; metagenomics; pyruvate kinase