UCSF

The composition and metabolic activity of the gut microbiome are implicated in childhood obesity, though etiology of the disease remains unclear. Using 16S bacterial and ITS2 fungal biomarker sequencing, we identify a precocious gut microbiota in more frequently formula fed 1-month-old infants that relates with higher relative risk for overweight or obesity (OW/OB) phenotypes at two years of age. Integrated shotgun metagenomic and untargeted metabolomic profiling revealed that higher-risk infant microbiomes exhibited accelerated functional maturation and broad-ranging metabolic reprogramming, including evidence for increased fermentation and amino acid catabolism. In vitro, exposure of enterocytes to cell-free fecal extracts of higher-risk infants who became OW/OB at 2-years reprogrammed transcription and cellular function, promoting obesity-associated gene expression and increasing triglyceride absorption. Of several microbial species screened, Candida albicans recapitulated accelerated triglyceride trafficking by enterocytes, via a small, secreted polar molecule in an infant formula-dependent manner. Thus, appropriately paced early life development of microbiome function and metabolism appear crucial determinants of childhood obesity.