Precocious infant gut microbiome reprograms enterocytes and promotes childhood obesity risk

Composition and metabolic activity of the gut microbiome are associated with childhood obesity, though microbial mechanistic contributions to disease origins remain unclear. Here, we identify a distinct gut microbiota in more frequently formula-fed 1-month-old infants that related with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including loss of microbial strategies for energy biogenesis and reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to cell-free fecal extracts of higher-risk infants induced expression of genes canonically associated with both obesity and nutrient sensing enteroendocrine progenitor cells; functionally, they reduced enterocyte barrier function. These data implicate dysregulation of infant microbiome functional development, and more specifically diminished microbial nutrient harvest, altered enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.