Neonatal Exposure to Antibiotics Triggers Obesity in Adulthood by Permanent Microbiota Dysbiosis and Reduction of Adipose Regulatory T Cells

Abstract

Neonatal dysbiosis of the gut microbiota represents a critical environmental factor promoting obesity, but the underlying immunological mechanisms remain unknown. We show here that neonatal treatment of mice with broad-spectrum antibiotics for the first 3 weeks of life (NeoATB) resulted in the development of obesity and metabolic abnormalities in adulthood. The NeoATB mice exhibited a permanent dysbiosis of gut microbiota, decreased CD4+Foxp3+ regulatory T cells (Tregs), and increased proinflammatory Th1 cells in visceral adipose tissue (VAT). Mechanistically, neonatal antibiotic treatment resulted in increased intestinal permeability that allowed bacterial translocation into the VAT and liver and an increase in systemic LPS levels. Consequently, VAT CD11c+MHCII+ cells were activated via the TLR4 pathway to increase IL-12-triggered Th1-inflammation. Moreover, the decrease in VAT Tregs in NeoATB mice was attributed to reduced infiltration of Tregs from the periphery, decreased expansion of adipose IL-33-mediated ST2+ Tregs, and reduced conversion of local Tregs from VAT CD4+CD25− Foxp3− T cells. Thus, we have revealed a previously unrecognized immunological link between neonatal microbiota dysbiosis and the development of obesity.