Senior Investigator, Section Chief National Institute of Dental and Craniofacial Research, National Institutes of Health Bethesda, Maryland, United States
Disclosure(s):
Wanjun Chen, MD: No financial relationships to disclose
Introduction/Rationale: The neonatal dysbiosis of gut microbiota represents a critical environmental factor promoting obesity, but the underlying immunological mechanisms remain unknown.
Methods: Neonatal mice (from day1) were treated with broad-spectrum antibiotics for the first 3 weeks of life (NeoATB) only . The mice were then hosted under a normal environment for rest of their life.
Results: 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 dendritic 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.
Conclusion: Thus, we have revealed a previously unrecognized immunological link between neonatal microbiota dysbiosis and the development of obesity.
