Small intestine microbiota development prevents early-life adiposity via IL-22-mediated intestinal PPARα suppression

Perturbation to the early-life microbiota has long-term detrimental effects on health and development, leading to increased risk for metabolic dysfunction and childhood obesity. Despite the central role of the small intestine (SI) in energy balance, the impact of SI microbiota establishment on the regulation of host metabolism and early-life adiposity remains unclear. Here, we report that disruption of a critical SI microbiota-intestinal epithelial cell circuit, specifically during a critical early-life period, drives long-lasting obesity. We demonstrate that the SI microbiota expands in abundance and diversity significantly between 2 and 3 weeks of life, and that segmented filamentous bacteria (SFB) and Lactobacillus intestinalis establish residence. Disruption of the early-life SI microbiota with antibiotics leads to enhanced lipid uptake and adiposity, driven by increased peroxisome proliferator-activated receptor alpha (PPARα) expression and activity in SI epithelial cells (IECs). We demonstrate that SFB and L. intestinalis are key regulators of PPARα in SI IECs by increasing intestinal IL-22 levels specifically during weaning, which is necessary for inhibition of antibiotic-induced adiposity in a PPARα-dependent manner. Together, this work provides mechanistic insights into beneficial microbiota-induced epithelial-immune crosstalk in the SI that is specific to early life, a critical protective mechanism against excessive adiposity in infancy, and offers insight into how antibiotics during infancy may increase the risk of childhood obesity.