An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism

The mechanisms by which the early-life microbiota protects against environmental factors that promote childhood obesity remain largely unknown. Using a mouse model in which young mice are simultaneously exposed to antibiotics and a high-fat (HF) diet, we show that Lactobacillus species, predominant members of the small intestine (SI) microbiota, regulate intestinal epithelial cells (IECs) to limit diet-induced obesity during early life. A Lactobacillus-derived metabolite, phenyllactic acid (PLA), protects against metabolic dysfunction caused by early-life exposure to antibiotics and a HF diet by increasing the abundance of peroxisome proliferator-activated receptor γ (PPAR-γ) in SI IECs. Therefore, PLA is a microbiota-derived metabolite that activates protective pathways in the small intestinal epithelium to regulate intestinal lipid metabolism and prevent antibiotic-associated obesity during early life. [Display omitted] •Early-life exposure to antibiotics and a HF diet exacerbates obesity•Loss of small intestinal Lactobacillaceae leads to increased adiposity•Antibiotics and a HF diet exacerbate adiposity via depletion of intestinal PPAR-γ•Lactobacillus-derived phenyllactic acid protects against antibiotic-induced obesity Shelton et al. determine that early-life antibiotics exacerbate diet-induced obesity by disrupting interactions between the gut microbiota and the small intestine epithelium. Their study identifies that a Lactobacillus-derived metabolite, phenyllactic acid, regulates intestinal PPAR-γ to limit fat accumulation, revealing a mechanism by which the early-life microbiota protects against metabolic dysfunction.