An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism
Catherine Shelton, E. L. Sing, Jessica Mo, Nicolas G. Shealy, Woongjae Yoo, Julia Thomas, Gillian N. Fitz, Pollyana Ribeiro Castro, Tara T. Hickman, Teresa P. Torres, Nora J. Foegeding, Jacob K. Zieba, M. Wade Calcutt, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Sun H. Peck, Fan Yang, Nicholas O. Markham, Min Liu, Mariana X. Byndloss
Abstract
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.