The Role of Microbiota – Epithelial Crosstalk in the Pathogenesis of Early-Life Obesity

Abstract

Childhood obesity is a significant public health concern. In 2020, 175 million children worldwide were considered obese, and predictions estimate that by 2035, 383 million children will also suffer from obesity. In addition to decreased physical activity and consumption of a Western-style high fat (HF) diet, researchers have proposed that early-life exposure to antibiotics increases a child’s risk for obesity. However, the mechanisms by which antibiotic treatment promotes obesity remain largely unknown. Findings described in this thesis reveal that concurrent exposure to early life antibiotics and a HF diet increase adiposity by perturbing the small intestinal microbiota and disrupting intestinal lipid metabolism. Specifically, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is depleted from the intestinal epithelium in mice given a HF diet and antibiotics, resulting in greater fat accumulation. Phenyllactic acid (PLA), a microbiota-metabolite produced by Lactobacillus species, is reduced in the small intestinal content of mice exposed to antibiotics and a HF diet. Supplementation with PLA restores intestinal PPAR-gamma abundance and protects against HF and antibiotic-induced adiposity. Work discussed in Chapter 2 and 3 of this thesis focused on the impact of concurrent exposure to antibiotics and a HF diet during early childhood and adolescence. However, associations have been found between antibiotic usage during infancy and increased adiposity. Therefore, in Chapter 4, experiments investigated how exposure to antibiotics from birth until weaning impacted the development of mice. Antibiotics perturbed the small intestinal microbiota of young mice and altered the differentiation of their intestinal epithelium. Exposure to early life antibiotics resulted in increased expression of genes related to nutrient absorption in the intestinal epithelium. Consistent with elevated expression of nutrient transporters, mice exposed to antibiotics during infancy gained more weight and abdominal fat than untreated mice. Together, this work identified how antibiotic exposure during early life increases the risk for childhood obesity by perturbing microbiota-epithelial crosstalk, resulting in greater fat accumulation.