Abstract
The consumption of high-fat diets (HFD) and an imbalance in gut microbiome are linked to obesity. However, the intricate connection between them and the underlying mechanisms involved in lipid digestion and absorption remain largely unclear. This study shows that after 12 weeks of HFD feeding, C57BL/6J mice exhibit two distinct metabolic phenotypes with significant differences in gut microbiota composition. The LOW and LOW FMT group mice with increased Bacteroides are protected from obesity, insulin resistance, and lipid accumulation. Supplementation with B. vulgatus or cholic acid (CA) alleviates HFD-induced obesity and metabolic dysfunction. This is due to the accumulation of lipid droplets and the retention of chyle particles in jejunal epithelial cells, which reduces chyle intake in the jejunal mesentery after HFD. Decreased 5-HT synthesis in the jejunal enterochromaffin cells of these mice, along with reduced chyle intake in the jejunal mesentery after HFD in Tph1△IEC, suggests that intestinal 5-HT is required for host lipid absorption. TRPV1, a calcium-permeable ion channel, mediates the basolateral 5-HT-induced increase of Isc and ion channel open probability. This study uncovers a novel signaling axis of microbiota-metabolite-5-HT and intracellular calcium-dependent lipid absorption, which may serve as the potential therapeutic targets for treating HFD-induced obesity.