The intestinal microbiota regulates body composition through NFIL3 and the circadian clock

The intestinal microbiota has been identified as an environmental factor that markedly impacts energy storage and body fat accumulation, yet the underlying mechanisms remain unclear. Here we show that the microbiota regulates body composition through the circadian transcription factor NFIL3. Nfil3 transcription oscillates diurnally in intestinal epithelial cells and the amplitude of the circadian oscillation is controlled by the microbiota through type 3 innate lymphoid cells (ILC3), STAT3, and the epithelial cell circadian clock. NFIL3 controls expression of a circadian lipid metabolic program and regulates lipid absorption and export in intestinal epithelial cells. These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism. Overall design: 1. RNAseq analysis of epithelial cell transcripts in Nfil3fl/fl and Nfil3?IEC mice at 6 time points across a circadian cycle. Laser captured epithelial cells from 3 mice were pooled together for RNAseq at each time point. 2. 16s sequencing analysis of fecal bacterial composition in Nfil3fl/fl and Nfil3?IEC mice before and after switching from chow diet to high-fat diet.