The intestinal microbiota reprograms intestinal lipid metabolism through long non-coding RNA Snhg9

The intestinal microbiota is a key regulator of mammalian lipid absorption, metabolism, and storage. Here we show that the microbiota reprograms intestinal lipid metabolism in mice by repressing the expression of long non-coding RNA (lncRNA) Snhg9 in small intestinal epithelial cells. Snhg9 suppressed the activity of the transcription factor peroxisome proliferator–activated receptor ? (PPAR?) – a central regulator of lipid metabolism – by dissociating the PPAR? inhibitor Sirtuin 1 from cell cycle and apoptosis protein 2 (CCAR2). Forced expression of Snhg9 in the intestinal epithelium of conventional mice lowered dietary lipid absorption, reduced body fat, and protected against diet-induced obesity. The microbiota repressed Snhg9 expression through an immune cell signaling relay encompassing myeloid cells and innate lymphoid cells. Our findings thus identify an unanticipated role for a lncRNA in microbial control of host metabolism. Overall design: 1. RNAseq analysis of laser captured epithelial cell transcripts in conventionally raised SPF mice and germ-free mice. 2. RNAseq analysis of ileal transcripts in villin-Snhg9 transgenic mice and wild-type mice. 3. 16s sequencing analysis of fecal bacterial composition in villin-Snhg9 transgenic mice and wild-type mice before and after switching from chow diet to high-fat diet.