The intestinal microbiota reprograms intestinal lipid metabolism through long non-coding RNA Snhg9. 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 γ (PPARγ) – a central regulator of lipid metabolism – by dissociating the PPARγ 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.

肠道微生物群是哺乳动物脂质吸收、代谢与储存的关键调控因子。本研究证实，小鼠肠道微生物群可通过抑制小肠上皮细胞内的长链非编码RNA（long non-coding RNA，lncRNA）Snhg9的表达，重编程肠道脂质代谢。Snhg9可通过将过氧化物酶体增殖物激活受体γ（peroxisome proliferator–activated receptor γ，PPARγ）的抑制剂沉默信息调节因子1（Sirtuin 1）从细胞周期与凋亡蛋白2（cell cycle and apoptosis protein 2，CCAR2）上解离，抑制该脂质代谢核心调控因子的活性。在常规饲养小鼠的肠上皮中强制过表达Snhg9，可降低膳食脂质吸收、减少体脂，并抵御饮食诱导的肥胖。肠道微生物群可通过包含髓系细胞与先天淋巴细胞的免疫细胞信号传导通路抑制Snhg9的表达。本研究揭示了长链非编码RNA在微生物调控宿主代谢过程中未曾发现的新作用。

总体设计：
1. 对常规饲养的无特定病原体（specific pathogen-free，SPF）小鼠与无菌小鼠的激光捕获上皮细胞转录本进行RNA测序分析。
2. 对villin-Snhg9转基因小鼠与野生型小鼠的回肠转录本进行RNA测序分析。
3. 对从普通饲料切换为高脂饲料前后的villin-Snhg9转基因小鼠与野生型小鼠的粪便细菌组成进行16S测序分析。