Hyperlipidemia is a worldwide epidemic with an obvious gender disparity in incidence. Modulations on gut microbiota by traditional Chinese medicines (TCM) are emerging as a potential rationale governing the profitable effects of drugs on hyperlipidemia. However, it is unclear how gut microbes regulate the progression of hyperlipidemia. Here, we found that mulberry leaf extract (MLE) and its active component 1-deoxynojirimycin (DNJ) diminished hyperglycemia and hypertriglyceridemia with similar efficacy in male and female mice but preferentially alleviated hypercholesterolemia in female mice. Further investigations showed that DNJ sex-specifically downregulated the expression of lipogenic genes, especially cholesterol-biosynthetic genes. Oral administration of DNJ imposed more profound modulation on gut microbiota in female mice than in male ones, as estimated by 16S rRNA metatranscriptomic analysis. DNJ markedly enriched Akkermansia and Clostridium group XIVa and promoted the production of indole-3-propionic acid (IPA) in a sexually dimorphic way. Importantly, IPA tightly associates with the antihyperlipidemic effect of DNJ and exhibited a potent lipid-lowering effect both in vitro and in vivo. Together, our results have established a regulatory mechanism by which DNJ sex-specifically improves hyperlipidemia, offering an in-depth theoretical basis for therapeutic exploitation of DNJ as a sex-specific intervention against hyperlipidemia.

中文翻译：

---

肠道微生物群产生的吲哚-3-丙酸赋予桑椹衍生的 1-脱氧野尻霉素抗高血脂作用

高脂血症是一种世界性流行病，发病率存在明显的性别差异。中药（TCM）对肠道微生物群的调节正在成为控制药物对高脂血症有利影响的潜在原理。然而，目前尚不清楚肠道微生物如何调节高脂血症的进展。在这里，我们发现桑叶提取物 (MLE) 及其活性成分 1-脱氧野尻霉素 (DNJ) 减少高血糖和高甘油三酯血症，在雄性和雌性小鼠中具有相似的功效，但优先减轻雌性小鼠的高胆固醇血症。进一步的研究表明，DNJ 性别特异性下调脂肪生成基因的表达，尤其是胆固醇生物合成基因。与雄性小鼠相比，口服 DNJ 对雌性小鼠的肠道微生物群产生了更深刻的调节，通过 16S rRNA 宏转录组学分析估计。DNJ 显着丰富Akkermansia和Clostridium group XIVa 并以性二态性方式促进吲哚-3-丙酸 (IPA) 的产生。重要的是，IPA 与 DNJ 的抗高血脂作用密切相关，并在体外和体内表现出有效的降脂作用。总之，我们的研究结果建立了一种调节机制，通过该机制，DNJ 可以通过性别特异性改善高脂血症，为将 DNJ 作为针对高脂血症的性别特异性干预的治疗开发提供深入的理论基础。