The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin

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. IMPORTANCE Hyperlipidemia has been intensively focused on by researchers around the world owing to its major contribution to cardiovascular diseases. Various evidence reveals that women are more susceptible than male counterparts to dyslipidemia, making sex-dependent therapeutic strategies and drugs urgently needed. In the present work, we demonstrate that DNJ, the main active component of mulberry leaves, exerts an obvious female-preferential antihyperlipidemic effect through specifically enriching Akkermansia and Clostridium XIVa and elevating an active microbial metabolite, indole-3-propionic acid (IPA), in female mice. Moreover, we have corroborated the potent lipid-lowering efficacy of IPA both in vitro and in vivo. These findings not only indicate a potential mechanism by which gut microbes and their metabolites confer the beneficial role of DNJ in ameliorating hyperlipidemia but also provide an in-depth theoretical basis for therapeutic exploitation of DNJ as a female-specific intervention against hyperlipidemia.