阐明药效显著但口服生物利用度差的天然产物的体内作用机制具有重要意义。小檗碱（BBR）降脂功效显著，但由于口服生物利用度差，其体内作用机制尚不清楚。虽已发现BBR可显著调节肠道菌群，但这种调节是否是其发挥降脂作用的重要原因有待明确。申请人近期通过改变给药途径、伪无菌动物模型和菌群移植等方法证明调节肠道菌群确实是BBR降脂的重要环节，且丁酸产生菌与其降脂活性密切相关。为深入揭示BBR通过调节肠道菌群发挥降脂作用的分子机制，本课题拟采用元基因组学、代谢组学、功能基因组学和药理学等多学科手段鉴定与BBR降脂功效密切相关的特征性功能菌种，发掘功能基因，剖析关键代谢通路，确认活性菌代谢产物，建立BBR——特征性菌种——功能基因和代谢通路——活性代谢产物——降脂功效的系统调节模型，阐明BBR降脂的肠道机制，并为其它药效明确但生物利用度差的中药来源天然产物的体内作用机制研究提供新思路。

Elucidating the in vivo mechanism of natural products with poor oral bioavailability is very important for the R&D of new drugs. Berebeine (BBR) is potent in decreasing blood lipids but its precise mechanism is still not clear due to the extremely low oral bioavailability. Previous studies showed that BBR can regulate gut microbiota. However, whether this regulation is a main cause for BBR’s antihyperlipidemic effect is still not clarified. Recently, we proved the key role of gut micribiota in BBR-mediated lipid-lowering actions via changing administration route, pseudo-sterile animal model and fecal bacteria transplantation, and found that butyrate generating bacteria were closely related to BBR’s antihyperlipidemic effect. To deeply exploring the molecular mechanism of BBR-induced lipid-lowering effect, this project will take advantage of multiple approaches including metagenomics, metabonomics, functional genomics and molecular pharmacology, aiming to identify the specific gut bacterial species which are tightly related to BBR’s antihyperlipidemic action, explore their functional genes, figure out the potential metabolic pathway which is significantly regulated by BBR, and find the active bacterial metabolites. This work will clarify the gut mechanism of BBR-induced antihyperlipidemic effect via establish a systemic regulation network comprised of BBR – specific bacterial species – functional genes and metabolic pathway – active metabolites – lipid-lowering effect. Our work will also provide a new means to explore the in vivo mechanism of other herbal products with low oral bioavailabilities.