脆弱拟杆菌-胆汁酸GUDCA-肠FXR代谢轴在二甲双胍降糖中的作用及机制研究

Metformin is the first-line antidiabetic drug. However, the mechanism has not been completely dissected. Recent pharmacological researches revealed that the major target of metformin was gut microbiota. But whether metformin-modified gut microbiota leads to glucose-lowering effect, or in contrast, remains to be explored. Our previous results showed that metformin directly inhibited the growth of Bacteroides fragilis and decreased the content of bile acid hydrolase (BSH), resulting an accumulation of GUDCA. GUDCA was identified as novel endogenous FXR antagonist in humans. Oral metformin inhibited the transcriptional activity of FXR to fulfill its glucose-lowering effect. The Bacteroides fragilis-GUDCA axis mediated metformin-induced inhibition of intestinal FXR, which was independent of AMPK. On this basis, we proposed our hypothesis: metformin inhibits hepatic gluconeogenesis in a Bacteroides fragilis-GUDCA-intestinal FXR axis; GUDCA is a new endogenous antagonist of human intestinal FXR, possessing the potential ability to treat type 2 diabetes (T2D). This project aims to systematically analyze the temporal and spatial dynamics of gut microbiota and glucose metabolism in metformin treatment by means of bioinformatics, metagenomics and metabolomics, and explore the direct targets of gut microbiota changes in microbiota-depleted mice, bacterial strain colonized and intestine specific knockout mice. This study will provide new strategies to intervene in metabolic diseases.

二甲双胍是治疗2型糖尿病的一线用药，主要通过抑制肝脏糖异生来发挥降糖作用，但其作用机制并不明确。最新研究表明二甲双胍作用的主要靶点在肠道菌群，但肠道菌群重塑与机体代谢改善之间的因果关系尚有待研究。我们的预试验结果显示：初诊2型糖尿病患者口服二甲双胍之后，肠道脆弱拟杆菌的丰度下降，胆汁酸GUDCA的含量升高；胆汁酸GUDCA对人肠法尼醇受体FXR信号有直接拮抗作用，二甲双胍通过抑制肠FXR发挥其降糖作用。由此我们提出假说：二甲双胍通过肠道脆弱拟杆菌-胆汁酸GUDCA-肠FXR代谢轴抑制肝脏糖异生，降低血糖；胆汁酸GUDCA作为人肠FXR内源性的拮抗剂，具有潜在的治疗2型糖尿病作用。本项目拟利用生物信息学、宏基因组学、代谢组学等手段，系统解析二甲双胍治疗中肠道菌群与机体胆汁酸代谢的时空动态变化调控规律；深入探究肠道菌群作用于宿主的靶点及其功能，找到治疗2型糖尿病的新策略。

二甲双胍可以改变肠道菌群稳态，但肠道菌群变化与宿主代谢改善之间的因果关系尚不清楚。我们发现2型糖尿病患者口服二甲双胍治疗后，肠道脆弱拟杆菌丰度降低，胆汁酸GUDCA水平增加。机制研究显示二甲双胍通过抑制脆弱拟杆菌的胆盐水解酶活性，增加GUDCA含量。GUDCA是人肠FXR的内源性拮抗剂，能够有效改善胰岛素抵抗，二甲双胍通过调控肠道脆弱拟杆菌—胆汁酸GUDCA—肠FXR轴发挥降糖作用。我们进一步研究发现高胆固醇血症患者肠FXR信号显著激活，而肠上皮细胞FXR可直接结合神经酰胺合成酶SMPD3的增强子区，上调其转录活性，促进肠源神经酰胺的生成。肠FXR内源性拮抗剂GUDCA或SMPD3抑制剂GW4869通过降低神经酰胺减轻动脉粥样硬化，且具有预防和治疗的双重作用。因此，我们阐明肠FXR可作为治疗代谢性疾病的新靶点，其人体内源性拮抗剂GUDCA具有成药潜质。除此之外，我们还揭示肠道菌群—胆汁酸轴调控3型天然淋巴细胞功能稳态在多囊卵巢综合征中的作用；发现猪体内富含的一类新胆汁酸—猪胆酸，通过同时抑制肠FXR并激活TGR5信号的独特模式降低血糖；提出宿主基因调控肠道菌群的全新模式，揭示宿主肠缺氧诱导因子HIF-2α通过调控肠道菌群稳态抑制脂肪产热的新机制；阐明脂肪HIF-1α与HIF-2α双向调控神经酰胺代谢介导脂肪—肝脏/血管对话的新机制，为代谢性疾病的防治提供新策略。相关的研究成果在Nature Medicine (2019)、Cell metabolism (2019, 2021a, 2021b)、Journal of Clinical Investigation (2021)等杂志发表SCI 论文11篇（标注本项目基金号91857115）；获得授权发明专利3项；获得中国青年科技奖、树兰医学青年奖、北美华人糖尿病学会青年科学家奖等奖励。