Oujiang Laboratory, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou, 325035, China.
Microbiome. 2024 Aug 24;12(1):157. doi: 10.1186/s40168-024-01872-3.
Diabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive.
We found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown.
Our study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator. Video Abstract.
糖尿病心肌病（DCM）是糖尿病相关死亡的主要原因之一。肠道微生物群衍生的支链氨基酸（BCAA）被报道在 DCM 的发生和发展中起核心作用，但潜在的机制仍不清楚。
我们发现由于肠道微生物群降低了 BCAA 的降解能力，1 型糖尿病（T1D）小鼠的循环 BCAA 水平升高。过量的 BCAA 通过抑制 PPARα 信号通路降低肝脏 FGF21 的产生，从而通过转录因子 Zbtb7c 导致心脏 LAT1 的表达水平更高。高心脏 LAT1 通过 mTOR 信号通路增加心脏中 BCAA 的水平，然后导致线粒体损伤和心肌细胞凋亡，导致 T1D 小鼠的心脏纤维化和功能障碍。此外，来自健康小鼠的粪便微生物群移植可缓解 T1D 小鼠的心脏功能障碍，但 FGF21 敲低可消除这种作用。
我们的研究揭示了肠道微生物群、肝脏和心脏之间通过 BCAA 进行的串扰，以促进 DCM 的发生，而 FGF21 则作为关键介质。
