Fang Zhengyu, Zang Qingce, Chen Jiemei, Li Zeyu, Yang Dawei, Wu Chongming, Yang Hongjun, Guo Na
Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
J Adv Res. 2025 Jul;73:411-426. doi: 10.1016/j.jare.2024.09.001. Epub 2024 Sep 11.
Heart failure (HF) is a systemic metabolic disorder disease, across multiorgan investigations advancing knowledge of progression and treatment of HF. Whole-body MSI provides spatiotemporal information of metabolites in multiorgan and is expected to be a potent tool to dig out the complex mechanism of HF.
This study aimed at exploring the systemic metabolic disorder in multiorgan and catecholamines biosynthesis alteration on heart-gut axis after HF.
Whole-body MSI was used to characterize metabolic disorder of the whole rat body after HF. An integrated method by MSI, LC-MS/MS and ELISA was utilized to analyze key metabolites and enzymes on heart, small intestine, cecum and colon tissues of rat. Gut microbiota dysbiosis was investigated by 16S rDNA sequencing and metagenomic sequencing. Validation experiments and in vitro experiments were performed to verify the effect of catecholamines biosynthesis alteration on heart-gut axis after HF.
Whole-body MSI exhibited varieties of metabolites alteration in multiple organs. Remarkably, catecholamine biosynthesis was significantly altered in the serum, heart and intestines of rats. Furthermore, catecholamines and tyrosine hydroxylase were obviously upregulated in heart and colon tissue. Turicibacter_sanguinis was relevant to catecholamines of heart and colon. Validation experiments demonstrated excessive norepinephrine induced cardio-intestinal injury, including significantly elevating the levels of BNP, pro-BNP, LPS, DAO, and increased the abundance of Turicibacter_sanguinis. These alterations could be reversed by metoprolol treatment blocking the effect of norepinephrine. Additionally, in vitro studies demonstrated that norepinephrine promoted the growth of Turicibacter_sanguinis and Turicibacter_sanguinis could import and metabolize norepinephrine. Collectively, excessive norepinephrine exerted bidirectional effects on cardio-intestinal function to participate in the progression of HF.
Our study provides a new approach to elucidate multiorgan metabolic disorder and proposes new insights into heart-gut axis in HF development.
心力衰竭（HF）是一种全身性代谢紊乱疾病，通过多器官研究可增进对HF进展和治疗的认识。全身质谱成像（MSI）可提供多器官中代谢物的时空信息，有望成为挖掘HF复杂机制的有力工具。
本研究旨在探讨HF后多器官的全身代谢紊乱以及心-肠轴上儿茶酚胺生物合成的改变。
采用全身MSI来表征HF后大鼠全身的代谢紊乱。运用MSI、液相色谱-串联质谱（LC-MS/MS）和酶联免疫吸附测定（ELISA）的综合方法，分析大鼠心脏、小肠、盲肠和结肠组织中的关键代谢物和酶。通过16S核糖体DNA测序和宏基因组测序研究肠道微生物群失调情况。进行验证实验和体外实验，以验证HF后儿茶酚胺生物合成改变对心-肠轴的影响。
全身MSI显示多个器官中存在多种代谢物改变。值得注意的是，大鼠血清、心脏和肠道中的儿茶酚胺生物合成显著改变。此外，心脏和结肠组织中的儿茶酚胺和酪氨酸羟化酶明显上调。 sanguinis）与心脏和结肠的儿茶酚胺有关。验证实验表明，过量的去甲肾上腺素会导致心-肠损伤，包括显著升高脑钠肽（BNP）、前脑钠肽（pro-BNP）、内毒素（LPS）、二胺氧化酶（DAO）水平，并增加 sanguinis的丰度。这些改变可通过美托洛尔治疗阻断去甲肾上腺素的作用而逆转。此外，体外研究表明，去甲肾上腺素促进了 sanguinis的生长，且 sanguinis可以摄取和代谢去甲肾上腺素。总体而言，过量的去甲肾上腺素对心-肠功能产生双向影响，参与了HF的进展。
我们的研究提供了一种阐明多器官代谢紊乱的新方法，并对HF发展过程中的心-肠轴提出了新的见解。
