Whole-body mass spectrometry imaging reveals the systemic metabolic disorder and catecholamines biosynthesis alteration on heart-gut axis in heart failure rat.

Abstract

Introduction: 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.

Objectives: This study aimed at exploring the systemic metabolic disorder in multiorgan and catecholamines biosynthesis alteration on heart-gut axis after HF.

Methods: 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.

Results: 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.

Conclusion: Our study provides a new approach to elucidate multiorgan metabolic disorder and proposes new insights into heart-gut axis in HF development.