Hatamnejad Mohammad Reza, Medzikovic Lejla, Dehghanitafti Ateyeh, Rahman Bita, Vadgama Arjun, Eghbali Mansoureh
Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA.
Int J Mol Sci. 2025 Mar 2;26(5):2242. doi: 10.3390/ijms26052242.
The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (HS), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, HS by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, HS, and PAGln.
肠道微生物群的影响不仅限于其在胃肠道的栖息地，还会延伸至包括心血管系统在内的远处器官。最近，人们对心脏与肠道微生物群之间的关系产生了研究兴趣。肠道微生物群会分泌多种代谢产物，包括氧化三甲胺（TMAO）、短链脂肪酸（SCFAs）、胆汁酸（BAs）、吲哚丙酸（IPA）、硫化氢（HS）和苯乙酰谷氨酰胺（PAGln）。在这篇综述中，我们通过总结临床研究和实验模型的现有知识，探讨了这些分泌的微生物群代谢产物在缺血性和非缺血性心力衰竭（HF）病理生理学中作用的越来越多的证据。升高的TMAO通过TGF-β/Smad信号介导的心肌肥大和纤维化、线粒体能量产生受损、DNA甲基化模式改变以及细胞内钙转运，导致非缺血性HF。此外，高水平的TMAO可通过炎症、组蛋白甲基化介导的血管纤维化、血小板过度活跃和血栓形成，以及胆固醇积累和MAPK信号激活，促进缺血性HF。SCFAs减少会上调Egr-1蛋白、T细胞心肌浸润以及HDAC 5和6的活性，导致非缺血性HF，而活性氧的产生和小窝蛋白-血管紧张素转换酶轴的过度激活则导致缺血性HF。BAs水平改变会使收缩力恶化，打开线粒体通透性转换孔诱导细胞凋亡，并增加胆固醇积累，最终加重缺血性和非缺血性HF。IPA通过抑制烟酰胺N-甲基转移酶表达并增加烟酰胺、NAD+/NADH和SIRT3水平，可改善非缺血性HF；同时，HS通过刺激PI3K/AKT途径抑制Nox4表达和线粒体ROS产生，也可预防非缺血性HF。此外，PAGln可影响肌节缩短能力和心肌细胞收缩。这个新兴的研究领域通过饮食干预、益生元、益生菌或粪便微生物群移植恢复肠道微生物群，从而使TMAO、SCFA、BAs、IPA、HS和PAGln的循环水平正常化，为HF治疗开辟了新途径。
