Chinese Medicine Formula HJ11 Alleviates Atherosclerosis by Inactivating the TLR4/MyD88/IκB-α Pathway and Modulating the Heart-Gut Axis Response

Fangyuan Zhang,1,* Fei Lu,2,* Mingfei Shi,3 Weiming Xu,4 Ziyun Li,5 Yuting Cui,6 Jiaxi Zou,7 Jingqing Hu8 1School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Traditional Chinese Medicine, Liaoning University, Shenyang, Liaoning, People’s Republic of China; 3School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 4China Science and Technology Development Center for Chinese Medicine, Beijing, People’s Republic of China; 5School of Acupuncture and Tuina, School of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 6Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 7School of Clinical Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 8School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingqing Hu, School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China, Tel/Fax +86-139-1154-6633, Email [email protected]: Extensive research has demonstrated that gut microbiota and its metabolites—including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids—play a crucial role in the pathophysiology of coronary artery disease (CAD).The bidirectional interaction between the gut microbiota and the cardiovascular system significantly influences host metabolic and inflammatory homeostasis. As a result, targeted modulation of the gut microbiota emerges as a promising adjunctive therapeutic strategy for CAD, offering potential benefits with minimal side effects.Purpose: This study aims to elucidate the therapeutic mechanisms of the clinically validated Chinese medicine formula HJ11 in mitigating coronary heart disease (CHD), with a particular focus on its regulation of the heart-gut axis and associated atherosclerotic processes.Study Design and Methods: This study established an ApoE−/− mouse model of atherosclerosis and treated with HJ11 via gavage.We investigated the effects of HJ11 on the gut microenvironment in these atherosclerotic mice. Gut microbial composition and faecal metabolite profiles were analyzed using 16S rDNA sequencing and metabolomics. Additionally, an in vitro model of atherosclerosis was used to examine whether HJ11 exerts anti-inflammatory effects by modulating the TLR4/MYD88/IκB-α signaling pathway.Results: HJ11 exerted protective effects on coronary atherosclerosis by reducing systemic serum lipid levels and inhibiting plaque formation, vascular inflammation, and collagen deposition, while also alleviating aortic injury. It suppressed endothelial inflammation and inhibited the proliferation of vascular smooth muscle cells. In the gut, HJ11 alleviated intestinal structural damage and enhanced barrier integrity. Notably, it promoted the function of Akkermansia, a beneficial bacterium known to influence TLR4 expression. Finally, in an in vitro atherosclerosis model, HJ11 decoction inhibited cell proliferation and migration by inactivating the TLR4/MYD88/IκB-α signaling pathway—an effect that was abolished by TLR4 overexpression.Keywords: HJ11 formula, atherosclerosis, inflammation, intestinal barrier, heart-gut axis