Gut microbiota dysbiosis promotes coronary heart disease comorbid with depression through lipopolysaccharides and TLR4 receptors

Background: Coronary heart disease (CHD) and depression often coexist, complicating patient care due to their intertwined pathophysiology. Gut microbiota plays a crucial role in overall health and is involved in both conditions. Dysbiosis, especially increased levels of lipopolysaccharides (LPS), can activate the TLR4 receptor, triggering inflammatory pathways linked to CHD and depression. Although some associations have been observed, the direct mechanistic link between gut dysbiosis, LPS, TLR4 activation, and the comorbidity of CHD with depression remains unclear. This study aims to explore this relationship and the potential of gut microbiota modulation as a therapeutic strategy. Methods: A rat model of CHD and depression was established using a high-fat diet and chronic unpredictable mild stress (CUMS), verified by electrocardiogram (ECG), behavioral assessments, and cardiac markers. Fecal microbiota transplantation (FMT) was performed, transferring microbiota from diseased rats to healthy rats (FMT-Disease group), compared to an FMT-Normal group. To explore inflammatory pathways, the TLR4 inhibitor TAK-242 was administered, creating Disease+TAK-242 and FMT-Disease-TAK-242 groups. Blood LPS levels, TLR4/MYD88/NF-κB marker expression in cardiac and hippocampal tissues, and health indicators were evaluated using 16S rRNA sequencing, ELISA, RT-qPCR, and Western blot. Results: Diseased rats showed significantly reduced gut microbiota α- and β-diversity, indicating dysbiosis. FMT from diseased rats increased LPS levels, activated the TLR4/MYD88/NF-κB pathway, and heightened susceptibility to CHD and depression in healthy rats. TAK-242 lowered LPS levels and reduced inflammatory markers, confirming the role of the TLR4 pathway in disease progression. The Disease+Normal FMT group demonstrated improved gut microbiota composition, reduced myocardial damage, and alleviated depressive behaviors, highlighting the therapeutic potential of healthy microbiota transplantation. Conclusion: This study establishes a link between gut dysbiosis and the comorbidity of CHD with depression. Dysbiosis, marked by elevated LPS, activates the TLR4/MYD88/NF-κB pathway, increasing susceptibility to both conditions. FMT from healthy rats alleviated symptoms, suggesting that gut microbiota modulation could be a promising therapeutic strategy for these comorbidities.