Gut microbiota dysbiosis promotes coronary heart disease comorbid with depression through lipopolysaccharides and Toll-like receptor 4

Sep 26, 2025BMC microbiology

Unbalanced gut bacteria may promote heart disease with depression through immune-triggering molecules and receptors

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Abstract

Elevated levels of (LPSs) were found in the serum of rats with altered gut microbiota, activating the inflammatory pathway.

in gut microbiota is associated with changes in microbial diversity and composition in a rat model of coronary heart disease (CHD) and depression.
Increased serum LPS levels activated the TLR4/MYD88/NF-κB inflammatory pathway, which is linked to higher susceptibility to comorbid CHD and depression.
Fecal microbiota transplantation from healthy rats restored gut microbiota balance in diseased rats, improving their general condition and normalizing health indicators.
The study suggests that modulation of gut microbiota composition may offer a novel therapeutic strategy to address the inflammatory pathways involved in CHD and depression.

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Coronary heart disease (CHD) and depression often coexist and complicate patient care. The gut microbiota plays a crucial role in overall health and is involved in both conditions. , particularly, increased levels of (LPSs), can activate the (TLR4), triggering inflammatory pathways associated with CHD and depression. Although some associations have been observed, the direct mechanistic association among gut dysbiosis, LPSs, TLR4 activation, and comorbidity of CHD and depression remains unclear. Thus, in the present study, we aimed to explore this association and the potential of modulating gut microbiota as a therapeutic strategy. METHODS: A rat model of CHD and depression was established using a high-fat diet and chronic unpredictable mild stress and verified by electrocardiogram, behavioral assessments, and cardiac marker analysis. Fecal microbiota transplantation (FMT) was performed by transferring microbiota from diseased rats to healthy rats (FMT-Disease group); the fecal microbiota of the rats from the FMT-Disease and FMT-Normal groups were compared. The TLR4 inhibitor TAK-242 was administered, creating the Disease + TAK-242 and FMT-Disease-TAK-242 groups. Gut microbiota composition was analyzed using 16 S rRNA high-throughput sequencing; LPS levels were measured using enzyme-linked immunosorbent assay. Polymerase chain reaction and western blotting were used to detect the expression of genes and proteins related to the TLR4/MYD88/NF-κB pathway in the heart and hippocampus, respectively. RESULTS: We confirmed that in the FMT-Disease group, the gut microbiota of diseased rats altered the gut microbial composition of healthy rats in terms of β-diversity, α-diversity, and community structure. Notably, LPS levels in the serum of FMT-Disease rats were elevated, thereby activating the TLR4/MYD88/NF-κB inflammatory pathway and increasing susceptibility to CHD comorbid with depression. Additionally, after receiving fecal microbiota from healthy rats, the Disease group showed a restoration of gut microbiota balance, improvement in general condition, and normalization of pathological, biochemical, and inflammatory indicators, indicating a suppressive effect on the progression of CHD with depression. CONCLUSION: Our findings further clarify the interrelationship between gut microbiota and CHD comorbid with depression, enhancing our understanding of its pathogenesis. Moreover, we propose a potential novel therapeutic strategy that focuses on modulating gut microbiota composition to block the TLR4/MYD88/NF-κB inflammatory pathway.

Key numbers

60%

Success Rate of CHDWD Model

Successful establishment of the CHDWD rat model

higher than control

Increased Lipopolysaccharide Levels

Serum LPS levels in diseased vs. control rats

significantly reduced

Reduction in Inflammatory Markers

Inflammatory markers post-transplantation

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Gut microbiota dysbiosis promotes coronary heart disease comorbid with depression through lipopolysaccharides and Toll-like receptor 4

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