Hyperglycemia-Driven Hepatic Immune Dysfunction Facilitates Microbial Dissemination Post-Myocardial Infarction
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Background
The gut microbiome is intimately connected to cardiovascular health through the gut-heart axis and plays a pivotal role in maintaining homeostasis. Myocardial infarction (MI) disrupts this homeostatic balance, leading to widespread adverse effects. Hyperglycemia, a hallmark of metabolic dysfunction, further exacerbates these disruptions, emphasizing the need to understand the underlying mechanisms to develop effective therapeutic strategies for mitigating the cascading complications along the gut-heart axis. This study aims to elucidate the dynamics of gut barrier disruption during MI, and explore the liver’s function as an immune sentinel in this process, with a focus on the impact of hyperglycemia on microbial dissemination, systemic inflammation, and liver immune function.
Methods
A murine MI model was used to evaluate gut permeability, bacterial translocation, and hepatic immune responses. MI was induced via permanent left anterior descending artery ligation. Hyperglycemia was established through streptozotocin injections and a high-fat, high-sugar diet. Gut barrier integrity was assessed using FITC-dextran assays, and microbial translocation was tracked through intravital imaging and anaerobic bacterial cultures from multiple organs. Hepatic immune function was analyzed via flow cytometry, cytokine profiling, and phagocytosis assays. 16S rRNA sequencing characterized the composition of translocated bacteria.
Results
MI significantly increased intestinal permeability, with hyperglycemia further exacerbating gut barrier dysfunction. Intravital imaging revealed bacterial translocation through the portal vein to the liver, highlighting the liver’s role in microbial interception. Hyperglycemia impaired hepatic macrophage function by activating NLRP3 inflammasome signaling, reducing bacterial clearance and promoting persistent liver colonization. Systemic inflammatory cytokines, particularly TNF-α, were elevated, further facilitating microbial dissemination. 16S rRNA sequencing demonstrated host-dependent stochastic variability in translocated bacterial composition.
Conclusion
The liver serves as a key immune regulator in the gut-liver-heart axis but is functionally compromised under hyperglycemia, exacerbating systemic inflammation and microbial dissemination post-MI. Targeting NLRP3 signaling and restoring gut barrier integrity may mitigate post-MI complications, particularly in hyperglycemic conditions. These findings underscore the need for integrated therapeutic strategies incorporating metabolic control and microbiome-targeted interventions to improve post-MI outcomes.
