Gut <i>Barnesiella intestinihominis</i> Exacerbates Post‐Myocardial Infarction Injury via Succinate‐Driven <scp>MAPK3</scp> Succinylation/Phosphorylation Cascade in γδ T Cells and Downstream <scp>IL</scp> ‐ <scp>17A</scp> – <scp>NLRP3</scp> Axis

ABSTRACT Background Interleukin‐17A (IL‐17A) is a key pro‐inflammatory cytokine implicated in acute myocardial infarction, but its upstream regulatory mechanisms remain unclear. Emerging evidence reveals the role of the gut–heart axis in cardiovascular diseases, suggesting that the gut microbiota influences inflammatory responses following myocardial ischemia. Methods and Results By performing Mendelian randomization analysis on human genomic data, we identified four gut bacterial genera with a potential causal relationship to elevated IL‐17A levels, including Barnesiella . Integrated multi‐omics network analysis reveals that Barnesiella regulates IL‐17A‐related inflammatory gene expression through its metabolite succinate. In a myocardial infarction (MI) mouse model, inoculating Barnesiella intestinihominis significantly elevated succinate concentrations in both serum and myocardial tissue, exacerbated cardiac injury, and amplified inflammatory responses in Pseudo‐Germ‐free (pGF) mice. Flow cytometry analysis demonstrated that within the CD3 + T cell population of the ischemic myocardium, IL‐17A + γδ T cells consistently outnumbered IL‐17A + CD4 + T cells across all experimental groups. Co‐immunoprecipitation (Co‐IP) assays further demonstrated that Barnesiella ‐derived succinate promotes MAPK3 lysine succinylation in the ischemic myocardium. In vitro Transwell co‐culture of HL‐1 cardiomyocytes and γδ T cells confirmed that succinate directly promotes IL‐17A expression in γδ T cells and upregulates MAPK3 and NLRP3/caspase‐1 pathways, effects that were abrogated by MAPK3 inhibition. Conclusion Barnesiella intestinihominis exacerbates myocardial injury and inflammatory responses following MI by promoting IL‐17A expression in γδ T cells through succinate‐mediated MAPK3 lysine succinylation and downstream NLRP3 inflammasome activation. This study reveals a novel “gut–metabolite–immune–heart” regulatory pathway linking a specific gut bacterium to localized myocardial immune pathology.