Abstract P1165: Gut Microbial Peptide Induced Cardiac Inflammation Via Cyclin Dependent/NFkB Signaling In Macrophages

Background: Millions of people in the United States are affected by Inflammatory Bowel Disease (IBD). Recently, gut dysbiosis and impaired gut-barrier permeability are known to contribute to cardiovascular diseases in IBD patients. However, its mechanisms are poorly understood. Here, we hypothesized that gut derived bacterial metabolites (such a peptidoglycan in this case) in a mice colitis model, promotes cardiac inflammation and heart failure. Methods: To induced colitis WT mice were treated with control/DSS (dextran sodium sulfate). Heart and intestine were collected to evaluate inflammatory genes expression(qPCR), immune cell infiltration (FACS), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify peptidoglycan (PGN) level. The effect of PGN on NFκB inflammatory pathways was evaluated in macrophages. Results: Echo-data showed cardiac dysfunction in DSS mice. Deteriorated intestinal villi in Masson’s trichrome staining and decreased Occludin and increased PV-1 in western data revealed leaky gut in DSS treated mice. Remarkably, PGN level was significantly increased in blood plasma 3 weeks following DSS treatment. Real-time gene expression data of pro-inflammatory cytokines (IL-6, IL-1 and TNFα) and fibrosis associated genes (col1α1, fibronectin) were increased in DSS mice heart. Increased CD68 expression in the immunostaining data of DSS mice heart indicated the recruitment of inflammatory macrophages. Intriguingly, we observed that CDK9 expression significantly increased upon PGN treatment leading to an increase in NFκB. Next, we inhibited CDK9 before PGN treatment and surprisingly we found that CDK9 inhibition reduces the effect of PGN. Conclusion: Taken together, data suggest that in gut dysbiosis state, PGN leaks into the blood and causes CDK9 mediated NFκB upregulation and cardiac inflammation.