Key result
DSS-induced colitis triggers cardiac inflammation in mice via peptidoglycan and CDK9-mediated NFκB activation.
In a mouse model of colitis, gut-derived bacterial products like peptidoglycan promote cardiac inflammation and dysfunction via CDK9-mediated NFκB signaling.
Background: Inflammatory bowel disease (IBD) has resulted in various comorbidities in the United States. Recently, an increase in cardiovascular-related deaths among IBD patients has been noted. However, the fundamental molecular mechanisms underlying this trend are still not fully understood. Therefore, we proposed that bacterial metabolites, such as peptidoglycan, released from the gut may trigger cardiac inflammation and, eventually, heart failure in mice after colitis. Methods: We treated C57 black mice with DSS (dextran sodium sulfate) to induce colitis. Further, we collected feaces for 16s rRNA and evaluated gut microbiome. Blood was drawn to quantify the circulating peptidoglycan (PGN) level. In addition, heart and intestine tissues were collected to determine inflammatory genes expression (qPCR), immune cell infiltration (FACS), and intestinal permeability (WB and IHC). Results: DSS mice showed cardiac dysfunction (echo-data). Masson's trichrome staining and WB data showed impaired intestinal villi and reduced tight junction proteins, respectively, suggesting leaky gut in DSS treated mice. Comparative analysis of 16s rRNA sequencing data revealed significant changes in the Firmicutes/Bacteroidetes ratio in DSS treated mice compared to control mice. Moreover, plasma PGN level was significantly increased 3 weeks following DSS treatment. Gene expression data showed increased pro-inflammatory cytokines (TNFα) and fibrosis-associated genes (col1α1, fibronectin) in DSS mice hearts. Expression of CD68 (immunostaining data) was increased in DSS mice hearts suggest the recruitment of inflammatory macrophages. At the molecular level, cyclin-dependent kinase 9 (CDK9) expression was significantly increased in macrophages following PGN treatment, which ultimately led to an increase in NFkB signaling. Finally, CDK9 inhibition attenuated PGN-induced NFkB signaling. Conclusion(s): Our study suggests that colitis-induced leaky gut leads to CDK9-mediated NFκB upregulation, contributing to cardiac inflammation. Ongoing research will shed light on the underlying molecular mechanisms of cardiovascular dysfunction.
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Ranjan et al. (2025) studied Colitis / Inflammatory Bowel Disease. DSS (dextran sodium sulfate) vs. Control mice was evaluated on Cardiac inflammation and dysfunction. DSS-induced colitis in mice increased plasma peptidoglycan levels at 3 weeks, leading to CDK9-mediated NFκB upregulation and subsequent cardiac inflammation.
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