Epigenetic Activation of BCL11B Mediates Profibrotic Cardiac Remodeling Triggered by Colitis-Associated Gut Dysbiosis

Inflammatory bowel disease (IBD) is linked to elevated cardiovascular risk, but the mechanisms connecting gut dysbiosis to heart pathology are unclear. This study investigated whether transplanting a dysbiotic microbiome (DM) from colitic mice could alter cardiac function in germ-free recipients. Results showed that DM transplantation impaired cardiac contractility and increased collagen deposition, indicating fibrosis. Transcriptomic analysis revealed widespread gene upregulation, particularly in females, with enrichment in histone acetylation and immune signaling pathways. Key epigenetic regulators, Nat8f7 and Tet1, were significantly upregulated, leading to increased histone acetylation and reduced DNA methylation at the Bcl11b promoter. This enhanced RNA polymerase II recruitment and Bcl11b transcription. In a model of dextran sodium sulfate (DSS)-induced colitis, similar upregulation of Nat8f7, Tet1, and Bcl11b occurred alongside increased fibrotic markers. Crucially, fecal microbiota transplantation from healthy donors reversed these molecular and fibrotic changes, normalizing Bcl11b expression and epigenetic status. Furthermore, functional assays demonstrated that BCL11B overexpression drives fibroblast proliferation and collagen production. In conclusion, these findings identify a novel gut-heart axis where a dysbiotic microbiome promotes cardiac fibrosis through the epigenetic activation of Bcl11b, and restoring a healthy microbiome mitigates these effects, pointing to microbiome-targeted strategies as potential therapies for IBD-related cardiovascular complications.