Fecal microbiota transplantation mitigates cardiac remodeling and functional impairment in mice with chronic colitis
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with significant extraintestinal manifestations, including cardiovascular derangements. However, whether and how chronic colitis impairs heart function remain unclear. We investigated the impact of chronic colitis on heart function and transcriptome using two mouse models: DSS-treated and Il10-/- mice. Echocardiography was employed to assess heart function and molecular characterization was performed using RNA-sequencing, RT-qPCR, and western blot. Both models exhibited significant cardiac impairment, including reduced ejection fraction and fractional shortening, along with increased collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed upregulation of fibrosis markers and ß-catenin reactivation, indicating a pro-fibrotic cardiac environment. RNA-sequencing unveiled a shared upregulation of eicosanoid-associated and inflammatory genes (Cyp2e1, Map3k6, Pck1, Cfd) across both models, along with model-specific alterations in pathways governing cAMP and cGMP signaling, arachidonic and linoleic acid metabolism, and immune cell responses. DSS colitis caused differential regulation of 232 cardiac genes, while Il10-/- colitis yielded 105 dysregulated genes. Importantly, therapeutic fecal microbiota transplantation (FMT) restored heart function in both models, characterized by reduced fibrosis markers and downregulated pro-inflammatory genes, while also mitigating intestinal inflammation. Notably, Il10-/- mice showed relatively less cardiac recovery following FMT, highlighting IL-10's cardioprotective and anti-inflammatory contribution. Our findings provide direct evidence that chronic colitis impairs heart function, elucidate novel insights into colitis-induced cardiac remodeling, and suggest that FMT mitigates cardiac dysfunction by attenuating systemic inflammation and correcting gut dysbiosis. Further evaluation of gut-heart interactions and microbiome-based therapies is needed to improve cardiovascular health in IBD patients. Overall design: To investigate the genetic and transcriptomic changes to the heart in chronic colitis and how therapeutic fecal microbiota transplantation affects such changes. Differential gene expression profile analysis was performed using RNA sequencing of total RNAs isolated from the colons of two independent mouse models using C57BL/6J mice and 129(B6)-Il10tm1Cgn/J mice strains. The comparative groups for C57BL/6J mice include (1) vehicle control, (2) DSS, (3) DSS+FMT. The comparative groups for 129(B6)-Il10tm1Cgn/J mice include (1) wild type, (2) IL-10 KO, and (3) IL-10 KO+FMT. Gene ontology and KEGG pathway encrichment was performed on the gene lists for each model, independently.