Fecal microbiota transplantation mitigates cardiac remodeling and functional impairment in mice with chronic colitis

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with significant extraintestinal manifestations, including cardiovascular derangements. However, the molecular mechanisms underlying the cardiac remodeling and dysfunction remain unclear.

We investigated the effects of chronic colitis on the heart using two mouse models: DSS-induced colitis and Il10-/-spontaneous colitis. Echocardiography was employed to assess heart function and molecular characterization was performed using bulk RNA-sequencing, RT-qPCR, and western blot.

Both models exhibited significant cardiac impairment, including reduced ejection fraction and fractional shortening as well as increased collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed upregulation of fibrosis markers (i.e. COL1A1, COL3A1, Fibronectin) and β-catenin reactivation, indicating a pro-fibrotic cardiac environment. Each model yielded common upregulation of eicosanoid-associated and inflammatory genes (Cyp2e1, Map3k6, Pck1, Cfd), and model-specific alterations in pathways regulating cAMP- and cGMP-signaling, arachidonic and linoleic acid metabolism, Cushing syndrome-related genes, and immune cell responses. DSS colitis caused differential regulation of 232 cardiac genes, while Il10-/- colitis yielded 105 dysregulated genes, revealing distinct molecular pathways driving cardiac dysfunction. Importantly, therapeutic fecal microbiota transplantation (FMT) restored heart function in both models, characterized by reduced fibrosis markers and downregulated pro-inflammatory genes (Lbp and Cdkn1a in Il10-/- mice and Fos in DSS mice), while also mitigating intestinal inflammation. Post-FMT cardiac RNA-sequencing revealed significant gene expression changes, with three altered genes in DSS mice and 67 genes in Il10-/- mice. Notably, Il10-/- mice showed relatively less cardiac recovery following FMT, highlighting IL-10’s cardioprotective and anti-inflammatory contribution.

Our findings elucidate novel insights into colitis-induced cardiac remodeling and dysfunction and suggest that FMT mitigates cardiac dysfunction by attenuating systemic inflammation and correcting gut dysbiosis. This study underscores the need for further evaluation of gut-heart interactions and microbiome-based therapies to improve cardiovascular health in IBD patients. Competing Interest Statement The authors have declared no competing interest. Non-standard Abbreviations and Acronyms - 5-ASA - 5-aminosalicylic acid - AA - arachidonic acid - BCL-2 - B-cell lymphoma 2 - BDNF - brain-derived neurotrophic factor - COL1A1 - collagen type I alpha 1 - COL3A1 - collagen type III alpha 1 - DEG - differentially expressed gene - DNMT3A - DNA methyltransferase 3 alpha - DSS - dextran sodium sulfate - FMT - fecal microbiota transplantation - FS - fractional shortening - GADPH - Glyceraldehyde 3-phosphate dehydrogenase - GO - gene ontology - IBD - inflammatory bowel disease - IFN-γ - interferon gamma - IL-10 - interleukin 10 - IL-1β - interleukin-1 beta - KEGG - Kyoto Encyclopedia of Genes and Genomes - LVEF - left ventricular ejection fraction - MI - myocardial infarction - MPO - myeloperoxidase - n-6 PUFA - n-6 polyunsaturated fatty acid - PCA - principle component analysis - SND1 - staphylococcal nuclease domain-containing 1 - TGF-β - transforming growth factor beta - TTE - transthoracic echocardiogram - Tudor-SN - Tudor-staphylococcal nuclease - WB - western blot - WT - wild type