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

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestines accompanied by profound extraintestinal manifestations. Although IBD shows a clear clinical association with cardiovascular derangements, whether and how chronic colitis impairs heart function remains unclear. To address this gap, we investigated the impact of chronic colitis on cardiac performance and the cardiac transcriptome using two mouse models: dextran sodium sulfate (DSS)-treated and Il10^-/- mice. Heart function was assessed by echocardiography and molecular characterization was performed using RNA-sequencing (RNA-Seq), reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and Western blot. Both models exhibited significant functional cardiac impairment, characterized by reduced ejection fraction and fractional shortening along with histologically evident increase in collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed a profibrotic cardiac environment. RNA sequencing unveiled a shared upregulation of eicosanoid-associated and inflammatory genes (Cyp2e1, Map3k6, Pck1, and Cfd) across both models, alongside 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, whereas Il10^-/- colitis yielded 105 dysregulated genes. Notably, reconstitution of a healthy balance of gut microbiota by therapeutic fecal microbiota transplantation (FMT), validated using quantitative polymerase chain reaction (qPCR), successfully rescued heart function and mitigated fibrosis in both models. However, Il10^-/- mice demonstrated relatively less cardiac recovery following FMT, highlighting interleukin-10 (IL-10)'s cardioprotective and anti-inflammatory contribution. Collectively, these findings provide evidence that chronic colitis impairs heart function, offer novel insights into colitis-induced cardiac remodeling, and suggest that FMT mitigates cardiac dysfunction by correcting gut dysbiosis, attenuating systemic inflammation, and reestablishing homeostasis along the gut-heart axis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) extends beyond the gut, as chronic inflammation and microbiota dysbiosis contribute to serious extraintestinal complications. This study demonstrates that chronic colitis induces cardiac remodeling and dysfunction in two mouse models, marked by reduced cardiac performance, fibrosis, and upregulated fibrotic and inflammatory genes. Importantly, fecal microbiota transplantation (FMT) alleviated cardiac injury, highlighting its therapeutic potential. These findings reveal FMT as a promising therapy against chronic inflammation contributing to cardiovascular complications in IBD.