Gut Dysbiosis Promotes Myocardial Hypertrophy via GBP2b/GBP1 in Chronic Colitis

Patients with inflammatory bowel disease are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. Inflammatory bowel disease is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction.

A chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA sequencing, coimmunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing.

Chronic dextran sulfate sodium colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide translocation; bone marrow chimera experiments demonstrated that hematopoietic TLR4 (toll-like receptor 4) signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified GBP2b (guanylate-binding protein 2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of lipopolysaccharide TLR4 signaling. Upon lipopolysaccharide stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 (dynamin-related protein 1) and FIS1 (fission 1 protein) to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling and cardiac dysfunction.

These findings establish the lipopolysaccharide TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with inflammatory bowel disease.