ATLANTA — Chronic intestinal inflammation drives cardiac dysfunction through a gut microbiota-dependent mediated pathway, suggesting a potential therapeutic target for reducing cardiovascular risk in patients with inflammatory bowel disease (IBD), according to a study led by researchers in the Institute for Biomedical Sciences at Georgia State University.
The findings published in Circulation Research demonstrated that chronic colitis (inflammation of the colon)-associated gut microbiota dysbiosis (an imbalance in the different microorganisms living together in a microbiome) causally contributes to cardiac hypertrophy and cardiac dysfunction by driving systemic immune cell metabolic and mitochondrial reprogramming in mice. Mitochondria are cell organelles that generate most of the chemical energy needed to power the cell's biochemical reactions.
Cardiovascular disease is a leading cause of global morbidity and mortality. People with IBD, which includes chronic inflammatory conditions of the digestive tract, have an increased risk of cardiovascular complications. IBD is also associated with changes in the gut microbiota, the community of microorganisms that normally lives in the intestine. However, exactly how these changes in the gut contribute to heart problems has remained unclear.
In this study, the researchers used a chronic colitis mouse model to assess gut microbiota dysbiosis, systemic immune cell metabolism and cardiac remodeling. Transferring gut microbiota from mice with colitis to healthy mice was sufficient to alter immune cell metabolism and promote cardiac abnormalities, providing evidence that changes in gut microbes can contribute to the effects of intestinal inflammation on the heart.
Furthermore, the researchers identified a bacterial component called lipopolysaccharide, or LPS, as an important link between the gut and heart. LPS is produced by certain types of gut bacteria and can enter the circulation when the intestinal environment is disrupted. The study found that increased LPS stimulates immune cells to produce a protein called GBP1, leading to changes in these cells that promote their recruitment to the heart.
"Our study provides evidence that chronic intestinal inflammation can affect the heart through changes in the gut microbiota and immune cells," said Jun Zou , an assistant professor in the Institute for Biomedical Sciences at Georgia State. "We found that bacterial signals from the gut can alter immune cells in ways that promote their movement into the heart, where they can contribute to abnormal heart enlargement and impaired function."
The study also revealed another way GBP1 may affect the heart. During colitis, GBP1 was increased in exosomes, tiny packages released by cells that circulate in the body and carry biological signals between cells. The researchers found that these GBP1-containing exosomes could be taken up by heart cells and contribute to their enlargement.
"This work may also have broader implications for infection-associated cardiac injury, as many pathogens strongly induce GBP family proteins," said Ye Ding, co-senior author of the study and a research associate professor in the Institute for Biomedical Sciences at Georgia State. "While GBP1 plays essential antimicrobial roles during infection, excessive or dysregulated GBP1 activation may inadvertently contribute to cardiac dysfunction."
The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Additional authors of the study include Yadong Wang, Jian Li, Junqing An, Vu L. Ngo, Shuhan Wang, Zhenkai Hao, Chao Li and Hirohito Abo of the Institute for Biomedical Sciences at Georgia State.
To read the study, visit https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.126.329058 .
