https://doi.org/10.1007/s00392-025-02625-4
1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; 3Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie und Stoffwechselkrankheiten Aachen, Deutschland; 4Uniklinik RWTH Aachen Klinik für Kinder- und Jugendmedizin Aachen, Deutschland; 5Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; 6Klinikum Traunstein Kardiologie Traunstein, Deutschland
Background: Cardiovascular disease is the main cause of death worldwide, despite advances in risk management and modern pharmacological therapies. Thus, novel therapeutic approaches have to be identified to reduce cardiovascular morbidity and mortality. In the last 2 decades inflammation has been increasingly recognized as one of the key contributors to cardiovascular disease. The gut, next to spleen and bone marrow, holds one of the largest immune cell reservoirs of our body. We could recently show that gut immune cells regulate energy metabolism and play an important role in atherosclerosis. However, the role of intestinal immune cells in heart failure is unknown.
Methods and Results: To investigate the role of gut immune cells in heart failure we performed transverse aortic constriction (TAC) to induce pressure-overload induced cardiac hypertrophy or sham surgery in C57BL/6J mice. After 5 weeks intestinal immune cell populations were analyzed by spectral flow cytometry (FACS). We found a significant increase in intestinal leukocytes in mice with heart failure compared to mice without heart failure in both intraepithelial space (2.5-fold increase of αβ and γδ T cells, p<0.05) and lamina propria (10-fold increase of T cells, p=0.036, 2.6-fold increase of macrophages, p<0.001).
To understand the functional role of activated gut immune cells in heart failure we performed TAC surgery in wild type (n=15) or Integrin-β7–/– mice (n=17), which are selectively deficient for intestinal immune cells while maintaining normal leukocyte counts in other organs. Interestingly, gut immune cell deficient β7–/– mice were protected against TAC surgery induced
left ventricular dysfunction [LV ejection fraction (EF-SAX): 54.1 ± 9.0% in sham WT, 49.7 ± 6.1% in sham β7–/–, 33.4 ± 5.6% in TAC WT, 41.5 ± 5.7% in TAC β7–/– mice, p<0.05, analyzed by echocardiography]. Furthermore, TAC surgery activated bone marrow hematopoiesis and increased lung inflammation, which was both downregulated in β7–/– mice lacking gut immune cells (BM Lin-Sca1+c-Kit+ fraction: 3.1-fold increase in TAC WT vs. 2.1-fold increase in TAC β7–/– mice, p<0.05; lung neutrophils: 1.7-fold increase in TAC WT vs. 1.4-fold increase in TAC β7–/– mice, p<0,05; analyzed by FACS). We validated these findings in the UK Biobank proteomics subset (47,940 patients, 993 events, ID 71300) and found a positive association of circulating Integrin-β7 with lifetime prevalence of heart failure and cardiovascular mortality (multivariable cox regression model adjusted for age, sex, hsCRP, BMI, NT-proBNP, diabetes, history of MI, coronary artery disease, total cholesterol and creatinine; Chi2: 1721.17; p=0.012).
Conclusion: Here we identified a heart-gut interorgan cross talk network. These findings suggest that intestinal immune cells might be a novel therapeutic target for heart failure.