Kidney disease reprograms microbiome-host signaling to promote heart failure
Yarritu, A.; Anders, W.; Thiele, A.; Potapenko, O.; Schumacher, F.; Szijarto, I. A.; Matz-Rauch, A.; Versnjak, J.; Gebremedhin, N.; McParland, V.; Heckscher, S.; Kamboj, S.; Trimarchi, G.; Anandakumar, H.; Fuckert, F.; Hoffmann, C.; Hassan, S. A.; Bonnekoh, P. M.; Wimmer, M. I.; Behrens, F.; Voelkl, J.; Kramann, R.; Kintscher, U.; Kuehne, T.; Kleuser, B.; Zernecke, A.; Oefner, P. J.; Gronwald, W.; Dettmer, K.; Eckardt, K.-U.; Mueller, D. N.; Kelm, M.; Holle, J.; Bartolomaeus, H.; Wilck, N.
Show abstract
Gut microbiome-derived metabolites regulate host physiology, with systemic levels controlled by renal excretion. In kidney disease, impaired clearance leads to metabolite accumulation, inflammation, and secondary cardiovascular damage. We show that adverse cardiac remodeling following kidney disease critically depends on the microbiome. We identify microbiome-derived indoxyl sulfate-mediated activation of the aryl hydrocarbon receptor (AhR) as a key mechanism inducing IL-17A-producing T cells, thereby promoting cardiac fibrosis. AhR inhibition attenuates inflammation and cardiac remodeling. On population level, IL-17A is elevated in chronic kidney disease, particularly with coexisting heart failure. Mechanistically, AhR and IL-17A signaling induce a conserved pro-fibrotic phenotype in both murine and human cardiac fibroblasts. This work identifies a microbiome-AhR-IL-17A axis as a mediator and druggable target of cardiovascular damage in kidney disease.
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