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| Item Type: | Preprint |
|---|---|
| Title: | Kidney disease reprograms microbiome-host signaling to promote heart failure |
| Creators: |
Yarritu, Alex  ORCID: https://orcid.org/0000-0002-1724-0559, Anders, Wibke ORCID: https://orcid.org/0009-0000-6069-4233, Thiele, Arne ORCID: https://orcid.org/0000-0003-0786-2239, Potapenko, Olena ORCID: https://orcid.org/0000-0002-4397-568X, Schumacher, Fabian ORCID: https://orcid.org/0000-0001-8703-3275, Szijártó, István A. ORCID: https://orcid.org/0000-0002-0796-9450, Matz-Rauch, Ariana ORCID: https://orcid.org/0000-0002-5152-5830, Versnjak, Jakob ORCID: https://orcid.org/0009-0009-6179-1014, Gebremedhin, Natnael ORCID: https://orcid.org/0009-0001-2250-9436, McParland, Victoria ORCID: https://orcid.org/0000-0003-0731-3272, Heckscher, Simon, Kamboj, Sakshi ORCID: https://orcid.org/0000-0001-9618-012X, Trimarchi, Giuseppe ORCID: https://orcid.org/0009-0009-5558-3112, Anandakumar, Harithaa ORCID: https://orcid.org/0009-0000-3326-5126, Fuckert, Franziska ORCID: https://orcid.org/0009-0000-1371-2929, Hoffmann, Carina ORCID: https://orcid.org/0009-0004-3653-3607, Hassan, Sara A. ORCID: https://orcid.org/0009-0003-1210-5045, Bonnekoh, Paul M. ORCID: https://orcid.org/0009-0009-3483-1041, Wimmer, Moritz I. ORCID: https://orcid.org/0009-0004-5793-0249, Behrens, Felix ORCID: https://orcid.org/0000-0002-6841-4192, Voelkl, Jakob ORCID: https://orcid.org/0000-0002-6318-5087, Kramann, Rafael ORCID: https://orcid.org/0000-0003-4048-6351, Kintscher, Ulrich ORCID: https://orcid.org/0000-0001-7386-0990, Kuehne, Titus ORCID: https://orcid.org/0009-0002-1849-4013, Kleuser, Burkhard ORCID: https://orcid.org/0000-0002-1888-9595, Zernecke, Alma ORCID: https://orcid.org/0000-0001-8551-4729, Oefner, Peter J. ORCID: https://orcid.org/0000-0002-1499-3977, Gronwald, Wolfram ORCID: https://orcid.org/0000-0003-3646-0060, Dettmer, Katja ORCID: https://orcid.org/0000-0001-7337-2380, Eckardt, Kai-Uwe ORCID: https://orcid.org/0000-0003-3823-0920, Müller, Dominik N. ORCID: https://orcid.org/0000-0003-3650-5644, Kelm, Marcus ORCID: https://orcid.org/0000-0003-4971-0452, Holle, Johannes ORCID: https://orcid.org/0000-0001-8032-4096, Bartolomaeus, Hendrik ORCID: https://orcid.org/0000-0003-4288-3828 and Wilck, Nicola ORCID: https://orcid.org/0000-0003-3189-5364
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| Abstract: | BACKGROUND: Heart failure is prevalent in chronic kidney disease (CKD) and linked to chronic inflammation. CKD-typical gut microbiome dysbiosis may stimulate inflammation, as bacterial aromatic metabolites are highly abundant and engage transcriptional programs through the aryl hydrocarbon receptor (AhR). Whether this axis drives cardiac remodeling and is therapeutically targetable remains unknown. METHODS: We used the subtotal nephrectomy model (STNx) and microbiome depletion by oral antibiotics. We investigated cardiac and renal function, AhR activity, metabolite profiles, and immunophenotypes by flow cytometry and transcriptomics. Candidate metabolite indoxyl sulfate (IxS) was tested in experimental HFpEF. In vivo and in vitro AhR inhibition (AhRi) was performed using a clinically tested compound. Mechanistic studies were performed in primary human and murine cardiac fibroblasts and T cells, as well as translational validation using UK Biobank data. RESULTS: Microbiome depletion lowered bacterial metabolites and attenuated cardiac fibrosis and diastolic dysfunction in STNx, identifying AhR-driven expansion of interleukin-17A (IL-17A)-producing T helper cells (TH17) as key effector. Plasma IL-17A was stage-dependently elevated in CKD patients, particularly in HFpEF, and associated with all-cause mortality. Bacterial metabolite IxS promoted TH17 polarization and exacerbated cardiac dysfunction in HFpEF. AhRi using a small molecule inhibitor reduced TH17 abundance and attenuated cardiac fibrosis in STNx. Mechanistically, AhR and IL-17A signaling synergistically induced a conserved pro-fibrotic phenotype in human and murine cardiac fibroblasts, and AhR inhibition blocked ECM production in response to CKD patient serum. CONCLUSION: A microbiome-AhR-IL-17A axis drives CKD-associated cardiac fibrosis. AhRi prevents remodeling, highlighting a potential therapeutic avenue to prevent cardiorenal multimorbidity. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.01.10.698142 |
| Date: | 8 June 2026 |
| Official Publication: | https://doi.org/10.64898/2026.01.10.698142 |
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