| Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Open Access Art: | Kein Open Access | ||||
| Titel eines Journals oder einer Zeitschrift: | Nephrology Dialysis Transplantation | ||||
| Verlag: | Oxford | ||||
| Band: | 40 | ||||
| Datum: | 10 Oktober 2025 | ||||
| Institutionen: | Medizin > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) | ||||
| Identifikationsnummer: |
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| Stichwörter / Keywords: | antibiotics echocardiography cardiovascular diseases inflammation extracellular matrix kidney failure, chronic left ventricle blood pressure fibrosis flow cytometry bone wires cardiovascular system endothelium feces genes interleukin-17 intestines ligands mesenteric arteries myography nephrectomy plasma aryl hydrocarbon receptor sequence analysis, rna tibia tryptophan uremia c-reactive protein measurement heart histology mice mortality pharmacology immune mediator intestinal bacteria correlation studies metabolites phenotype determination microbiome small molecule attenuation th17 cells metabolomics rna-seq gastrointestinal microbiome microbiota | ||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Zum Teil | ||||
| Dokumenten-ID: | 78146 |
Zusammenfassung
Background and Aims Chronic kidney disease (CKD) represents a major cardiovascular (CV) risk factor, leading to a disproportionately high mortality from CV disease (CVD). Alterations of the gut microbiome composition and function are evident in CKD, leading to an increased production and accumulation of metabolites of bacterial origin. Tryptophan (Trp) metabolites are of particular interest ...
Zusammenfassung
Background and Aims
Chronic kidney disease (CKD) represents a major cardiovascular (CV) risk factor, leading to a disproportionately high mortality from CV disease (CVD). Alterations of the gut microbiome composition and function are evident in CKD, leading to an increased production and accumulation of metabolites of bacterial origin. Tryptophan (Trp) metabolites are of particular interest and are known to act as ligands of the aryl hydrocarbon receptor (AhR), which integrates various environmental signals and has been described as a mediator of immune responses.
We hypothesize that CKD-associated bacterial metabolites from the intestinal microbiome influence AhR-dependent inflammation and cardiac remodeling, thereby promoting the development of CVD.
Method
Experimental CKD was induced in 129/Sv mice by subtotal nephrectomy (STNx), followed by either microbiome depletion using oral antibiotics (Abx) or pharmacological AhR-inhibition (AhRi) with a small molecule AhR inhibitor (BAY 2416964). Phenotyping was conducted by echocardiography, radiotelemetry blood pressure measurements, assessment of vascular reactivity, histology, qPCR and cardiac bulk RNA sequencing, immune phenotyping by multicolor flow cytometry, plasma metabolomics, and in vitro assays for AhR activity and T helper 17 cell (TH17) polarization.
Results
Sequencing (16S) of the fecal microbiome confirmed the suppression of the intestinal microbial load by Abx, along with significant differences in the abundance of Trp metabolites in plasma. AhR reporter assay showed a lower serum AhR activation under Abx treatment. The STNx-induced increase in the heart weight/tibia length was reduced by Abx (10.1 ± 0.5 g/m vs. 7.0 ± 0.2 g/m; P < 0.001). Hearts of STNx + Abx displayed significantly less remodeling than STNx despite similar blood pressure levels. Histological analyses of the left ventricle with Picrosirius Red staining revealed STNx-induced cardiac fibrosis that was ameliorated by Abx (PSR-positive area 12.0 ± 1.5% vs. 5.8 ± 1.8%; P = 0.008) and AhRi (13.64 ± 3.1% vs. 6.9 ± 2.4%; P = 0.060). Differential expression analysis of bulk RNA sequencing identified 2,833 genes significantly upregulated in STNx hearts, of which 1,179 were also among the 1,342 genes downregulated in STNx+Abx. Vascular function, as assessed by wire myography of mesenteric arteries, indicated an impaired endothelium-dependent relaxation in STNx, which improved in STNx+Abx. Both STNx+Abx and STNx+AhRi exhibited reduced systemic inflammation, with significantly lower plasma C-reactive protein levels (0.08 ± 0.005 vs. 0.05 ± 0.01 mg/l; P = 0.034 and 0.09 ± 0.005 vs. 0.07 ± 0.004 mg/l; P = 0.040). Ex vivo flow cytometry analysis revealed a STNx-induced TH17 signature that was attenuated in both treatments. In vitro assays confirmed the effects of BAY 2416964 in reducing uremia-induced TH17 polarization. Gene ontology (GO) term enrichment analysis of the cardiac bulk RNA-Seq data displayed an elevated expression of different TH17-pathways in STNx that were attenuated by Abx and AhRi. Correlation analysis revealed a significant positive association with extracellular matrix gene sets (r = 0.6, P = 0.002), suggesting an effect of TH17 cells in the development of cardiac fibrosis.
Conclusion
Our findings demonstrate that both the Abx-induced reduction of microbial metabolite production in the intestine as well as inhibition of the AhR significantly protect against STNx-induced immune activation, inflammation, and cardiac fibrosis. The reduced IL17A-signature in both Abx and AhRi-treated groups indicates a potential mechanistic link between microbiota-driven AhR activation, TH17 cells, and adverse cardiac remodeling in CKD.
Metadaten zuletzt geändert: 17 Nov 2025 10:45
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