Gut Microbiota Drives Kidney Damage and Cardiac Remodeling in Experimental CKD

Background: Chronic kidney disease (CKD) represents a major, often overlooked cardiovascular (CV) risk factor. CV disease (CVD) is the leading cause of mortality in CKD. Alterations in gut microbiome composition and function are evident in CKD, leading to increased production of detrimental metabolites of bacterial origin, impacting inflammation and end-organ damage. We hypothesize that CV remodeling and preservation of kidney function are influenced by the microbiome. Methods: Experimental CKD was induced in 129/Sv mice by subtotal nephrectomy (STNx). To suppress the microbiome mice received antibiotics (Abx) orally over the course of 13 weeks. CV damage was quantified by echocardiography, histological and gene expression analysis, as well as radiotelemetry blood pressure measurements and analysis of endothelial function. Results: Compared to STNx, STNx+Abx mice exhibited a significantly improved kidney function quantified by plasma cystatin c (0.66±0.41 mg/l vs. 1.14±0.54 mg/l; p = 0.012). This was confirmed by the expression of renal damage markers (e.g. Ngal, Tgfb, Ctgf) and histological analyses. We observed an increase in heart weight/tibia length in STNx (10.1±0.5 g/m) that was attenuated by Abx (7.0±0.2 g/m; p < 0.001). Hearts of STNx+Abx mice displayed significantly less remodeling, independent of similarly elevated blood pressures in both groups. Cardiac expression of hypertrophy and pro-fibrotic markers were reduced in STNx+Abx (e.g. Nppb, Myh7, Ctgf). Histological analysis of the left ventricle by picrosirius red revealed STNx-induced cardiac fibrosis (PSR-positive area 12.0±1.5%), that was ameliorated by Abx (5.8±1.8%; p=0.008). Vascular function, as assessed by wire myography of mesenteric arteries, indicated an impaired endothelium-dependent relaxation in STNx that was improved in STNx+Abx. In addition, we performed functional analysis by echocardiography, organ-specific immune phenotyping, and bulk RNA sequencing of the heart. Conclusion: In experimental CKD, kidney function and cardiac remodeling depend on the dysbiotic microbiome, highlighting the interplay between the microbiome, CKD progression, and the development of CV complications in CKD.