Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
Biochem Biophys Res Commun. 2023 Oct 1;675:92-98. doi: 10.1016/j.bbrc.2023.07.015. Epub 2023 Jul 10.
Chronic kidney disease (CKD) induces an imbalance in the intestinal microbiota, affecting various physiological functions and leading to cardiovascular inflammation and fibrosis. However, the cardiotoxic impact of intestinal microbiota-derived uremic substances in advanced renal dysfunction remains unexplored. Therefore, we developed a 5/6 nephrectomy (5/6Nx) mouse model to investigate the intestinal microbiota and the effects of administering vancomycin (VCM) on the microbiota and the cardiac pathology associated with CKD. Despite VCM administration after the development of irreversible glomerulosclerosis and tubulointerstitial fibrosis, blood indoxyl sulfate and phenyl sulfate levels, which are intestinal bacteria-derived uremic substances, brain natriuretic peptide levels, and the fibrotic area in the heart were decreased. Moreover, VCM administration prevented 5/6Nx-induced weight loss and prolonged survival time. Our findings suggest that VCM-induced changes in the intestinal microbiota composition ameliorate heart failure and improve survival rates by reducing intestinal microbiota-derived cardiotoxic substances despite advanced renal dysfunction. This highlights the potential of using the intestinal microbiota as a target to prevent and treat cardiovascular conditions associated with CKD.
慢性肾脏病（CKD）会导致肠道微生物群落失衡，影响各种生理功能，导致心血管炎症和纤维化。然而，在肾功能严重受损的情况下，肠道微生物群衍生的尿毒症物质对心脏的毒性影响仍未得到探索。因此，我们构建了 5/6 肾切除术（5/6Nx）小鼠模型，以研究肠道微生物群以及给予万古霉素（VCM）对肠道微生物群和与 CKD 相关的心脏病理学的影响。尽管在不可逆的肾小球硬化和肾小管间质纤维化发展后给予 VCM，但血液吲哚硫酸酯和苯硫酸酯水平（肠道细菌衍生的尿毒症物质）、脑钠肽水平和心脏纤维化面积均降低。此外，VCM 给药可预防 5/6Nx 引起的体重减轻并延长存活时间。我们的研究结果表明，VCM 诱导的肠道微生物群落组成变化通过减少肠道微生物群衍生的心脏毒性物质，改善心力衰竭并提高存活率，尽管存在严重的肾功能障碍。这突显了将肠道微生物群作为预防和治疗与 CKD 相关的心血管疾病的靶点的潜力。
