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Natural intestinal metabolite xylitol reduces BRD4 levels to mitigate renal fibrosis

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机构： [1]Organ Transplant Center, Affiliated Hospital of Zunyi Medical University, Zunyi, China. [2]Department of Nephrology, Affiliated Hospital of Zunyi Medical University, Zunyi, China. [3]Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. [4]Sichuan Medicine Key Laboratory of Clinical Genetics, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China. [5]Organ Transplant Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. [6]Department of Urology, Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. [7]Department of Critical Care Medicine, Maoming People's Hospital, Maoming, China. [8]School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China. [9]Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

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Renal fibrosis is a typical pathological change from chronic kidney disease (CKD) to end-stage renal failure, which presents significant challenges in prevention and treatment. The progression of renal fibrosis is closely associated with the "gut-kidney axis," therefore, although clinical intervention to modulate the "gut-kidney axis" imbalance associated with renal fibrosis brings hope for its treatment. In this study, we first identified the close relationship between renal fibrosis development and the intestinal microenvironment through fecal microtransplantation and non-absorbable antibiotics experiments. Then, we analyzed the specific connection between the intestinal microenvironment and renal fibrosis using microbiomics and metabolomics, screening for the differential intestinal metabolite. Potential metabolite action targets were initially identified through network simulation of molecular docking and further verified by molecular biology experiment. We used flow cytometry, TUNEL apoptosis staining, immunohistochemistry, and Western blotting to assess renal injury and fibrosis extent, exploring the potential role of gut microbial metabolite in renal fibrosis development. We discovered that CKD-triggered alterations in the intestinal microenvironment exacerbate renal injury and fibrosis. When metabolomic analysis was combined with experiments in vivo, we found that the differential metabolite xylitol delays renal injury and fibrosis development. We further validated this hypothesis at the cellular level. Mechanically, bromodomain-containing protein 4 (BRD4) protein exhibits strong binding with xylitol, and xylitol alleviates renal fibrosis by inhibiting BRD4 and its downstream transforming growth factor-β (TGF-β) pathway. In summary, our findings suggest that the natural intestinal metabolite xylitol mitigates renal fibrosis by inhibiting the BRD4-regulated TGF-β pathway.© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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出版当年[2023]版：

大类 | 3 区医学

小类 | 3 区医学：研究与实验

最新[2025]版：

大类 | 3 区医学

小类 | 3 区医学：研究与实验

第一作者：

第一作者机构： [1]Organ Transplant Center, Affiliated Hospital of Zunyi Medical University, Zunyi, China. [2]Department of Nephrology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.

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通讯机构： [3]Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. [9]Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. [*1]Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, China [*2]Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, 183 Zhongshan Avenue West, Guangzhou, China.

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