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      Gut Microbiota Mediates the Protective Effects of Traditional Chinese Medicine Formula Qiong-Yu-Gao against Cisplatin-Induced Acute Kidney Injury

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          ABSTRACT

          Our previous study found that Qiong-Yu-Gao (QYG), a traditional Chinese medicine formula derived from Rehmanniae Radix, Poria, and Ginseng Radix, has protective effects against cisplatin-induced acute kidney injury (AKI), but the underlying mechanisms remain unknown. In the present study, the potential role of gut microbiota in the nephroprotective effects of QYG was investigated. We found that QYG treatment significantly attenuated cisplatin-induced AKI and gut dysbiosis, altered the levels of bacterial metabolites, with short-chain fatty acids (SCFAs) such as acetic acid and butyric acid increasing and uremic toxins such as indoxyl sulfate and p-cresyl sulfate reducing, and suppressed histone deacetylase expression and activity. Spearman’s correlation analysis found that QYG-enriched fecal bacterial genera Akkermansia, Faecalibaculum, Bifidobacterium, and Lachnospiraceae_NK4A136_group were correlated with the altered metabolites, and these metabolites were also correlated with the biomarkers of AKI, as well as the indicators of fibrosis and inflammation. The essential role of gut microbiota was further verified by both the diminished protective effects with antibiotics-induced gut microbiota depletion and the transferable renal protection with fecal microbiota transplantation. All these results suggested that gut microbiota mediates the nephroprotective effects of QYG against cisplatin-induced AKI, potentially via increasing the production of SCFAs, thus suppressing histone deacetylase expression and activity, and reducing the accumulation of uremic toxins, thereby alleviating fibrosis, inflammation, and apoptosis in renal tissue.

          IMPORTANCE Cisplatin-induced acute kidney injury is the main limiting factor restricting cisplatin’s clinical application. Accumulating evidence indicated the important role of gut microbiota in pathogenesis of acute kidney injury. In the present study, we have demonstrated that gut microbiota mediates the protective effects of traditional Chinese medicine formula Qiong-Yu-Gao against cisplatin-induced acute kidney injury. The outputs of this study would provide scientific basis for future clinical applications of QYG as prebiotics to treat cisplatin-induced acute kidney injury, and gut microbiota may be a promising therapeutic target for chemotherapy-induced nephrotoxicity.

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          Most cited references54

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          From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites.

          A compelling set of links between the composition of the gut microbiota, the host diet, and host physiology has emerged. Do these links reflect cause-and-effect relationships, and what might be their mechanistic basis? A growing body of work implicates microbially produced metabolites as crucial executors of diet-based microbial influence on the host. Here, we will review data supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs). SCFAs can directly activate G-coupled-receptors, inhibit histone deacetylases, and serve as energy substrates. They thus affect various physiological processes and may contribute to health and disease.
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            Diversity, stability and resilience of the human gut microbiota.

            Trillions of microbes inhabit the human intestine, forming a complex ecological community that influences normal physiology and susceptibility to disease through its collective metabolic activities and host interactions. Understanding the factors that underlie changes in the composition and function of the gut microbiota will aid in the design of therapies that target it. This goal is formidable. The gut microbiota is immensely diverse, varies between individuals and can fluctuate over time - especially during disease and early development. Viewing the microbiota from an ecological perspective could provide insight into how to promote health by targeting this microbial community in clinical treatments.
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              Mechanisms of Cisplatin Nephrotoxicity

              Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.
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                Author and article information

                Contributors
                Role: Editor
                Role: ad hoc peer reviewer
                Journal
                Microbiol Spectr
                Microbiol Spectr
                spectrum
                Microbiology Spectrum
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2165-0497
                28 April 2022
                May-Jun 2022
                28 April 2022
                : 10
                : 3
                : e00759-22
                Affiliations
                [a ] Department of Pharmaceutical Analysis, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
                [b ] Department of Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
                [c ] Department of Respiratory Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
                Nanchang University
                Zhejiang University
                Author notes

                The authors declare no conflict of interest.

                Article
                00759-22 spectrum.00759-22
                10.1128/spectrum.00759-22
                9241845
                35481834
                5e9f89ac-1e1c-46ab-98f7-c7a6b8e174c2
                Copyright © 2022 Zou et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 28 February 2022
                : 12 April 2022
                Page count
                supplementary-material: 1, Figures: 6, Tables: 1, Equations: 0, References: 54, Pages: 17, Words: 8651
                Funding
                Funded by: National Natural Science Foundation of China (NSFC), FundRef https://doi.org/10.13039/501100001809;
                Award ID: 81603262
                Award Recipient :
                Funded by: Natural Science Foundation of Jiangsu Province (Jiangsu Natural Science Foundation), FundRef https://doi.org/10.13039/501100004608;
                Award ID: BK20161081
                Award Recipient :
                Funded by: Science and Technology Development Program of Traditional Chinese Medicine of Jiangsu Provience;
                Award ID: YB2020021
                Award Recipient :
                Funded by: Project Program of Jiangsu Provience Academy of Traditional Chinese Medicine;
                Award ID: BM2018024-2019001
                Award Recipient :
                Funded by: Postgraduate Researdh & Practice Innovation Program of Jiangsu Provience;
                Award ID: KYCX20_1516
                Award Recipient :
                Categories
                Research Article
                open-peer-review, Open Peer Review
                host-microbial-interactions, Host-Microbial Interactions
                Custom metadata
                May/June 2022

                gut microbiota,qiong-yu-gao,acute kidney injury,cisplatin,short-chain fatty acids,uremic toxins,antibiotics-induced gut microbiota depletion,fecal microbiota transplantation

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