Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1
Introduction: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. Objectives: This study aimed to investigate the potential roles...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Journal of Advanced Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224003618 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850114721804451840 |
|---|---|
| author | Yan Zeng Man Guo Qi Wu Xiaozhen Tan Chunxia Jiang Fangyuan Teng Jiao Chen Fanjie Zhang Xiumei Ma Xinyue Li Junling Gu Wei Huang Chunxiang Zhang Betty Yuen-Kwan Law Yang Long Yong Xu |
| author_facet | Yan Zeng Man Guo Qi Wu Xiaozhen Tan Chunxia Jiang Fangyuan Teng Jiao Chen Fanjie Zhang Xiumei Ma Xinyue Li Junling Gu Wei Huang Chunxiang Zhang Betty Yuen-Kwan Law Yang Long Yong Xu |
| author_sort | Yan Zeng |
| collection | DOAJ |
| description | Introduction: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. Objectives: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. Methods: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. Results: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin–proteasome degradation, restoring SIRT1′s role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. Conclusion: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management. |
| format | Article |
| id | doaj-art-d59196d1d8054dba8565cde9db81f6fc |
| institution | OA Journals |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-d59196d1d8054dba8565cde9db81f6fc2025-08-20T02:36:46ZengElsevierJournal of Advanced Research2090-12322025-07-017360763010.1016/j.jare.2024.08.018Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1Yan Zeng0Man Guo1Qi Wu2Xiaozhen Tan3Chunxia Jiang4Fangyuan Teng5Jiao Chen6Fanjie Zhang7Xiumei Ma8Xinyue Li9Junling Gu10Wei Huang11Chunxiang Zhang12Betty Yuen-Kwan Law13Yang Long14Yong Xu15Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, ChinaDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, ChinaDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, ChinaDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, ChinaDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, ChinaDepartment of Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, ChinaSichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan, ChinaSecond Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610000, Sichuan, ChinaDepartment of Endocrinology, Yibin Second People’s Hospital-West China Yibin Hospital, Sichuan University, Yibin 644000, Sichuan, ChinaDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, ChinaDepartment of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Southwest Medical University, Luzhou 646000, Sichuan, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Corresponding authors at: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China. Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Corresponding authors at: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China. Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Corresponding authors at: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China. Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.Introduction: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. Objectives: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. Methods: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. Results: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin–proteasome degradation, restoring SIRT1′s role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. Conclusion: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.http://www.sciencedirect.com/science/article/pii/S2090123224003618Indole-3-propionic acidSIRT1Oxidative stressMitochondriaDiabetic kidney diseaseGlomerular endothelial cells |
| spellingShingle | Yan Zeng Man Guo Qi Wu Xiaozhen Tan Chunxia Jiang Fangyuan Teng Jiao Chen Fanjie Zhang Xiumei Ma Xinyue Li Junling Gu Wei Huang Chunxiang Zhang Betty Yuen-Kwan Law Yang Long Yong Xu Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 Journal of Advanced Research Indole-3-propionic acid SIRT1 Oxidative stress Mitochondria Diabetic kidney disease Glomerular endothelial cells |
| title | Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 |
| title_full | Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 |
| title_fullStr | Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 |
| title_full_unstemmed | Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 |
| title_short | Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 |
| title_sort | gut microbiota derived indole 3 propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated degradation of sirt1 |
| topic | Indole-3-propionic acid SIRT1 Oxidative stress Mitochondria Diabetic kidney disease Glomerular endothelial cells |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003618 |
| work_keys_str_mv | AT yanzeng gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT manguo gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT qiwu gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT xiaozhentan gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT chunxiajiang gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT fangyuanteng gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT jiaochen gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT fanjiezhang gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT xiumeima gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT xinyueli gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT junlinggu gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT weihuang gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT chunxiangzhang gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT bettyyuenkwanlaw gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT yanglong gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 AT yongxu gutmicrobiotaderivedindole3propionicacidalleviatesdiabetickidneydiseasethroughitsmitochondrialprotectiveeffectviareducingubiquitinationmediateddegradationofsirt1 |