2. Academic Validation
  3. Toralactone alleviates cisplatin-induced acute kidney injury by modulating the gut microbiota-renal axis

Toralactone alleviates cisplatin-induced acute kidney injury by modulating the gut microbiota-renal axis

  • Int Immunopharmacol. 2024 Dec 5;142(Pt A):113115. doi: 10.1016/j.intimp.2024.113115.
Yan Tian 1,  Ruixue Tian 2,  Juan He 3,  Yafan Guo 4,  Pan Yan 4,  Yunxi Chen 5,  Rongshan Li 4,  Baodong Wang 6
Affiliations

Affiliations

  • 1 Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China; Department of Endocrinology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
  • 2 Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China; Clinical Research Center, the Second Affiliated Hospital of Nanchang University, 1 Min De Road, Nanchang 330008, China.
  • 3 The Third Clinical Medical College, Shanxi University of Chinese Medicine, 121 Da Xue Street, Jinzhong 030619, China.
  • 4 Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China.
  • 5 Department of Endocrinology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
  • 6 Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China. Electronic address: docwangbaodong@163.com.
PMID: 39276451 DOI: 10.1016/j.intimp.2024.113115
Abstract

Background: Gut microbiota has been reported to be perturbed by cisplatin and to modulate the nephrotoxicity of chemotherapeutic agents. However, the critical role of toralactone, a bioactive components of Cassia obtusifolia L. seeds, in modulating the gut microbiota in the pathogenesis of cisplatin-induced nephrotoxicity remains to be elucidated.

Methods: In this study, we verified the reno-protective effects of toralactone and compared the composition and function of the gut microbiota in the normal, cisplatin-treated and low or high dose of toralactone-treated mice using 16S rDNA gene Sequencing. We also investigated the gut microbiota related LPS/TLR4/NF-κB/TNF-α pathway in renal tissue. To elucidate the causal relationship between gut dysbiosis and cisplatin nephrotoxicity, an Antibiotic cocktail was administered to deplete the gut microbiota and fecal microbiota transplantation (FMT) was performed prior to cisplatin treatment.

Results: The renal histopathology showed that toralactone significantly alleviated cisplatin-induced renal injury. 16S rDNA gene Sequencing analysis demonstrated that toralactone treatment effectively reversed cisplatin-induced gut microbiota dysbiosis in mice. FMT from toralactone-treated mice to cisplatin-induced kidney injury mice was observed to have the reno-protective effects, and deletion of gut microbiota by Antibiotics was found to negate the reno-protective effect of toralactone. Interestingly, the renal tissue of cisplatin-associated kidney injury mice showed activation of the LPS/TLR4/NF-κB pathway and increase in TNF-α within the renal tissue, whereas toralactone treatment was observed to inhibit the LPS/TLR4/NF-κB/TNF-α pathway.

Conclusion: This study elucidated the reno-protective effects for the first time, demonstrating that it exerts its beneficial effects through the gut microbiota, which mediate the LPS/TLR4/NF-κB/TNF-α inflammatory pathway. It may help to develop therapeutic approaches using toralactone and targeted restoration of the gut microbiota.

Keywords

Cisplatin; Gut microbiota; NF-κB; Nephrotoxicity; TLR4; Toralactone.

Figures
Products