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

Cisplatin induces the disruptions in gut microbiota and gut microbiota related LPS leakage, LPS leaking from the gut reaches the heart through absorption into the venous bloodstream and then through the arteries to the kidney tissue, causing activation of TLR4/NF-κB/TNF-α pathway and acute kidney injury in mice. Toralactone can protected against cisplatin-induced renal damage by repairing gut microbiota disruption and inhibiting LPS/TLR4/NF-κB/TNF-α pathway (by FigDraw). [Display omitted] • Toralactone alleviates cisplatin-induced acute kidney injury in mice. • Toralactone regulating the gut microbiota. • Toralactone inhibiting the gut related LPS/TLR4/NF-κB/TNF-α signaling pathway in kidney. 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. [ABSTRACT FROM AUTHOR]